Clinical trial NCT04362072
Conditions: Carcinoma Non-Small-Cell Lung
Sponsor: Pfizer
Start date: 2020-09-29; Completion date: 2024-10-23
Enrollment: 71 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this clinical trial is to learn whether the study medicine (called lorlatinib) is safe and effective for the treatment of non-small cell lung cancer that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene.

This study is seeking participants whose lung cancer has progressed after receiving either alectinib or ceritinib as their first treatment.

Participants will take part in this study for up to approximately 4 years, depending on when the study is completed and how their cancer responds to the study treatment. They will take lorlatinib orally (by mouth) once daily.

Participants will visit the study site about every six weeks to meet with the study team. During these visits, the study team will monitor the safety and effects of lorlatinib.

Detailed description:

Arms: arm 1: Participants will take 100 mg (four, 25 mg tablets) once daily.
Interventions: intervention 1: Lorlatinib
Intervention descriptions: intervention 1: 25 milligram (mg) tablet

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: Single-Arm Study of Lorlatinib in Participants with Anaplastic Lymphoma 
Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC) Whose Disease Progressed 
After One Prior Second-Generation ALK Tyrosine Kinase Inhibitor (TKI)
Protocol Number: B7461027
Amendment Number: Not applicable
Compound Number: PF-06463922
Study Phase: Phase 4
Short Title: Study of Lorlatinib In Participants with Anaplastic Lymphoma Kinase 
(ALK) -Positive NSCLC
Acronym: Not Applicable
Sponsor Name: Pfizer, Inc
Legal Registered Address: 235 East 42nd Street, New York, NY 10017-5755, USA
Regulatory Agency Identifier Number(s)
Registry
ID
IND
118,296
EudraCT
2019-002504-41
Approval Date: 22 January 2020
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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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
22 Jan 2020
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
1. PROTOCOL SUMMARY.....................................................................................................7
1.1. Synopsis ....................................................................................................................7
1.2. Schema ....................................................................................................................11
1.3. Schedule of Activities (SoA)...................................................................................12
1.3.1. Screening and Cycle 1 ................................................................................12
1.3.2. Visits on Day 1 of Every Other Cycle (up to 35 cycles and 
>35 cycles).......................................................................................................14
1.3.3. End of Treatment and Follow-Up...............................................................16
2. INTRODUCTION ...............................................................................................................18
2.1. Study Rationale .......................................................................................................19
2.2. Background .............................................................................................................19
2.3. Benefit/Risk Assessment.........................................................................................19
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS ............................................................20
4. STUDY DESIGN.................................................................................................................22
4.1. Overall Design.........................................................................................................22
4.2. Scientific Rationale for Study Design.....................................................................23
4.3. Justification for Dose ..............................................................................................23
4.4. End of Study Definition ..........................................................................................23
5. STUDY POPULATION......................................................................................................23
5.1. Inclusion Criteria.....................................................................................................23
5.2. Exclusion Criteria....................................................................................................26
5.3. Lifestyle Considerations..........................................................................................28
5.4. Screen Failures ........................................................................................................29
6. STUDY INTERVENTION..................................................................................................29
6.1. Study Intervention(s) Administered........................................................................29
6.2. Preparation/Handling/Storage/Accountability ........................................................29
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................31
6.4. Study Intervention Compliance...............................................................................31
6.5. Concomitant Therapy..............................................................................................31
6.5.1. Prohibited Concomitant Treatments...........................................................31
6.5.2. Permitted Concomitant Treatments............................................................33
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6.6. Dose Modification...................................................................................................36
6.7. Intervention after the End of the Study...................................................................39
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................39
7.1. Discontinuation of Study Intervention ....................................................................39
7.1.1. Temporary Discontinuation........................................................................40
7.2. Participant Discontinuation/Withdrawal from the Study........................................40
7.3. Lost to Follow up ....................................................................................................41
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................42
8.1. Efficacy Assessments..............................................................................................43
8.1.1. Tumor Assessments....................................................................................43
8.2. Safety Assessments .................................................................................................43
8.2.1. Physical Examinations................................................................................43
8.2.2. Electrocardiograms.....................................................................................44
8.2.3. Echocardiograms/Multigated (MUGA) Acquisition Scan .........................44
8.2.4. ECOG Performance Status .........................................................................44
8.2.5. Clinical Safety Laboratory Assessments ....................................................44
8.2.6. Pregnancy Testing ......................................................................................45
8.3. Adverse Events and Serious Adverse Events..........................................................45
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......46
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................46
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF .................47
8.3.2. Method of Detecting AEs and SAEs ..........................................................47
8.3.3. Follow-up of AEs and SAEs.......................................................................47
8.3.4. Regulatory Reporting Requirements for SAEs...........................................47
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................48
8.3.5.1. Exposure During Pregnancy......................................................48
8.3.5.2. Exposure During Breastfeeding ................................................48
8.3.5.3. Occupational Exposure .............................................................48
8.3.6. Medication Errors .......................................................................................49
8.4. Treatment of Overdose............................................................................................49
8.5. Pharmacokinetics ....................................................................................................50
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8.6. Pharmacodynamics..................................................................................................50
8.7. Genetics...................................................................................................................50
8.7.1. Specified Genetics ......................................................................................50
8.7.2. Banked Biospecimens for Genetics............................................................50
8.8. Biomarkers ..............................................................................................................50
8.9. Health Economics ...................................................................................................50
9. STATISTICAL CONSIDERATIONS ................................................................................50
9.1. Estimands and Statistical Hypotheses.....................................................................50
9.1.1. Estimands....................................................................................................51
9.2. Sample Size Determination.....................................................................................52
9.3. Populations for Analyses.........................................................................................52
9.4. Statistical Analyses .................................................................................................53
9.4.1. Efficacy Analyses .......................................................................................53
9.4.2. Safety Analyses ..........................................................................................56
9.5. Interim Analyses .....................................................................................................57
9.5.1. Data Monitoring Committee (DMC)..........................................................57
9.5.2. Independent Central Radiological Review .................................................57
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................58
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............58
10.1.1. Regulatory and Ethical Considerations ....................................................58
10.1.2. Financial Disclosure .................................................................................59
10.1.3. Informed Consent Process ........................................................................59
10.1.4. Data Protection .........................................................................................60
10.1.5. Committees Structure ...............................................................................60
10.1.6. Dissemination of Clinical Study Data ......................................................60
10.1.7. Data Quality Assurance ............................................................................61
10.1.8. Source Documents....................................................................................63
10.1.9. Study and Site Closure..............................................................................63
10.1.10. Publication Policy...................................................................................64
10.1.11. Sponsor’s Qualified Medical Personnel .................................................64
10.2. Appendix 2: Clinical Laboratory Tests .................................................................66
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................68
10.3.1. Definition of AE .......................................................................................68
10.3.2. Definition of SAE.....................................................................................69
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE.........................70
10.3.4. Reporting of SAEs....................................................................................73
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................75
10.5. Appendix 5: RECIST (version 1.1) Tumor Assessment Criteria21 .......................78
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........84
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................86
10.8. Appendix 8: Country-specific Requirements........................................................88
10.9. Appendix 9: ECOG Classification of Performance Status....................................89
10.10. Appendix 10: Abbreviations ...............................................................................90
11. REFERENCES ..................................................................................................................94
LIST OF TABLES
Table 1.
Pharmacokinetic Properties of Statins......................................................34
Table 2.
Pharmacokinetic properties of Lipid Lowering Agents............................35
Table 3.
Recommended Lorlatinib Dose Modifications for Adverse 
Reactions...................................................................................................36
Table 4.
Protocol Required Safety Laboratory Assessments..................................66
Table 5.
Response Evaluation Criteria in Solid Tumors ........................................82
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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: Single-Arm Study of Lorlatinib in Participants with Anaplastic Lymphoma 
Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC) Whose Disease Progressed 
After One Prior Second-Generation ALK Tyrosine Kinase Inhibitor (TKI)
Short Title: Study of Lorlatinib In Participants with Anaplastic Lymphoma Kinase 
(ALK) -Positive NSCLC
Rationale:
On the basis of pivotal Phase 1/2 study B7461001, lorlatinib received Conditional Marketing 
Authorization (CMA) by the European Medicine Agency (EMA) on 7 May 2019 for the 
treatment of patients with ALK-positive metastatic non-small-cell lung cancer whose disease 
has progressed after: 

alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; or

crizotinib and at least one other ALK inhibitor. 
However, in view of the limited sample size of 28 patients post second generation ALK TKI 
from the pivotal phase 1/2 study B7461001, in addition to the ongoing Phase 3 study 
B7461006 (CROWN), the EMA requested a post-authorization efficacy study (PAES) to 
obtain additional data on the activity of lorlatinib in the second-line setting.
Objectives, Estimands and Endpoints
Objectives
Estimands
Endpoints
Primary 

To assess Overall and 
Intracranial Response 
Rate of single-agent 
lorlatinib in participants 
with advanced 
ALK-positive NSCLC 
whose disease has 
progressed on alectinib 
or ceritinib as the first 
ALK tyrosine kinase 
inhibitor (TKI) therapy

The primary estimand is 
the treatment effect of 
lorlatinib by independent 
central review (ICR)
from time of first dose 
until progression is met 
or subsequent anti-
cancer therapy is 
administered for all 
participants who receive 
at least one dose of 
lorlatinib without regard 
to discontinuation from 
treatment

Confirmed Objective 
Tumor Response 
assessed by Response 
Evaluation Criteria in 
Solid Tumor (RECIST) 
version 1.1 per ICR
Secondary
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
To assess secondary 
measures of clinical 
efficacy

The estimand for 
Objective Response 
(OR) by investigator 
(INV) follows the 
estimand specified for 
the primary endpoint
except that the treatment 
effect is based on INV

The estimand for 
Intracranial (IC)
response is the 
Intracranial treatment 
effect (ie in brain 
lesions) of lorlatinib 
from time of first dose 
until Intracranial 
progression is met or 
subsequent anti-cancer 
therapy is administered 
for all participants who 
receive at least one dose 
of lorlatinib without 
regard to discontinuation 
from treatment

The estimand for Time 
to Tumor Response 
(TTR) is the treatment 
effect from the time of 
first dose to the first date 
of response that is 
subsequently confirmed 
for responders to 
lorlatinib

The estimand for 
Duration of Response 
(DOR) is the treatment 
effect from the first date 
of OR that is 
subsequently confirmed 
for responders to 
lorlatinib until 
progression or death, 
without regard to 
discontinuation from 

Every endpoint assessed 
by RECIST version 1.1

Confirmed Objective 
Tumor Response 
assessed by INV

Confirmed Intracranial 
tumor response assessed 
per ICR and INV

TTR per ICR and INV

DOR per ICR and INV

Duration of Intracranial 
response (IC-DOR) per 
ICR and INV

TTP per ICR and INV

PFS per ICR and INV
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treatment unless new 
anti-cancer therapy is 
initiated or extended gap 
in tumor assessment is 
present prior to 
progression or death

The estimand for 
IC-DOR follows the 
estimand specified for 
the DOR, but limited to 
intracranial lesions

The estimand for Time 
to Tumor Progression 
(TTP) is the treatment 
effect from the time of 
first dose for all 
participants who receive 
at least one dose of 
lorlatinib until 
progression, without 
regard to discontinuation 
from treatment unless 
participant dies, new 
anti-cancer therapy is 
initiated or extended gap 
in tumor assessment is 
present prior to 
progression

The estimand for 
Progression Free 
Survival (PFS) is the 
treatment effect from the 
time of first dose for all 
participants who receive 
at least one dose of 
lorlatinib until 
progression or death, 
without regard to 
discontinuation from 
treatment unless new 
anti-cancer therapy is 
initiated or an extended 
gap in tumor assessment 
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is present prior to 
progression or death

To confirm the safety 
and tolerability of 
lorlatinib

The estimand for safety 
is the incidence of 
Adverse Events from the 
time of first dose to 
28 days post last dosing 
date or the date of 
initiation of a new anti-
cancer therapy for all 
participants who receive 
at least one dose of 
lorlatinib

Adverse Events as 
characterized by type, 
frequency, severity (as 
graded by National 
Cancer Institute 
Common Terminology 
Criteria for Adverse 
Events [NCI CTCAE] 
v.4.03), seriousness, and 
relationship to study 
therapy
Overall Design:
This is a Phase 4 open-label, multi center, multi-national, non-randomized, prospective, 
single-arm study of lorlatinib in adult participants with ALK-positive NSCLC who 
progressed on alectinib or ceritinib as first line of treatment for metastatic disease.
Disclosure Statement:
This is a Single Group Treatment study with 1 Arm that has No masking.
Number of Participants:
Approximately 85 participants will be screened to achieve 70 participants assigned to study 
intervention. 
Intervention Groups and Duration:
Participants will take lorlatinib at the approved dose of 100 mg QD (once daily). Participants 
will be treated until disease progression, participant refusal/lost to follow-up, or unacceptable 
toxicity.
Data Monitoring Committee: No
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1.2. Schema
a
alectinib or certinib
b
Treatment until disease progression, patient refusal/lost to follow-up, or unacceptable toxicity.
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1.3. Schedule of Activities (SoA)
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to Section 8 of the protocol for 
detailed information on each 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 participant.
1.3.1. Screening and Cycle 1
Visit Identifier
Screening*
Cycle 1
(21 days)
Notes
*to be obtained within 28 days prior to registration
Visit Window
≤28 days
Day 1
(±1 day)
(X) refer to specific footnote when the measurement may be optional /repeat 
measurement might not be required.
Informed consent
X
Must be obtained prior to undergoing any study specific procedures that are not 
considered standard of care.
Tumor history
X
Medical history
X
Data on prior anti-cancer therapy will be collected along with the best-known response 
from the previous ALK inhibitor.
Physical examination
X
X
Weight
X
X
Performance Status
X
X
Contraception check (as 
appropriate)
X
Laboratory
Hematology 
X
(X)
No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that 
date. For those visits after C1D1, hematology labs should be performed according to 
lorlatinib product information. 
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Visit Identifier
Screening*
Cycle 1
(21 days)
Notes
*to be obtained within 28 days prior to registration
Visit Window
≤28 days
Day 1
(±1 day)
(X) refer to specific footnote when the measurement may be optional /repeat 
measurement might not be required.
Blood Chemistry
X
(X)
No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that 
date.   For those visits after C1D1, blood chemistry should be performed according to 
lorlatinib product information.
Pregnancy test 
X
(X)
For female participants of childbearing potential, a serum or urine pregnancy test will be 
performed once at the start of screening and once at the baseline visit, immediately 
before study intervention administration.  The pregnancy test should be performed at the 
clinical site’s local laboratory.
Cardiac Monitoring
12-lead ECG
X
(X)
No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that 
date.  During study treatment additional triplicate ECGs may be performed as clinically 
indicated and according to lorlatinib product information.
LVEF Assessment
X
Echocardiogram or MUGA will be performed. During study treatment additional
assessments may be performed as clinically indicated and according to lorlatinib product 
information.
For France and Germany, a transthoracic echocardiogram (TTE) will be performed 
every 6 months (± 2 weeks) during treatment, and only at the end of treatment visit if the 
previous assessment was > 1 month. Pulmonary arterial pressure (PAP) will be assessed.
Registration
Registration
(X)
Registration will be within 2 days prior to study treatment start.
Tumor Assessments
CT and MRI Scan or Equivalent
X
Tumor assessments will include all known or suspected disease sites.  CT or MRI scans 
of Chest Abdomen Pelvis [CAP] and MRI of the brain will be performed at screening.  
Bone scans (or bone MRI if preferred by investigator) will be performed at baseline for 
all participants and repeated every 12 weeks on study only if evidence of bone 
metastases is observed at baseline.  
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Visit Identifier
Screening*
Cycle 1
(21 days)
Notes
*to be obtained within 28 days prior to registration
Visit Window
≤28 days
Day 1
(±1 day)
(X) refer to specific footnote when the measurement may be optional /repeat 
measurement might not be required.
Cerebrospinal fluid if 
leptomeningeal/carcinomatous 
meningitis [LM/CM] disease is 
present
X
CSF is mandatory for participants who have asymptomatic radiologically suspected 
leptomeningeal disease (LM) or carcinomatous meningitis (CM) but negative spinal 
fluid.
Other Clinical Assessments
Adverse Events
X
X
For AEs and SAEs, the active reporting period to Pfizer or its designated representative 
begins from the time that the participant provides informed consent, which is obtained 
prior to the participant’s participation in the study through and including a minimum of 
28 calendar days after the last administration of the study intervention.  Refer to 
Section 8.3.1 for all specifications.
Concomitant medications and non-
drug supportive interventions
X
X
1.3.2. Visits on Day 1 of Every Other Cycle (up to 35 cycles and >35 cycles)
Visit Identifier
Visits on Day 1 
of Every Other 
Cycle up to 
35 cycles (up to 
24 months)
Visits on Day 1 
of Every Other 
Cycle 
(> 35 cycles or 
24 months)
Notes
(X) refer to specific footnote when the measurement may be optional /repeat 
measurement might not be required.
Visit Window
±4 days
±4 days
Physical examination
X
Weight
X
Contraception check (as 
appropriate)
X
(every cycle 
±2 days)
X
(every cycle 
±2 days)
At cycle not requiring site visit the participant may be contacted by phone to 
confirm contraception is still appropriate per the protocol.  
Laboratory
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Visit Identifier
Visits on Day 1 
of Every Other 
Cycle up to 
35 cycles (up to 
24 months)
Visits on Day 1 
of Every Other 
Cycle 
(> 35 cycles or 
24 months)
Notes
(X) refer to specific footnote when the measurement may be optional /repeat 
measurement might not be required.
Visit Window
±4 days
±4 days
Pregnancy test 
X
(every cycle 
±2 days)
X
(every cycle 
±2 days)
Pregnancy tests will be routinely repeated at every cycle (±2 days) during the active 
treatment period and additionally whenever one menstrual cycle is missed or when 
potential pregnancy is otherwise suspected.  The pregnancy test should be 
performed at the clinical site’s local laboratory.  Where that is not possible, 
participants will provide the laboratory test results carried out at a non-clinical site 
laboratory, eg, by telephone, and bring a copy of the laboratory test results at the 
next cycle visit.  The copy of the laboratory test results must be retained in the 
participants’ file at the clinical site for documentation purposes.
Study Intervention
Study Intervention
Once a day continuously
Tumor Assessments
CT and MRI Scan or 
Equivalent
(every 6 weeks ± 
1 week)
(As per local 
clinical practice)
CT and MRI scans to be done at every 6 weeks ±1 week up to approximately 24 
months (cycle 35) and then as per local clinical practice.
Other Clinical Assessments
Adverse Events
X
X
Concomitant medications and 
non-drug supportive 
interventions
X
All concomitant medications and non-drug supportive interventions should be 
recorded in the CRF until the participant has completed 35 cycles of treatment 
(approximately 24 months).  After cycle 35 the data will be reported in the medical 
chart, but not collected in the CRF.
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1.3.3. End of Treatment and Follow-Up
End of Treatment Visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments up to 
24 months).  
Follow up: At least 28 days, and no more than 35 days after discontinuation of treatment participants will return to undergo review for 
resolution of any treatment related toxicity.  Participants continuing to experience toxicity at this point following discontinuation of 
treatment 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.  Participants discontinuing treatment for reasons other than progression of 
disease will continue to perform tumor assessments until PD up to approximately 24 months (cycle 35).
Visit Identifier
End of 
Treatment
Follow-up
Notes
(X) refer to specific footnote when the measurement may be optional /repeat 
measurement might not be required.
Visit Window
±2 days
±7 days
Physical examination
X
Weight
X
Contraception check (as 
appropriate)
X
X
The participant may be contacted by phone to confirm contraception is still 
appropriate per the protocol.  Males and females of childbearing potential must be 
contacted after study intervention discontinuation to ensure that they continue to 
use appropriate contraception for at least 98 and 35 days, respectively, after the last 
dose of study intervention.
Laboratory
Pregnancy test 
X
X
The pregnancy test should be performed at the clinical site’s local laboratory.  
Where that is not possible, participants will provide the laboratory test results 
carried out at a non-clinical site laboratory, eg, by telephone, and bring a copy of 
the laboratory test results at the next cycle visit.  The copy of the laboratory test 
results must be retained in the participant’s file at the clinical site for 
documentation purposes.
Tumor Assessments
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Visit Identifier
End of 
Treatment
Follow-up
Notes
(X) refer to specific footnote when the measurement may be optional /repeat 
measurement might not be required.
Visit Window
±2 days
±7 days
CT and MRI Scan or 
Equivalent
(X)
Tumor assessment should be repeated at the end of treatment if more than 6 weeks 
have passed since the last evaluation. Tumor assessment should not be repeated at 
the end of treatment if progression occurs when the participant has shifted to the 
local clinical practice.
Other Clinical Assessments
Adverse Events
X
X
Concomitant medications and 
non-drug supportive 
interventions
(X)
Abbreviations: AE = adverse events; CAP = Chest abdomen pelvis; c; CNS = central nervous system; CT = computed tomography; CRF = case report form; 
CSF = cerebrospinal fluid; C1D1 = cycle 1 day 1; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; LM = leptomeningeal 
meningitis; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NCI CTCAE = National Cancer 
Institute common terminology criteria for adverse events; PD = progression of disease; RECIST = Response Evaluation Criteria in Solid Tumors; TTE = 
transthoracic echocardiogram
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2. INTRODUCTION
Lung cancer is one of the most common cancers in the world (2.1 million new cases 
estimated in 2018), 12% of all new cancers world-wide.1 Non-small cell lung cancer 
(NSCLC) constitutes approximately 85% of all lung cancer.
In 2007, two research groups independently reported the discovery of an NSCLC oncogenic 
fusion gene (echinoderm microtubule-associated protein-like 4 [EML4]-ALK) that combines 
portions of the EML4 gene and the anaplastic lymphoma kinase (ALK) gene.2, 3  This fusion 
gene encodes for the cytoplasmic fusion protein EML4-ALK which upon dimerization, 
results in constitutive activation of the kinase domain of ALK. Approximately 3-5% of 
NSCLC is histologically defined as ALK+4 and the vast majority of ALK fusion positive 
cases were observed in young, non-smoking patients with lung adenocarcinoma, and are 
rarely coincident with c-ROS oncogene-1 (ROS1), epidermal growth factor receptor (EGFR), 
human epidermal growth factor receptor 2 (HER2), or Kirsten Rat Sarcoma (KRAS)
mutations.2  Rearrangements of ALK gene represent a clinically and molecularly distinct 
subtype that shows sensitivity to therapy with ALK tyrosine kinase inhibitors.  Standard 
initial treatment for ALK-positive non-small-cell lung cancer includes first-line crizotinib 
and, more recently, first-line alectinib or ceritinib. 
Although most participants with ALK-positive NSCLC derive substantial clinical benefit 
from crizotinib and the second generation ALK-TKIs alectinib and ceritinib5-8, some 
participants will not respond to treatment (intrinsic resistance), and other participants who 
initially experience clinical benefit will later develop resistance (acquired resistance) or 
develop disease progression in the central nervous system (CNS).9, 10
Among patients whose disease has progressed on second-generation TKIs used either in the 
first- or second-line setting, chemotherapy and/or immunotherapy would be the fall back 
standard of care. 
Outcomes with chemotherapy alone have been modest. In a randomized Phase 3 trial of 
ceritinib vs chemotherapy (docetaxel or pemetrexed) in patients with ALK-positive NSCLC 
who had been previously treated with chemotherapy and crizotinib, chemotherapy had an 
objective response rate (ORR) of 6.9% and median PFS of 1.6 months, as determined by 
blinded ICR. Chemotherapy also has a limited intracranial (IC) ORR even in a treatment-
naïve setting.  In a randomized Phase 3 study of first-line ceritinib versus platinum-based 
chemotherapy in advanced ALK-rearranged NSCLC, the platinum doublet was reported to 
have an IC ORR by ICR of 21.2% (95% confidence interval [CI]: 11.1, 34.7).5
In addition to standard chemotherapy regimens and anti-vascular agents, immunotherapy is 
also indicated for the second-line treatment of patients with ALK positive NSCLC after 
failure of a first line ALK-TKI (atezolizumab11) or as monotherapy in patients whose tumors
express PD-L1 with a ≥ 1% tumor proportion score (TPS) and who have received at least one 
prior chemotherapy regimen and a target therapy (pembrolizumab12).
Although, these treatments have shown very promising results13, 14, few patients with ALK 
positive tumors were enrolled and conclusive results in this specific subpopulation are still 
warranted.
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As outlined in Section 2.2, the third-generation ALK TKI lorlatinib offers a therapeutic 
option active in this setting.
2.1. Study Rationale
On the basis of pivotal Phase 1/2 B7461001, lorlatinib received CMA by the European 
Medicine Agency (EMA) on 7 May 2019 for the treatment of participants with ALK-positive 
metastatic non-small-cell lung cancer whose disease has progressed after: 

alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; or

crizotinib and at least one other ALK inhibitor. 
However, in view of the limited sample size of 28 participants post second generation ALK 
TKI from the pivotal phase 1/2 study B7461001, in addition to the ongoing Phase 3 study 
B7461006 (CROWN), the EMA requested a PAES to obtain additional data on the activity of 
lorlatinib in the second-line setting.
2.2. Background
Lorlatinib is a highly potent, selective third-generation tyrosine kinase inhibitor directed at 
the ALK and c-ros oncogene 1 (ROS1) kinases.  Using structure-based drug design, this 
macrocyclic tyrosine kinase inhibitor was developed to retain potency against most known 
ALK resistance mutations and to penetrate the blood–brain barrier.  Lorlatinib demonstrated 
marked antitumor activity in mice bearing tumor xenografts that express echinoderm 
microtubule-associated protein-like 4 (EML4) fusions with ALK variant 1 (v1), including 
ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, 
G1202R and I1171T, are known to confer resistance to alectinib, brigatinib, ceritinib, and 
crizotinib. Lorlatinib was also capable of penetrating the blood-brain barrier and 
demonstrated activity in mice bearing orthotopic EML4-ALK or EML4-ALKL1196M brain 
tumor implants.
In the pivotal single-arm, multicenter Phase 2 study, treatment with lorlatinib showed 
clinically relevant response rates and duration of response in participants with ALK-positive 
non-small-cell lung cancer who had previously received at least 1 ALK tyrosine kinase 
inhibitor, including the second-generation drugs ceritinib and alectinib.  In the cohort of 
participants previously treated with a second generation ALK-TKI, a high proportion of 
participants achieved an OR (12 [42.9%] of 28) and durable responses (median duration of 
response 5.6 months [95% CI 4.2–not reached]). 
Substantial intracranial activity was also observed in these participants suffering from 
frequent brain metastases. The proportion of participants with objective intracranial response 
to lorlatinib was 66.7% in participants with at least one measurable brain lesion at baseline.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of lorlatinib may be found in the Summary of Product 
Characteristics (SmPC), which is the single reference safety document (SRSD) for this study. 
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3. OBJECTIVES, ESTIMANDS AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary

To assess Overall and 
Intracranial Response 
Rate of single-agent 
lorlatinib in participants 
with advanced ALK-
positive NSCLC whose 
disease has progressed on 
alectinib or ceritinib as 
the first ALK tyrosine 
kinase inhibitor (TKI) 
therapy

The primary estimand is 
the treatment effect of 
lorlatinib by independent
central review (ICR) from 
time of first dose until 
progression is met or 
subsequent anti-cancer 
therapy is administered 
for all participants who 
receive at least one dose 
of lorlatinib without 
regard to discontinuation 
from treatment

Confirmed Objective 
Tumor Response assessed 
by Response Evaluation 
Criteria in Solid Tumor 
(RECIST) version 1.1 per 
ICR
Secondary

To assess secondary 
measures of clinical 
efficacy 

The estimand for 
Objective Response (OR)
by investigator (INV)
follows the estimand 
specified for the primary 
endpoint except that the 
treatment effect is based 
on INV

The estimand for 
Intracranial (IC) response 
is the Intracranial 
treatment effect (ie in 
brain lesions) of lorlatinib 
from time of first dose 
until Intracranial 
progression is met or 
subsequent anti-cancer 
therapy is administered 
for all participants who 
receive at least one dose 
of lorlatinib without 
regard to discontinuation 
from treatment

Every endpoint assessed by 
RECIST version 1.1

Confirmed Objective 
Tumor Response assessed 
by INV

Confirmed Intracranial 
tumor response assessed per 
ICR and INV

TTR per ICR and INV

DOR per ICR and INV

Duration of Intracranial 
response (IC-DOR) per ICR
and INV

TTP per ICR and INV

PFS per ICR and INV
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
The estimand for Time to 
Tumor Response (TTR) is 
the treatment effect from 
the time of first dose to 
the first date of response 
that is subsequently 
confirmed for responders 
to lorlatinib

The estimand for 
Duration of Response 
(DOR) is the treatment 
effect from the first date 
of OR that is 
subsequently confirmed 
for responders to 
lorlatinib until 
progression or death, 
without regard to
discontinuation from 
treatment unless new 
anti-cancer therapy is 
initiated or extended gap 
in tumor assessment is 
present prior to 
progression or death

The estimand for IC-DOR 
follows the estimand 
specified for the DOR, 
but limited to intracranial 
lesions

The estimand for Time to 
Tumor Progression (TTP)
is the treatment effect 
from the time of first dose 
for all participants who 
receive at least one dose 
of lorlatinib until 
progression, without 
regard to discontinuation
from treatment unless 
participant dies, new anti-
cancer therapy is initiated 
or extended gap in tumor 
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assessment is present
prior to progression

The estimand for 
Progression Free Survival 
(PFS) is the treatment 
effect from the time of 
first dose for all 
participants who receive 
at least one dose of 
lorlatinib until 
progression or death, 
without regard to 
discontinuation from 
treatment unless new anti-
cancer therapy is initiated 
or an extended gap in 
tumor assessment is 
present prior to 
progression or death

To confirm the safety and 
tolerability of lorlatinib

The estimand for safety is 
the incidence of Adverse 
Events from the time of 
first dose to 28 days post 
last dosing date or the 
date of initiation of a new 
anti-cancer therapy for all 
participants who receive 
at least one dose of 
lorlatinib

Adverse Events as 
characterized by type, 
frequency, severity (as 
graded by National Cancer 
Institute Common 
Terminology Criteria for 
Adverse Events [NCI 
CTCAE] v.4.03), 
seriousness, and 
relationship to study 
therapy
This protocol will use an independent endpoint adjudication committee to determine whether 
certain investigator-reported events meet the definition of disease-related efficacy endpoints, 
using predefined endpoint criteria (see Section 9.5.2).  
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 4 open-label, multi-center, multi-national, non-randomized, prospective, 
single arm study of lorlatinib in adult participants with ALK-positive NSCLC who 
progressed on alectinib or ceritinib as first line of treatment for metastatic disease.  
Approximately 85 participants will be screened to achieve 70 participants assigned to study 
intervention.  
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Participants will take lorlatinib at the approved dose of 100 mg QD.  Participants will be 
treated until disease progression per RECIST 1.1, participant refusal/lost to follow-up, or 
unacceptable toxicity.
4.2. Scientific Rationale for Study Design
The pivotal phase 1/2 study B7461001 has included 28 participants who have progressed 
after a second generation ALK inhibitors used as a first line treatment.  In order to allow for a 
more precise estimation of the 95% confidence interval (CI) of the primary endpoint the 
proposed study increases the sample size in this population.
4.3. Justification for Dose
The dose of 100 mg QD is the approved dose based on the safety and efficacy data provided 
by the Phase 1 portion of pivotal study B7461001.
4.4. End of Study Definition
The End of Trial is defined as 12 calendar months after the “last patient first visit” (LPFV) 
date in the study.
Participants who still experience clinical benefit at the End of Trial will discontinue from the 
study and continue treatment per standard of care (SOC). A number of options for ensuring 
continued supply with lorlatinib will be considered based on the local availability of the 
treatment and local country laws/regulation.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.  Participant eligibility should be reviewed and documented by an appropriately 
qualified member of the investigator’s study team before participants are included in the 
study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be ≥18 years of age inclusive (or ≥20 years of age if required by 
local regulation), at the time of signing the informed consent.
Type of Participant and Disease Characteristics
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2. Participants must have evidence of histologically or cytologically confirmed 
diagnosis of metastatic NSCLC (Stage IV, American Joint Committee on Cancer 
[AJCC] v7.0) that carries an ALK rearrangement, as determined by the Food and 
Drug Administration (FDA) approved fluorescence in situ hybridization (FISH) assay 
(Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc).
3. Disease Status Requirements: disease progression after alectinib or ceritinib as first 
line therapy (the study will limit enrollment of participants with best response of 
progression or indeterminate on prior alectinib to 8 participants).  Participants may 
have had prior chemotherapy, but only if before starting treatment with alectinib or 
ceritinib.
4. Tumor Requirements: All Participants must have at least one measurable target 
extracranial lesion according to RECIST v1.1.  Participants with asymptomatic CNS 
metastases (including participants controlled with stable or decreasing steroid use 
within the last 2 weeks prior to study entry) will be eligible.  The brain metastases 
may be newly diagnosed or be present as progressive disease after surgery, whole 
brain radiotherapy or stereotactic radiosurgery.  Participants who have 
leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligible if the 
LM/CM is visualized on magnetic resonance imaging (MRI) or if documented 
baseline cerebral spinal fluid (CSF) positive cytology is available.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
6. Adequate bone marrow functioning, 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.
7. Adequate pancreatic function, including:
a.
Serum total amylase ≤1.5 x upper limit of normal (ULN)*;
b. Serum lipase ≤1.5 ULN.
*if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, the 
participant may be enrolled.
8. 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.
9. Adequate liver function, including:
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).
10. Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade 
≤1 except for adverse events (AEs) that in the investigator’ judgment do not 
constitute a safety risk for the participant.
11. Systemic anti-cancer therapy with alectinib or ceritinib discontinued within a 
minimum of 5 half-lives prior to first dose of lorlatinib on the study (unless clinically 
meaningful tumor flare per discretion of the investigator, in which discussion with the 
sponsor is warranted).
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Sex
12. Male or Female
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
     
a.
Male participants:
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 98 days after the last dose of study intervention: 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual or homosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent.
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom when engaging in any activity that allows passage of 
ejaculate to another person.

Female partner of childbearing potential who is currently not pregnant must use 
an additional highly effective contraceptive method with a failure rate of <1% per 
year as described in Appendix 4 if having sexual intercourse with male 
participant.
b. Female participants:

A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:

Is not a woman of childbearing potential (WOCBP) (refer to Appendix 4) for 
definition.
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described 
in Appendix 4 during the intervention period and for at least 35 days after the last 
dose of study intervention and agrees not to donate eggs (ova, oocytes) for the 
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purpose of reproduction during this period. The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention.

A WOCBP must have a negative highly sensitive (at least 25 IU/Ml) pregnancy 
test (urine or serum as required by local regulations) immediately before the first 
dose of study intervention.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.2.6.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
13. Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
14. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Prior ALK TKI treatment or anti-cancer treatment other than first line alectinib or 
ceritinib. 
2. Spinal cord compression unless the participant has good pain control attained through 
therapy, and there is stabilization or recovery of neurological function for the 4 weeks 
prior to randomization.
3. 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.
4. Active and clinically significant bacterial, fungal, or viral infection including hepatitis 
B virus (HBV) or hepatitis C virus (HCV) (eg, in case of known hepatitis b surface 
antigen [HBsAg] or HCV antibody positivity), known human immunodeficiency 
virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.
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5. Clinically significant vascular (both arterial and venous) and non-vascular cardiac 
conditions, (active or within 3 months prior to enrollment), which may include, but 
are not limited to: 
a.
Arterial disease such as cerebral vascular accident/stroke (including 
Transient Ischemic Attack [TIA]), myocardial infarction, unstable angina;
b. Venous diseases such as cerebral venous thrombosis, symptomatic 
pulmonary embolism;
c.
Non vascular cardiac disease such as congestive heart failure (New York 
Heart Association Classification Class ≥ II), second degree or third degree 
atrioventricular (AV) block (unless paced) or any AV block with PR 
interval >220 msec; or ongoing cardiac dysrhythmias of NCI CTCAE Grade 
≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 
beats per minute (bpm) (unless participant is otherwise healthy such as long 
distance runners, etc.), machine read Electrocardiogram (ECG) with QTc 
>470 msec, or congenital long QT syndrome.
6. Participants presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by 
echocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutional 
lower limits.
7. Participants with predisposing characteristics for acute pancreatitis according to 
investigator judgment (eg, uncontrolled hyperglycemia, hypertriglyceridemia, current 
gallstone disease, alcoholism [more than 4 drinks on any day or 14 drinks per week 
where 1 drink is defined as the alcoholic beverage containing approximately 14 grams 
of pure alcohol, eg, 12 fl oz/360 mL regular beer or 5 fl oz/150 mL of wine] in the 
last month.
8. History or known presence of interstitial fibrosis, interstitial lung disease, 
pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative 
bronchiolitis, and pulmonary fibrosis.
9. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the participant
inappropriate for entry into this study.
10. Evidence of active malignancy (other than current NSCLC, non-melanoma skin 
cancer, in situ cervical cancer, papillary thyroid cancer, ductal carcinoma in situ 
(DCIS) of the breast or localized and presumed cured prostate cancer) within the last 
3 years prior to randomization.
Prior/Concomitant Therapy
11. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study 
entry.  Palliative radiation (10 fractions) must have been completed at least 48 hours 
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prior to study entry. Stereotactic or small field brain irradiation must have completed 
at least 2 weeks prior to study entry. Whole brain radiation must have completed at 
least 4 weeks prior to study entry.
12. Prior irradiation to >25% of the bone marrow.
13. 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: 
a.
Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s Wort). 
b. Known strong CYP3A inhibitors (eg, strong CYP3A4 inhibitors: grapefruit 
juice or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, 
pomelos], boceprevir, cobicistat, clarithromycin, conivaptan, diltiazem, 
idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, 
nelfinavir, paritaprevir 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]). The topical use of these medications (if 
applicable), such as 2% ketoconazole cream, is allowed.  Note that strong 
CYP3A inhibitors can be stopped up to one day prior to first dose of lorlatinib 
on study.
c.
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 United 
States [US] market).
d. Known permeability glycoprotein (P-gp) substrates with a narrow therapeutic 
index (eg, digoxin). 
14. Major surgery within 4 weeks prior to enrollment.  Minor surgical procedures (eg, 
port insertion) are not excluded, but sufficient time should have passed for adequate 
wound healing.
Other Exclusions
15. Known prior or suspected severe hypersensitivity to study interventions or any 
component in their formulations.
16. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.
5.3. Lifestyle Considerations
1. See Appendix 4 for mandatory contraception information.
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2. Refrain from consumption of grapefruit/grapefruit related citrus fruits (eg, Seville 
oranges pomelos) from 1 day before the start of study intervention until after the final 
dose.
3. Lorlatinib has moderate influence on the ability to drive and use machines. Cautions 
should be exercised when driving or operating machines as participants may experience 
CNS effects.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.  
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1. Study Intervention(s) Administered
ARM Name
Lorlatinib 100 mg QD
Intervention Name
lorlatinib
Type 
Small molecule
Dosage Form
Tablet
Dose Strength
25 mg
Dosage
100 mg QD
Route of Administration
Oral
Sourcing
Provided centrally by the Sponsor
Packaging and Labeling
Study Intervention will be provided in bottles. Each bottle 
will be labeled as required per country requirement.
Current/Former Name(s) 
or Alias(es)
PF-06463922/lorlatinib
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.  At a minimum, daily 
minimum and maximum temperatures for all site storage locations must be 
documented and available upon request.  Data for nonworking days must indicate the 
minimum and maximum temperature since previously documented for all site storage 
locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  All study 
interventions will be accounted for using an investigational product accountability 
form/record. 
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the investigational product (IP) manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels.
7. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
8. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention 
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion.  Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation.  Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site in the IP manual.
9. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented.
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6.3. Measures to Minimize Bias: Randomization and Blinding
Open-label using 
IVRS/IWRS
This is an open-label study; however, the specific intervention to be 
taken by a participant will be assigned using an interactive voice 
response system (IVRS)/interactive web response system (IWRS).  
The site will contact the IVRS/IWRS prior to the start of study 
intervention administration for each participant.  The site will 
record the intervention assignment on the applicable case report 
form, if required.
6.4. Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Compliance 
will be assessed by counting returned tablets. Deviation(s) from the prescribed dosage 
regimen should be recorded in the electronic case report form (eCRF).
6.5. Concomitant Therapy
All concomitant medications and non-drug supportive interventions should be recorded in the 
CRF until the participant has completed 35 cycles of treatment (approximately 24 months).  
After cycle 35 the data will be reported in the medical chart, but not collected in the CRF.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1. Prohibited Concomitant Treatments
Concomitant treatment considered necessary for the participant’s wellbeing may be given at 
discretion of the treating physician.
In vitro studies have demonstrated that CY3A and UGT1A4 are primarily involved in the 
metabolism of lorlatinib, with additional minor contribution from cytochrome P450 
(CYP)2C8, CYP2C19, CYP3A5 and UGT1A3. Inhibition or induction of the above enzymes 
may result in potential alteration of lorlatinib systemic exposure. 
To protect participant safety the following cautions are provided:  

Lorlatinib metabolism may be inhibited by strong CYP3A4/5 inhibitors leading to a 
potential increase in lorlatinib toxicities.  Concomitant administration of lorlatinib 
with strong CYP3A4/5 inhibitors (e.g. boceprevir, cobicistat, itraconazole, 
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ketoconazole, posaconazole, troleandomycin, voriconazole, ritonavir, paritaprevir in 
combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in 
combination with either elvitegravir, indinavir, lopinavir or tipranavir) may increase 
lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib 
plasma concentrations and should be avoided. An alternative concomitant medicinal 
product with less potential to inhibit CYP3A4/5 should be considered. If a strong 
CYP3A4/5 inhibitor must be co-administered, the starting lorlatinib dose of 100 mg 
once daily should be reduced to once daily 75 mg dose. In participants who have had 
a dose reduction to 75 mg orally once daily due to adverse reactions and who initiate 
a strong CYP3A4/5 inhibitor, reduce lorlatinib dose to 50 mg orally once daily.  If 
concurrent use of the strong CYP3A4/5 inhibitor is discontinued, lorlatinib should be 
resumed at the dose used prior to the initiation of the strong CYP3A4/5 inhibitor and 
after a washout period of 3 to 5 half-lives of the strong CYP3A4/5 inhibitor. The 
participant should be closely monitored for safety and reduction of the lorlatinib dose 
if necessary.

The use of a strong CYP3A4/5 inducer (eg, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s Wort) with lorlatinib is contraindicated and it should 
be avoided, if possible, as they may also reduce lorlatinib plasma concentration 
Furthermore, when lorlatinib was coadministered with rifampin (Study B7461011), 
increases in AST and ALT were noted.  Discontinue strong CYP3A inducers for 3 
plasma half-lives of the strong CYP3A inducer prior to initiating lorlatinib and until 
study treatment discontinuation. In addition, use with moderate CYP3A inducers 
should be avoided due to the potential reduction in lorlatinib exposure.  

Lorlatinib inhibits CYP2C9 (in vitro), so concurrent use of drugs that are 
CYP2C9 substrates with narrow therapeutic indices, such as warfarin, phenytoin or 
celecoxib, may have increased effect.  Concomitant CYP2C9 substrates should be 
used with caution, as the net clinical effect of lorlatinib on CYP2C9 is currently being 
investigated.

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 (e.g. bupropion, efavirenz) should be used with 
caution, as the net clinical effect of lorlatinib on CYP2B6 is currently being 
investigated. 

In vitro studies indicated that lorlatinib is a time-dependent inhibitor as well as an 
inducer of CYP3A4/5 and it activates the human pregnane-X-receptor (PXR), with 
the net effect in vivo being induction. Thus, concurrent administration of lorlatinib 
with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited 
to alfentanil, ciclosporin dihydroergotamine, ergotamine, fentanyl, hormonal 
contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided 
since the concentration of these medicinal products may be reduced by lorlatinib.  
However, if it is absolutely necessary to use, sponsor approval is required and the 
dose of the CYP3A4/5 substrate may need to be increased.  The narrow therapeutic 
index (NTI) CYP3A4/5 substrate should be started only after at least 14 days of 
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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 
CYP3A4/5 substrate should be stopped and resumed at a readjusted dose only after at 
least 14 days of resumed lorlatinib dosing.

In vitro studies indicated that lorlatinib may inhibit P-gp (systemically and at the 
gastrointestinal tract), breast cancer resistance protein (BCRP) (gastrointestinal [GI]
tract), OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 at clinically relevant 
concentrations. 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.

In vitro studies indicated that lorlatinib may have the potential to inhibit UGT1A1.
Other Anti-Tumor or Experimental Drugs
No additional systemic anti-tumor therapy will be permitted while participants are receiving 
a study therapy.  Additionally, the concurrent use of select herbal supplements (St John’s 
wort, ginseng, and goldenseal)15 is not permitted.
Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first cycle but they may be used to treat treatment emergent neutropenia as per standard 
of care. 
If approved and available for use per country regulations, erythropoietin may be used at the 
investigator’s discretion for the supportive treatment of anemia.
6.5.2. Permitted Concomitant Treatments
Bisphosphate Therapy
Bisphosphonate therapy for metastatic bone disease is permitted.  Bisphosphonate therapy 
should be given as per local medical practice.
Lipid-Lowering Therapy
Since statins can be metabolized or inhibited by the same CYP450 pathways as lorlatinib 
(Table 1), pitavastatin or pravastatin followed by rosuvastatin should be the agents to use 
concomitantly with lorlatinib since they are the least involved with the CYP450 enzyme 
systems. However, no clinical drug-drug interactions have been formally studied with 
lorlatinib and careful monitoring is advised.
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Table 1.
Pharmacokinetic Properties of Statins
Pitavastatin
Pravastatin
Rosuvastatin
Atorvastatin
Simvastatin
Lovastatin
Fluvastatin
Livalo
Pravachol
Crestor
Lipitor
Zocor
Mevacor, 
Altocor
Lescol
Metabolism†
++
+
+
+++
+++
+++
+++
Metabolizing 
CYP enzymes 
(of lactone or 
acid form)
(2C9)
(3A4)
2C9 (2C19)
3A4 (2C8)
3A4 2C8
3A4 2C8
2C9
Inhibitor of 
CYP3A4‡
-
-
+
+
+
+
+
Inhibitor of 
CYP2C9‡
-
-
(+)
-
-
-
+
Triglyceride 
lowering effect
22%-31%**
11%-14%*
17%*
14%-19%*
10%-14%*
13%*
5%***
Adapted from Neuvonen et al, 200616.
Parentheses indicate minor significance.
†Three plus signs indicate extensively metabolized, and 1 plus sign indicates limited metabolism, eliminated mainly unchanged.
‡A plus sign indicates yes, and a minus sign indicates no.
* Baseline TG 100-200 mg/dL; Effect of Statins vs Placebo on Triglyceride Levels in 10 Primary and Secondary Placebo-Controlled Outcome Trials table 
in Miller 200917.
** Baseline TG 150 mg/dL; Kajinami et al, 200318.
*** Schaefer et al, 200419.
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If hypertriglyceridemia requires treatment beyond a statin that was administered for 
hypercholesterolemia, fenofibrate or fish oils followed by nicotinic acid should be 
administered as they have the least involvement with the CYP450 enzyme systems (Table 2).  
No clinical drug-drug interactions have been formally conducted with lorlatinib and agents 
listed in Table 2 so careful monitoring is advised. 
Table 2.
Pharmacokinetic properties of Lipid Lowering Agents
Fibric Acids
Fish Oils
Generic Name
Nicotinic Acid
Gemfibrozil
Fenofibrate
Ethyl esters of 
omega-3 fatty acids
Tradename
Niaspan®, Nicor®a
Lopid®b
TriCor®c
Lovaza®d
Dose
100–2000 mg QD
600 mg BID
200 mg QD
4 gm QD/ 2 gm 
BID
Metabolism‡
-
-
-
-
Metabolizing CYP
enzymes (of 
lactone or acid 
form)‡
-
-
-
-
Inhibitor of 
CYP3A4‡
-
-
-
-
Inhibitor of 
CYP2C9‡
-
+++
++
-
Inhibitor of 
CYP2C19‡
-
++
+
-
Inhibitor of 
CYP1A2‡
-
+
-
-
Triglyceride 
lowering effect
(TG 150 mg/dL)
20%-50%*
20%-50%*
36%-55%e
45%
Drug Interactions
Caution should be 
used when 
prescribing niacin 
with statins
Concomitant 
administration with 
statins is 
contraindicated
May increase 
exposure to 
pravastatin and its 
metabolite (13%-
26%) when used 
concomitantly
-
‡A plus sign indicates yes, and a minus sign indicates no.
* NCEP-ATP III, 2001.
BID = twice daily; QD = once daily.
a.
PI, 4/2015
b.
PI, 11/2014
c.
PI, 12/2014
d.
PI, 05/2014
e.
Primary hypertriglyceridemia – severe hypertriglyceridemia (Baseline TG levels 500 to 1500 mg/dL)
Radiotherapy
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
providing the lesions were known at the time of study entry and the investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression.  In 
view of the current lack of data about the interaction of lorlatinib with radiotherapy, lorlatinib
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treatment should be interrupted during palliative radiotherapy, stopping 1 day before and 
resuming treatment after recovery from acute radiation toxicities to baseline.
Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and lorlatinib required to minimize the risk of 
impaired wound healing and bleeding has not been determined.  Stopping lorlatinib is 
recommended at least 2 days prior to surgery.  Postoperatively, the decision to reinitiate 
lorlatinib treatment should be based on a clinical assessment of satisfactory wound healing 
and recovery from surgery.
6.6. Dose Modification
Dosing interruption or dose reduction may be required based on individual safety and 
tolerability.
Lorlatinib dose reduction levels are summarized below:

First dose reduction: 75 mg taken orally once daily

Second dose reduction: 50 mg taken orally once daily
Lorlatinib should be permanently discontinued if the participant is unable to tolerate the 
50 mg dose taken orally once daily.
Dose modification recommendations for toxicities and for participants who develop 
atrioventricular (AV) block are provided in Table 3
Table 3.
Recommended Lorlatinib Dose Modifications for Adverse Reactions
Adverse Reactiona
Lorlatinib Dosing
Hypercholesterolemia and Hypertriglyceridemia
Mild hypercholesterolemia (cholesterol between 
ULN and 300 mg/dL or between ULN and 7.75 
mmol/L)
OR
Moderate hypercholesterolemia (cholesterol between 
301 and 400 mg/dL or between 7.76 and 10.34 
mmol/L)
OR
Mild hypertriglyceridemia (triglycerides between 
150 and 300 mg/dL or 1.71 and 3.42 mmol/L)
OR
Introduce or modify lipid-lowering therapyb in
accordance with respective prescribing information;
continue lorlatinib at same dose.
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Table 3.
Recommended Lorlatinib Dose Modifications for Adverse Reactions
Adverse Reactiona
Lorlatinib Dosing
Moderate hypertriglyceridemia (triglycerides 
between 301 and 500 mg/dL
or 3.43 and 5.7 mmol/L)
Severe hypercholesterolemia (cholesterol between 
401 and 500 mg/dL or between 10.35 and 12.92 
mmol/L)
OR
Severe hypertriglyceridemia (triglycerides between 
501 and 1,000 mg/dL or 5.71 and 11.4 mmol/L)
Introduce the use of lipid-lowering therapyb; if 
currently on lipid-lowering therapy, increase the 
dose of this therapyb in accordance with respective 
prescribing information; or change to a new lipid-
lowering therapyb. Continue lorlatinib at the same 
dose without interruption.
Life-threatening hypercholesterolemia (cholesterol 
over 500 mg/dL or over 12.92 mmol/L)
OR
Life-threatening hypertriglyceridemia (triglycerides 
over 1,000 mg/dL or over 11.4 mmol/L)
Introduce the use of lipid-lowering therapyb or 
increase the dose of this therapyb in accordance with 
respective prescribing information or change to a 
new lipid-lowering therapyb. Withhold lorlatinib 
until recovery of hypercholesterolemia and/or 
hypertriglyceridemia to moderate or mild severity 
grade.
Re-challenge at same lorlatinib dose while 
maximizing lipid-lowering therapyb in accordance 
with respective prescribing information.
If severe hypercholesterolemia and/or 
hypertriglyceridemia recur despite maximal 
lipid-lowering therapyb in accordance with 
respective prescribing information, reduce lorlatinib 
by 1 dose level.
Central Nervous System Effects (changes in cognition, mood, or speech)
Grade 2: Moderate
OR
Grade 3: Severe
Withhold dose until toxicity is less than or equal to 
Grade 1. Then resume lorlatinib at 1 reduced dose 
level.
Grade 4: Life-threatening/urgent intervention 
indicated
Permanently discontinue lorlatinib
Lipase/Amylase Increase
Grade 3: Severe 
OR
Grade 4: Life-threatening/urgent intervention 
indicated
Withhold lorlatinib until lipase or amylase returns to 
baseline. Then resume lorlatinib at 1 reduced dose 
level.
Interstitial Lung Disease (ILD)/Pneumonitis
Grade 1: Mild 
OR
Grade 2: Moderate
Withhold lorlatinib until symptoms have returned to 
baseline and consider initiating corticosteroids.
Resume lorlatinib at 1 reduced dose level.  
Permanently discontinue lorlatinib if 
ILD/pneumonitis recurs or fails to recover after 6 
weeks of lorlatinib hold and steroid treatment.
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Table 3.
Recommended Lorlatinib Dose Modifications for Adverse Reactions
Adverse Reactiona
Lorlatinib Dosing
Grade 3: Severe 
OR
Grade 4: Life-threatening/urgent intervention 
indicated
Permanently discontinue lorlatinib
PR interval prolongation/Atrioventricular (AV) block
First Degree AV Block
Asymptomatic
Continue lorlatinib at the same dose without 
interruption. Consider effects of concomitant 
medicinal products and assess and correct electrolyte 
imbalance that may prolong PR interval. Monitor 
ECG/symptoms potentially related to AV block 
closely.
First Degree AV Block
Symptomatic
Withhold lorlatinib. Consider effects of concomitant 
medicinal products and assess and correct electrolyte 
imbalance that may prolong PR interval. Monitor 
ECG/symptoms potentially related to AV block 
closely. If symptoms resolve, resume lorlatinib at 
1 reduced dose level.
Second Degree AV Block
Asymptomatic
Withhold lorlatinib. Consider effects of concomitant 
medicinal products and assess and correct electrolyte 
imbalance that may prolong PR interval. Monitor 
ECG/symptoms potentially related to AV block 
closely. If subsequent ECG does not show second 
degree AV block, resume lorlatinib at 1 reduced dose 
level.
Second Degree AV Block
Symptomatic
Withhold lorlatinib. Consider effects of concomitant 
medicinal products and assess and correct electrolyte 
imbalance that may prolong PR interval. Refer for 
cardiac observation and monitoring. Consider 
pacemaker placement if symptomatic AV block 
persists. If symptoms and the second-degree AV 
block resolve or if participants revert to 
asymptomatic first-degree AV block, resume 
lorlatinib at 1 reduced dose level.
Complete AV Block
Withhold lorlatinib. Consider effects of concomitant 
medicinal products and assess and correct electrolyte 
imbalance that may prolong PR interval. Refer for 
cardiac observation and monitoring. Pacemaker 
placement may be indicated for severe symptoms 
associated with AV block. If AV block does not 
resolve, placement of a permanent pacemaker may 
be considered.
If pacemaker placed, resume lorlatinib at full dose. If 
no pacemaker placed, resume lorlatinib at 1 reduced 
dose level only when symptoms resolve, and PR 
interval is less than 200 msec.
Other Adverse Reactions
Grade 1: Mild 
OR
Consider no dose modification or reduce by 1 dose 
level, as clinically indicated.
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Table 3.
Recommended Lorlatinib Dose Modifications for Adverse Reactions
Adverse Reactiona
Lorlatinib Dosing
Grade 2: Moderate
Greater than or equal to Grade 3: Severe
Withhold lorlatinib until symptoms resolve to less 
than or equal to Grade 2 or baseline. Then resume 
lorlatinib at 1 reduced dose level.
Abbreviations: AV=Atrioventricular; CTCAE=Common Terminology Criteria for Adverse Events; 
ECG=electrocardiogram;
HMG CoA=3-hydroxy-3-methylglutaryl coenzyme A; NCI=National Cancer Institute; ULN=upper limit of
normal.
a.
Grade categories are based on NCI CTCAE classifications.
b.
Lipid lowering therapy may include: HMG CoA reductase inhibitor, nicotinic acid, fibric acid 
derivatives, or ethyl esters of omega 3 fatty acids.
6.7. Intervention after the End of the Study
At the End of Trial a number of options for ensuring continued supply with lorlatinib will be 
considered based on the local availability of the treatment and local country laws/regulation.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a patient to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study to complete all remaining scheduled assessments.
See Table 3 for dose modification recommendations due to adverse events.
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined Appendix 6 or if the 
investigator believes that it is in best interest of the participant.
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using Fridericia’s formula (QTcF) after enrollment 
(Appendix 7), the investigator or qualified designee will determine if the participant can 
continue in the study and if any change in participant management is needed. This review of 
the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE.
If a clinically significant finding is identified after enrollment, the investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed.
See the schedule of activities (SoA) for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.
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Note that discontinuation of study intervention does not represent withdrawal from the study.
7.1.1. Temporary Discontinuation
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the Investigator.  
Doses may be held as needed until toxicity resolution.  Depending on when the adverse event 
resolved, a treatment interruption may lead to the participant missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed.  Doses omitted for toxicity are not replaced within the 
same cycle.  The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in Table 3 unless expressly agreed otherwise following 
discussion between the Investigator and the Sponsor.  If a dose reduction is applied in the 
same cycle, the participant will need to return to the clinic to receive new drug supply.
In the event of a treatment interruption for reasons other than treatment related toxicity (eg, 
elective surgery) lasting >1 week, treatment resumption will be decided in consultation with 
the Sponsor.
Participants not recovering from lorlatinib related toxicity within 42 days since last dose 
should discontinue lorlatinib treatment. 
If a treatment interruption continues beyond Day 21 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle.  Every effort should be 
made to maintain the tumor assessments scheduling as every 6 weeks (±1 week) or per local 
practice versus the date of Cycle 1 Day 1.
7.2. Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need 
to be completed.

The early discontinuation visit applies only to participants who are enrolled and then 
are prematurely withdrawn from the study.  Participants should be questioned 
regarding their reason for withdrawal.  The participant will be permanently 
discontinued both from the study intervention and from the study at that time.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records and notify the sponsor accordingly.
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
If the participant withdraws from the study and also withdraws consent (see below) 
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.

When a participant withdraws from the study because of an SAE, the SAE must be 
recorded on the case report form (CRF) and reported on the clinical trial serious 
adverse event (CT SAE) Report.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Reasons for withdrawal of study treatment may include:

Objective disease progression; 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Participant refused further treatment;

Study terminated by sponsor;

Death.
7.3. Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES

The investigator (or an appropriate delegate at the investigator site) must obtain a 
signed and dated ICF before performing any study-specific procedures.  

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may 
be circumstances outside the control of the investigator that may make it unfeasible to 
perform the test.  In these cases, the investigator must take all steps necessary to 
ensure the safety and well-being of the participant.  When a protocol-required test 
cannot be performed, the investigator will document the reason for the missed test 
and any corrective and preventive actions that he or she has taken to ensure that 
required processes are adhered to as soon as possible.  The study team must be 
informed of these incidents in a timely manner.
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
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
8.1. Efficacy Assessments
8.1.1. Tumor Assessments
Tumor assessments will include all known or suspected disease sites.  Computed tomography 
(CT) or MRI scans of Chest Abdomen Pelvis (CAP) and MRI of the brain will be performed 
at screening.  Gadolinium contrast enhanced MRI must be used for assessment of CNS 
lesions with contingent slices of 1 mm for lesions 5 mm – 10 mm in size, 5 mm for lesions 
greater than 10 mm.  Bone scans (or bone MRI if preferred by investigator) will be 
performed at baseline for all participants and repeated every 12 weeks on study only if 
evidence of bone metastases is observed at baseline (however, if a participant has bone 
involvement, assessment of those sites via appropriate modality is required every 6 weeks ±1 
week up to 24 months or progressive disease whichever occurred first).  For all tumor 
assessments, the method of assessment that was used at baseline should be the same method 
used throughout the study.  CT and MRI scans to be done at every 6 weeks ±1 week up to 
approximately 24 months (cycle 35) and then as per local clinical practice. Tumor assessment 
should be repeated at the end of treatment if more than 6 weeks have passed since the last 
evaluation. Tumor assessment should not be repeated at the end of treatment if progression 
occurs when the participant has shifted to the local clinical practice. Moreover, radiological 
tumor assessments will be conducted whenever disease progression is suspected (eg, 
symptomatic deterioration).
Assessment of response will be made using RECIST version 1.1 (Appendix 5).  
Confirmation of response will be required at least 4 weeks after initial response is observed.
All participants’ files and radiologic images must be available for source verification and for 
peer/independent central radiology review as determined by the sponsor. Instructions for 
submission of these images will be provided in the Study Reference Manual.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA and in the lorlatinib 
product information.  Unscheduled clinical laboratory measurements may be obtained at any 
time during the study to assess any perceived safety concerns.
8.2.1. Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems and ECOG 
status. Weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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8.2.2. Electrocardiograms

Triplicate 12-lead (with a 10-second rhythm strip).  ECG will be obtained as outlined 
in the SoA (see Section 1.3) using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 7 for QTc 
withdrawal criteria and any additional QTc readings that may be necessary.  Refer to 
Section 6.6 for PR interval prolongation/AV block.

At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes.

If at any of these time points the mean PR interval is prolonged (≥200 msec) or QTc 
is prolonged (≥501 msec), the ECGs should be re-evaluated by a qualified person at 
the institution for confirmation.

PR interval prolongation and AV block have been reported in participants receiving 
lorlatinib.  ECG will be monitored prior to initiating lorlatinib and monthly thereafter, 
particularly in participants with predisposing conditions to the occurrence of 
clinically significant cardiac events. Dose modification may be required for those 
participants who develop AV block (See Section 6.6).

ECG values of potential concern are listed in Appendix 7.
8.2.3. Echocardiograms/Multigated (MUGA) Acquisition Scan
Echocardiogram or MUGA will be performed at screening. Additional assessments may be 
performed as clinically indicated and according to lorlatinib product information.  LVEF 
decrease has been reported in participants receiving lorlatinib. In participants who develop 
relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF 
assessment, should be considered.  The same method should be used throughout the study.
For France and Germany, a transthoracic echocardiogram (TTE) will be performed every 
6 months (± 2 weeks) during treatment, and only at the end of treatment visit if the previous 
assessment was > 1 month. Pulmonary arterial pressure (PAP) will be assessed.
8.2.4. ECOG Performance Status
Refer to Appendix 9 for ECOG Performance Status Criteria.
8.2.5. Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA 
for the timing and frequency.

The use of lorlatinib has been associated with increases in serum cholesterol and 
triglycerides.  Serum cholesterol and triglycerides should be monitored before 
initiation of lorlatinib; 2, 4 and 8 weeks after initiating lorlatinib; and regularly 
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thereafter. Initiate or increase the dose of lipid-lowering medicinal products, if 
indicated (see Section 6.6).

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator, then the 
SAE or AE or dose modification must be recorded in the CRF.
8.2.6. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in women of childbearing potential 
(WOCBP) at the times listed in the SoA (Section 1.3).  Following a negative pregnancy test 
result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit prior to the participant’s receiving 
the study intervention.  Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise 
suspected), at the end of the study, and at follow-up.  Pregnancy tests may also be repeated if 
requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required.  In such cases, the participant must be excluded if the 
serum pregnancy result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE, or that caused the participant to discontinue 
the study intervention (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain the adequate 
supporting documentation, including laboratory tests and cardiac assessments, to elaborate 
the AEs and SAEs occurring during the course of the study and any subsequent safety 
follow-up. in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’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 participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section.
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 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the clinical trial SAE Report Form immediately and under no circumstance should 
this exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.
If a participant 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.
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SAEs occurring in a participant 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.
8.3.1.2. 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.
If a participant 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.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information 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 participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
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
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the SmPC and will notify the IRB/IEC, if 
appropriate according to local requirements.
8.3.5. Exposure 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.
8.3.5.1. Exposure During Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and until 35 and 98 
days for female and male participants, respectively after the last dose.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. 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.
8.3.5.3. 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 participant 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.
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8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
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
Medication errors include:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating participant.
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.
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.
8.4. Treatment of Overdose
For this study, any dose of lorlatinib greater than 100 mg within a 24-hour time period will 
be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.  There is no antidote for 
lorlatinib.
In the event of an overdose, the investigator should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE and given the dose dependent effect 
on PR interval, ECG monitoring is recommended.  
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3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with a SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic samples are not being collected in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
Banked biospecimen samples are not being collected in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Health Economics
Not applicable to this study.
9. STATISTICAL CONSIDERATIONS
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.
9.1. Estimands and Statistical Hypotheses
The primary objective of the study is to evaluate overall and intracranial anti-tumor activity 
of single-agent lorlatinib in participants with advanced ALK-positive NSCLC whose disease 
has progressed on alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) 
therapy, by showing a superiority of lorlatinib versus historical control, of which the ORR is 
≤30%.  The study will be considered to show this superiority if the lower limit of the 95% 
confidence interval around the estimated ORR excludes 30%.
Tumor responses and progressions will be evaluated as per RECIST V 1.1.
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9.1.1. Estimands
The primary estimand by ICR is the treatment effect of lorlatinib from time of first dose until 
progression is met or subsequent anti-cancer therapy is administered for all participants who 
receive at least one dose of lorlatinib without regard to discontinuation from treatment. 
Point estimates of ORR (defined as the percentage of participants with confirmed complete 
response [CR] or confirmed partial response [PR]) and confidence intervals (following the 
methodology outlined in Section 9.4.1) will be calculated.  Both CR and PR must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.
The definition of primary estimand also applies to the secondary endpoint of OR by INV, 
except that the treatment effect is based on INV.
The estimand for intracranial objective response (IC-OR) by ICR/INV is the intra cranial 
treatment effect of lorlatinib from time of first dose until intra cranial progression is met or 
subsequent anti-cancer therapy is administered for all participants who receive at least one 
dose of lorlatinib without regard to discontinuation from treatment. 
Point estimates of intracranial objective response rate (IC-ORR) by ICR/INV (defined as the 
percentage of participants with confirmed CR or confirmed PR in brain) and confidence 
intervals (following the methodology outlined in Section 9.4.1) will be calculated.  Both CR 
and PR in brain must be confirmed by repeat assessments performed no less than 4 weeks 
after the criteria for response are first met.
The estimand for TTR by ICR/INV is the treatment effect from the time of first dose to the
first date of OR (CR or PR) that is subsequently confirmed for responders to lorlatinib.  TTR 
is defined as the time from the date of first dose to the date of first documentation of 
confirmed OR (CR or PR).
The estimand for DOR by ICR/INV is the treatment effect from the first date of OR that is 
subsequently confirmed for responders to lorlatinib until progression or death, without regard 
to discontinuation from treatment unless new anti-cancer therapy is initiated or extended gap 
in tumor assessment is present prior to progression or death.  DOR is defined as the time 
from first documentation of confirmed OR (CR or PR) to the date of first documentation of 
progression of disease (PD) or death due to any cause, whichever occurs first.
The estimand for IC-DOR by ICR/INV is the treatment effect from the first date of OR that 
is subsequently confirmed in brain for responders to lorlatinib, until intra cranial progression 
or death, without regard to discontinuation from treatment unless new anti-cancer therapy is 
initiated or extended gap in tumor assessment is present prior to intra cranial progression or 
death.  IC-DOR is defined as the time from first documentation of confirmed OR in brain 
(CR or PR) to the date of first documentation of PD in brain or death due to any cause, 
whichever occurs first.
The estimand for TTP by ICR/INV is the treatment effect from the time of first dose for all 
participants who receive at least one dose of lorlatinib until progression, without regard to 
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discontinuation from treatment unless death occurs, new anticancer therapy is initiated or an 
extended gap in tumor assessment is present prior to progression. TTP is defined as the time 
from date of first dose to the date of the first documented PD due to any cause.
The estimand for PFS by ICR/INV is the treatment effect from the time of first dose for all 
participants who receive at least one dose of lorlatinib until progression or death due to any 
cause, without regard to discontinuation from treatment unless new anticancer therapy is 
initiated or an extended gap in tumor assessment is present prior to progression or death. PFS 
is defined as the time from date of first dose to the date of the first documented disease 
progression or death due to any cause, whichever occurs first.
9.2. Sample Size Determination
The primary endpoint is Objective tumor response assessed by RECIST version 1.1 per ICR. 
Analysis of tumor response will be based on both Overall tumor response and on Intra-
Cranial tumor response. 
OR is defined as a confirmed CR or confirmed PR from the first dose of study treatment until 
disease progression, start of anticancer therapy or death due to any cause. Both CR and PR 
must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.
ORR is defined as the proportion of treated participants with confirmed CR or confirmed PR 
per ICR assessment and will be estimated together with its 2-sided exact 95% CI (using an 
exact Clopper-Pearson CI).
According to literature, platinum-based doublet chemotherapy in patients with ALK + 
NSCLC refractory to second generation TKIs has an objective response rate of 
approximately 30%.20 Setting as target for lorlatinib a response rate of about 43% (as 
observed in cohort EXP-3B of phase 2 portion of study B7461001), a sample size of 
60 participants would result in an exact two-sided 95% CI of the ORR with lower limit of the 
CI greater than 30%.  In order to compensate for a potential 15% drop out rate (participants 
with death prior to first post-baseline assessment, inadequate baseline assessment, new anti-
cancer therapy started prior to first post-baseline assessment, post-baseline disease 
assessments missing), the overall sample size for the study is set to 70 participants. 
The study will be considered to have met its primary endpoint if the lower limit of the 95% 
confidence interval around the estimated ORR excludes 30%.
9.3. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF
Intent to Treat (ITT)/Safety
All enrolled participants who take at least 1 dose of lorlatinib
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Population
Description
Per Protocol Population:
Participants with CNS 
metastases based on 
Independent Central Review
Subset of the ITT analysis set including only participants with CNS 
metastases at study entry (i.e. with Lesions having Disease Site=Brain) 
according to Independent Central Review
Per Protocol Population:
Participants with CNS 
metastases based on 
Investigator Assessment
Subset of the ITT analysis set including only participants with CNS 
metastases at study entry (i.e. with Lesions having Disease Site=Brain) 
according to Investigator Assessment
9.4. Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints.
9.4.1. Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Confirmed OR by ICR 

Population: ITT
Using an exact method based on binomial distributions, estimate the 
confirmed ORR by ICR and corresponding two-sided 95% CI, 
based on OR from the time of first dose until progression is met or 
subsequent anti-cancer therapy is administered without regard to 
discontinuation from treatment. Participants with death prior to first 
post-baseline assessment, inadequate baseline assessment, new anti-
cancer therapy started prior to first post-baseline assessment, and all 
post-baseline disease assessments missing will be considered as 
non-responders.  
Secondary
Confirmed OR by INV 

Population: ITT
Use the same statistical analysis methods as for the primary 
endpoint except that the treatment effect is based on INV.
Confirmed IC-OR by ICR

Population: Per protocol population of participants with CNS 
metastases based on Independent Central Review
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Endpoint
Statistical Analysis Methods
Using an exact method based on binomial distributions, estimate the 
confirmed IC-ORR by ICR and corresponding two-sided 95% CI, 
based on intra cranial OR from the time of first dose until intra 
cranial progression is met or subsequent anti-cancer therapy is 
administered without regard to discontinuation from treatment. 
Participants with death prior to first post-baseline assessment, 
inadequate baseline assessment, new anti-cancer therapy started 
prior to first post-baseline assessment, and all post-baseline disease 
assessments missing will be considered as non-responders.  
TTR by ICR/INV and IC-TTR by ICR/INV

TTR is defined as the time from first dose to first documentation of 
objective tumor response (CR or PR) that is subsequently 
confirmed.  For patients whose OR proceeds from PR to CR, the 
onset of PR is taken as the onset of response.  TTR will only be 
calculated for the subgroup of patients with a confirmed objective 
tumor response.  
All the analyses will be repeated also for Time to Intracranial 
Response (IC-TTR) considering patients with intracranial response 
(i.e. Best Overall Intracranial Response as confirmed Complete 
Response (CR) or confirmed Partial Response (PR) considering 
only the Lesions having Disease Site=Brain).  
TTR and IC-TTR will be summarized based on both ICR and 
derived investigator assessments using descriptive statistics.
DOR by ICR/INV

Using the Kaplan-Meier method, estimate its associated statistics on 
DOR (including the median DOR with two-sided 95% CI) for 
responders to lorlatinib, without regard to discontinuation from 
treatment unless new anti-cancer therapy is initiated or extended gap 
in tumor assessment is present prior to progression or death. DOR is 
defined as the time from first documentation of OR (CR or PR) that 
is subsequently confirmed to the date of first documentation of PD 
or death due to any cause, whichever occurs first. 
This analysis is based on responders only from the ITT population. 
Participants with an event more than 12 weeks (24 weeks post the 
first 42 weeks) after the last adequate tumor assessment will be 
censored on the date of the last adequate tumor assessment prior to 
the gap that documented no progression. If a new anti-cancer 
therapy starts prior to an event, the participant will be censored on 
the date of the last adequate tum or assessment that documented no 
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Endpoint
Statistical Analysis Methods
progression prior to start of the new anti-cancer therapy. The CI for 
the median DOR will be calculated according to Brookmeyer and 
Crowley method.
IC-DOR by ICR/INV

Using the Kaplan-Meier method, estimate its associated statistics on 
IC-DOR (including the median IC-DOR with two-sided 95% CI) for 
intra cranial responders to lorlatinib, without regard to 
discontinuation from treatment unless new anti-cancer therapy is 
initiated or extended gap in IC tumor assessment is present prior to 
progression or death. IC-DOR is defined as the time from first 
documentation of IC-OR (CR or PR) that is subsequently confirmed 
to the date of first documentation of intra cranial PD or death due to 
any cause, whichever occurs first. 
This analysis is based on intra cranial responders only from 
Participants with CNS metastases populations. Participants with an 
event more than 12 weeks (24 weeks post the first 42 weeks) after 
the last adequate tumor assessment will be censored on the date of 
the last adequate tumor assessment prior to the gap that documented 
no progression. If a new anti-cancer therapy starts prior to an event, 
the participant will be censored on the date of the last adequate 
tumor assessment that documented no progression prior to start of 
the new anti-cancer therapy. The CI for the median DOR will be 
calculated according to Brookmeyer and Crowley method.
TTP by ICR/INV

Using the Kaplan-Meier method, estimate its associated statistics on 
TTP (including the median TTP with two-sided 95% CI, the TTP 
rates at clinically meaningful timepoints with two-sided 95% CI) for 
all participants who received at least one dose of lorlatinib without 
regard to discontinuation from treatment unless death occurs, new 
anti-cancer therapy is initiated or extended gap in tumor assessment
is present prior to progression. TTP is defined as the time from date 
of first dose to the date of the first documented PD. 
This analysis is based on ITT population. Participants with an event 
more than 12 weeks (24 weeks post the first 42 weeks) after the last 
adequate tumor assessment will be censored on the date of the last 
adequate tumor assessment prior to the gap that documented no 
progression. If the participant dies before progression, the 
participant will be censored on the date of death. If a new anti-
cancer therapy starts prior to an event, the participant will be 
censored on the date of the last adequate tumor assessment that 
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Endpoint
Statistical Analysis Methods
documented no progression prior to start of the new anti-cancer 
therapy. Participants with inadequate baseline assessment or with no 
adequate post-baseline tumor assessments within 12 weeks after the 
start date will be censored on the start date, unless the participant
dies within 12 weeks of the start date, in which case, the patient will 
be censored on date of death. The CI for the median TTP will be 
calculated according to Brookmeyer and Crowley method, and the 
CIs for the survival function estimates at the timepoints will be 
derived using the log(-log) method.
PFS by ICR/INV

Using the Kaplan-Meier method, estimate its associated statistics on 
PFS (including the median PFS with two-sided 95% CI, the PFS 
rates at clinically meaningful timepoints with two-sided 95% CI) for 
all participants who received at least one dose of lorlatinib without 
regard to discontinuation from treatment unless new anti-cancer 
therapy is initiated or an extended gap in tumor assessment is 
present prior to progression or death. PFS is defined as the time 
from date of first dose to the date of the first documented PD or 
death due to any cause, whichever occurs first. 
This analysis is based on ITT population. Participants with an event 
more than 12 weeks (24 weeks post the first 42 weeks) after the last 
adequate tumor assessment will be censored on the date of the last 
adequate tumor assessment prior to the gap that documented no 
progression. If a new anti-cancer therapy starts prior to an event, the 
participant will be censored on the date of the last adequate tumor 
assessment that documented no progression prior to start of the new 
anti-cancer therapy. Participants with inadequate baseline 
assessment or with no adequate post-baseline tumor assessments
within 12 weeks after the start date will be censored on the start 
date, unless the participant dies within 12 weeks of the start date, in 
which case, death will be an event on date of death. The CI for the 
median PFS will be calculated according to Brookmeyer and 
Crowley method, and the CIs for the survival function estimates at 
the timepoints will be derived using the log(-log) method.
9.4.2. Safety Analyses
All safety analyses will be performed on the Safety Population.
Drug exposure will be summarized using descriptive statistics.
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All AEs will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). The investigator will classify the severity of AEs using the CTCAE v4.03. A 
treatment emergent AE (TEAE) is defined as any event that occurs for the first time during 
the on-treatment period or AEs that were observed prior to the start of study treatment but 
increased in severity during the on-treatment period. Only TEAEs with an onset date prior to 
date of last dose + 28 days or the date of initiation of a new anti-cancer therapy (whichever 
occurs first) will be tabulated in summary tables. All data will be listed.
The number and percentage of participants with AEs will be summarized by MedDRA 
system organ class, preferred term, relationship to study intervention, and severity. A by-
participant listing will be provided for those participants who experience an SAE, including 
death, or experience an AE associated with discontinuation of study intervention.
9.5. Interim Analyses
No interim analysis is planned for this study.
9.5.1. Data Monitoring Committee (DMC)
This study will not use a data monitoring committee.
9.5.2. Independent Central Radiological Review
An independent core imaging laboratory will be used in this study. All sites will be required 
to submit images to the core imaging laboratory for ICR as soon as they are performed at the 
site so that imaging scans may be read in real time. The requirements of submitting images 
will be provided to sites by the core imaging laboratory.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICF, SmPC, and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor and submitted to an IRB/IEC 
by the investigator and reviewed and approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
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.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
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10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.

The investigator must ensure that each study participant is fully informed about the 
nature and objectives of the study, the sharing of data related to the study and possible 
risks associated with participation, including the risks associated with the processing 
of the participant’s personal data. The participant must be informed that his/her 
personal study-related data will be used by the sponsor in accordance with local data 
protection law. The level of disclosure must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The investigator further must ensure that each study participant is fully informed 
about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
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10.1.4. Data Protection

All parties will comply with all applicable laws, including laws regarding the 
implementation of organizational and technical measures to ensure protection of 
participant data.

Participants’ personal data will be stored at the study site in encrypted electronic 
and/or paper form and will be password protected or secured in a locked room to 
ensure that only authorized study staff have access.  The study site will implement 
appropriate technical and organizational measures to ensure that the personal data can 
be recovered in the event of disaster.  In the event of a potential personal data breach, 
the study site shall be responsible for determining whether a personal data breach has 
in fact occurred and, if so, providing breach notifications as required by law.

To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical 
code. Any participant records or datasets that are transferred to the sponsor will 
contain the numerical code; participant names will not be transferred. All other 
identifiable data transferred to the sponsor will be identified by this single, 
participant-specific code. The study site will maintain a confidential list of 
participants who participated in the study, linking each participant’s numerical code 
to his or her actual identity. In case of data transfer, the sponsor will protect the 
confidentiality of participants’ personal data consistent with the Clinical Study 
Agreement and applicable privacy laws. 
10.1.5. Committees Structure
See Section 9.5.2.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study 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 addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
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 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally 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.
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PCD is defined as the date that the final participant 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 prespecified protocol or was terminated.
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 [CSR] synopses in which any 
data that could be used to identify individual participants have 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.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods.  Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
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investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.

The investigator must ensure that the CRFs are securely stored at the study site in 
encrypted electronic and/or paper form and are password protected or secured in a 
locked room to prevent access by unauthorized third parties.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits 
and possible audits or inspections and that sufficient time is devoted to the process.

Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the clinical monitoring plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. The investigator must ensure that the records continue to 
be stored securely for so long as they are maintained.

When participant data are to be deleted, the investigator will ensure that all copies of 
such data are promptly and irrevocably deleted from all systems.

The investigator(s) will notify sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will 
cooperate with sponsor or its agents to prepare the investigator site for the inspection 
and will allow sponsor or its agent, whenever feasible, to be present during the 
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inspection.  The investigator site and investigator will promptly resolve any 
discrepancies that are identified between the study data and the participant's medical 
records.  The investigator will promptly provide copies of the inspection findings to 
sponsor or its agent.  Before response submission to the regulatory authorities, the 
investigator will provide sponsor or its agents with an opportunity to review and
comment on responses to any such findings.
10.1.8. Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the clinical monitoring 
plan.
10.1.9. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to contract 
research organization (CRO) if requested to do so by the responsible IRB/IEC or if such 
termination is required to protect the health of Study Participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol the contract will control as to termination rights.
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10.1.10. Publication Policy

The results of this study may be published or presented at scientific meetings by the 
Investigator after publication of the overall study results or one year after end of the 
study (or study termination), whichever comes first. 

The investigator agrees to refer to the primary publication in any subsequent 
publications such as secondary manuscripts, and submit all manuscripts or abstracts 
to the sponsor 30 days before submission. This allows the sponsor to protect 
proprietary information and to provide comments and the Investigator will, on 
request, remove any previously undisclosed confidential information before 
disclosure, except for any study- or Pfizer intervention-related information necessary 
to the appropriate scientific presentation or understanding of the study results.

For all publications relating to the study, the Investigator will comply with recognized 
ethical standards concerning publications and authorship, including those established 
by the International Committee of Medical Journal Editors.

The sponsor will comply with the requirements for publication of the overall study 
results covering all Investigator sites. In accordance with standard editorial and 
ethical practice, the sponsor will support publication of multicenter studies only in 
their entirety and not as individual site data. In this case, a coordinating investigator 
will be designated by mutual agreement.

Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors 
authorship requirements.

If publication is addressed in the clinical study agreement, the publication policy set 
out in this section will not apply.
10.1.11. 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 team SharePoint site.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant 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 
participant’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.  For sites other than 
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a Pfizer clinical research unit (CRU), the contact number is not intended for use by the 
participant directly, and if a participant calls that number, he or she will be directed back to 
the investigator site.
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10.2. Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.

Pregnancy Testing 

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

For details of timing of recommended pregnancy testing see Section 8.2.6
Table 4.
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Hemoglobin
White blood cell (WBC) count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry1
Blood urea 
nitrogen (BUN) or 
Urea
Potassium
Aspartate 
Aminotransferase
(AST)
Total bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)
Phosphorus or 
Phosphate
Glucose (fasting)
Total Calcium
Alk Phos
Serum total 
amylase2
Uric Acid
Magnesium
Albumin
Serum lipase
Other Screening 
Tests

Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)

Lipids:  Total Cholesterol, low density lipoproteins (LDL), high density 
lipoproteins (HDL), Triglycerides.
The results of each test must be entered into the CRF at screening only or C1D1 if 
baseline assessment not performed within 7 days before.
NOTES:
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 7.1 and Appendix 6. All events of ALT 3 × upper limit of 
normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international 
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Table 4.
Protocol Required Safety Laboratory Assessments
normalized ratio (INR) >1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law), 
must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).
2.
Pancreatic isoenzyme required if serum total amylase not within normal limits per local institutional 
ranges.
Investigators must document their review of each laboratory safety report.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.

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.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity
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
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

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).
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF
and for reporting serious adverse 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 study during pregnancy or breastfeeding, and occupational 
exposure.  
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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
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
None
All (And exposure during 
pregnancy [EDP]
supplemental form for 
EDP)  

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of CT SAE Report Form
/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:
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GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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
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" and "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.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
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
Contacts for SAE reporting can be found in the investigator site file.
SAE Reporting to Pfizer Safety via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to Pfizer Safety.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the investigator site file.
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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above conditions can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female

A postmenopausal state is defined as age 60 or older or no menses for 12 months 
without an alternative medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT).

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
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P F -0 6 4 6 3 9 2 2 ( L orlati ni b)
B 7 4 6 1 0 2 7
Fi nal Pr ot oc ol, 2 2 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6
C o ntrace pti o n G ui da nce:
C o ntr ace pti o n –
f or w o me n
Fe male partici pa nts m ust use hi g hl y effecti ve c o ntrace pti o n w hile ta ki n g st u d y  i nter ve nti o n 
a n d f or at least 3 5 d a y s after st o p pi n g st u dy i nter ve nti o n.
L orlati ni b ma y  re d uce t he effecti ve ness of h or m o nal c o ntrace pti ve met h o ds; t heref ore, 
h or m o nal c o ntrace pti ves ma y  n ot be c o nsi dere d hi g hly effecti ve. If h or m o nal c o ntrace pti o n 
is u na v oi da ble it m ust be use d i n c o m bi nati o n wit h a c o n d o m.
Hi g hl y Effecti ve Met h o ds T h at H a ve L o w User De pe n de nc y 
1.
I ntra uteri ne de vice (I U D).
2.
Bilateral t u bal occl usi o n.
3.
Vasect o mize d part ner .

Vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti ve met h o d pr o vi de d t hat 
t he part ner is t he s ole se x ual part ner of t he W O C B P a n d t he a bse nce of s perm 
has bee n c o nfir me d.  If n ot, a n a d diti o nal hi g hl y effecti ve met h o d of 
c o ntrace pti o n s h o ul d be use d.  T he s per mat o ge nesis c y cle is a p pr o xi matel y 9 0 
da y s.
C o ntr ace pti o n –
f or me n
Male partici pa nts m ust use a c o n d o m w hile ta ki n g st u d y i nter ve nti o n a n d f or a t least 9 8 d a y s 
after st o p pi n g st u d y i nter ve nti o n. 
C ollecti o n of Pre g na nc y  Inf or mati o n:
F or b ot h u na p pr o ve d/ u nlice nse d pr o d ucts a n d f or mar kete d pr o d ucts, a n E D P occ urs if:

A fe male bec o mes, or is f o u n d t o be, pre g na nt eit her w hile recei vi n g or ha vi n g 
bee n e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he st u d y 
i nter ve nti o n; or t he fe male bec o mes or is f o u n d t o be pre g na nt after disc o nti n ui n g 
a n d/ or bei n g e x p ose d t o t he st u d y i nter ve nti o n;

A n e xa m ple of e n vir o n me ntal e x p os ure w o ul d be a case i n v ol vi n g direct 
c o ntact wit h a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a n urse re p orts t hat s he 
is pre g na nt a n d has bee n e x p ose d t o c he m ot hera pe utic pr o d ucts).

A male has bee n e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o 
t he st u d y i nter ve nti o n pri or t o or ar o u n d t he ti me of c o nce pti o n a n d/ or is e x p ose d 
d uri n g his part ner’s pre g na nc y . 
If a partici pa nt or partici pa nt’s part ner bec o mes or is f o u n d t o be pre g na nt d uri n g t he 
partici pa nt’s treat me nt wit h t he st u d y i nter ve nti o n, t he i n vesti gat or m ust re p ort t his 
0 9 0 1 7 7 e 1 9 2 a 9 4 2 1 3\ A p pr o v e d\ A p pr o v e d O n: 2 7- J a n- 2 0 2 0 1 0: 5 6 ( G M T)


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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 
participant 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 study intervention.
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 participant with the Pregnant Partner Release of Information Form to deliver 
to his partner.  The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner.
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10.5. Appendix 5: RECIST (version 1.1) Tumor Assessment Criteria21
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or not, according to the criteria summarized below:
Measurable Lesions
Lesions that can 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 for lesions other than lymph nodes and assessed by CT scan (CT scan slice 
thickness no greater than 5 mm)

10 mm for lesions assessed clinically by caliper measurement (lesions which cannot 
be accurately measured with calipers should be recorded as non-measurable).

20 mm for lesions assessed by chest X-ray.

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
Non-measurable Lesions 
Non-measurable lesions include small lesions (longest diameter <10 mm or pathological 
lymph nodes with a ≥ 10 but < 15 mm short axis) as well as truly non-measurable lesions.  
Truly non-measurable lesions include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam and not measurable by reproducible imaging techniques.
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed. 
Special Considerations Regarding Specific Lesions 
Bone lesions:

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above.

Blastic bone lesions are non-measurable. 
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Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.
Solitary lesions:
If a measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). 
The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter of all target lesions will be calculated and recorded as the baseline sum diameter to 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment. 
One exception to the above described approach is related to pathological lymph nodes.  
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of ≥ 15 mm by CT scan is met.  Only the short axis of 
these nodes will contribute to the baseline sum.  Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal).  The smaller 
of these measures is the short axis. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
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All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.  In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on 
the case record form (eg ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
Definition of Tumor Response 
Target Lesions
Response in target lesions is defined as follows:

Complete Response (CR): disappearance of all target lesions. 

Partial Response (PR): at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  The appearance of one 
or more new lesions is also considered a sign of progression.

Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes.  As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the CRF.
Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Response in non-target lesions is defined as follows:

Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
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
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression).
Cytology, histology 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to 
be a potential adverse effect of treatment (eg taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response or stable disease and progressive 
disease.
For patients having effusions or ascites, only cases having cytological proof of malignancy 
should be recorded on the CRF.  Effusions that have not been evaluated using cytology or 
were found to be non-malignant should not be recorded on the CRF. 
New Lesions 
The appearance of new malignant lesions indicates PD. New lesion should be unequivocal 
(eg not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor). If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease. If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan. 
The use of fluorodeoxyglucose (FDG)-PET is sometimes reasonable to complement a CT 
scan assessment of a PD (particularly for possible ‘new’ disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up 

No FDG-PET at baseline and a positive FDG-PET at follow- up: if the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.
Confirmation of Tumor Response 
Confirmation of response is required for non-randomized trials with primary endpoint of 
response, but is not required in randomized studies since the control arm serves as 
appropriate means of interpretation of data.
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Determination of Overall Response by RECIST v 1.1 
When both target and non-target lesions are present, individual assessments will be recorded 
separately. The overall assessment of response will involve all parameters as depicted in 
Table 5.
Table 5.
Response Evaluation Criteria in Solid Tumors
Target lesions
Non-target lesions
New
Lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
not all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Best overall response
The best overall response is determined once all the data for the patient is known.  Best 
response in trials in which confirmation of complete or partial response is not required (ie. 
randomized trials) is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response of PR).  When SD is believed to be the best response, it must also 
meet the protocol specified minimum time from baseline.  If the minimum time is not met 
when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments.  For example, a patient who has SD at first assessment, PD at 
second and does not meet minimum duration for SD, will have a best response of PD.  The 
same patient lost to follow-up after the first SD assessment would be considered non-
evaluable. 
When confirmation of CR and PR is required (ie, non-randomized trials with primary 
endpoint of response), the best overall response is defined according to the tumor response 
along the study.  Complete or partial responses may be claimed only if the criteria for each 
are met at a following time point as specified in the protocol (generally 4 weeks later).
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
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objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 
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 participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants 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 
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 
participant’s individual baseline values and underlying conditions.  Participants 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:

Participants 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 participants 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 participant 
should return to the investigator site and be evaluated as soon as possible, preferably within 
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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 for suspected cases of 
Hy’s Law, additional 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, and alkaline phosphatase. 
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 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) and collection of serum sample for acetaminophen drug and/or protein 
adduct levels 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 test (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.
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >220 msec.

New prolongation of QTcF to >470 msec (absolute) or by 60 msec from 
baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole 3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).
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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.
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10.8. Appendix 8: Country-specific Requirements
France specific requirements
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 study intervention.
3. Inspections
The investigator(s) will notify Pfizer or its service provider immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with Pfizer or its service provider to prepare the study site for the inspection and will allow 
Pfizer or its service provider (if not prohibited by law) to be present during the inspection. 
The study 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 service provider. Before response 
submission to the regulatory authorities, the investigator will provide Pfizer or its service 
provider with an opportunity to review and comment on responses to any such findings.
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10.9. Appendix 9: 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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10.10. Appendix 10: Abbreviations
Abbreviation
Term
AE
adverse event
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophils count
AST
aspartate aminotransferase
AV
atrioventicular
BCRP
breast cancer resistance protein
bpm
beats per minute
BID
twice daily
BUN
blood urea nitrogen
CAP
chest abdomen pelvis
C1D1
cycle 1 day 1
CI
confidence interval
CIOMS
Council for International Organizations of 
Medical Sciences
CFR
code of federal regulations
CK
creatine kinase
CM
carcinomatous meningitis
CMA
conditional marketing authorization
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
case report form
CRM
continual reassessment method
CRO
contract research organization
CRU
clinical research unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse 
Events
CT SAE
clinical trial serious adverse event
CYP
cytochrome P450
DCIS
ductal carcinoma in situ
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
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Abbreviation
Term
DOR
duration of response
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EML4
echinoderm microtubule-associated 
protein-like 4
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United 
States)
FDG
fluorodeoxyglucose
FISH
fluorescence in situ hybridization
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high density lipoprotein
HER2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and 
Accountability Act
HIV
human immunodeficiency virus
HMG CoA
3-hydroxy-3-methylglutaryl coenzyme
HRT
hormone replacement therapy
IB
investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IC
intracranial
IC-OR
intracranial objective response
IC-ORR
intracranial objective response rate
IC-TTR
time to intracranial response
ICR
independent central review 
ID
identification
IHC
immunohistochemistry
ILD
interstitial lung disease
IND
investigational new drug application
INR
international normalized ratio
INV
investigator
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Abbreviation
Term
IP
investigational product
IRB
institutional review board
IRT
interactive response technology
ITT
intent to treat
IVR
interactive voice response system
IWR
interactive web response system
KRAS
Kirsten Rat Sarcoma
LDL
low density protein
LFT
liver function test
LPFV
last patient first visit
LM
leptomeningeal meningitis
LVEF
left ventricular ejection fraction
MEDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multigated acquisition
NCI
National Cancer Institute
NE
inevaluable
NSCLC
non-small cell lung cancer
NTI
narrow therapeutic index
OR
objective response
ORR
objective response rate
OS
overall survival
PAES
post authorization efficacy study
PAP
pulmonary arterial pressure
PD
progression of disease
PCD
primary completion date
PET
positron emission tomography
PFS
progression-free survival
P-gp
permeability glycoprotein
PI
principal investigator
PR
partial response
PS
performance status
PT
prothrombin time
PVC
premature ventricular complexes
PXR
human pregnane-X-receptor 
QD
once daily
QTcF
Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumor
ROS1
c-ROS oncogene-1
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SmPC
summary of product characteristics
SoA
schedule of activities
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Abbreviation
Term
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse 
reactions
TBili
total bilirubin
TEAE
treatment emergent adverse event
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
TPS
tumor proportion score
TTE
trans thoracic echocardiogram
TTP
time to tumor progression
TTR
time to tumor response
ULN
upper limit of normal
US
United States
WBC
white blood cell 
WOCBP
women of childbearing potential
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11. REFERENCES
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Atlanta, GA: American Cancer Society; 2011.
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3. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK 
fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-6.
4. Sasaki T, Rodig SJ, Chirieac LR, et al. The biology and treatment of EML4-ALK non-
small cell lung cancer. Eur J Cancer. 2010;46(10):1773-80.
5. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based 
chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a 
randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-29.
6. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-
Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829-38.
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non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 
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cancer. N Engl J Med. 2014;370(13):1189-97.
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Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov. 
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12. Keytruda [SmPC]. The Netherlands: Merck Sharp and Dohme BV; 2015.
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Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-301.
14. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy 
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20. Lin JJ, Schoenfeld AJ, Zhu VW, et al. Efficacy of platinum-pemetrexed combination 
chemotherapy in ALK+ non-small cell lung cancer refractory to second-generation ALK 
TKIs. American Society of Clinical Oncology; 2019.
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SAP_001.pdf: 
Protocol B7461027 (PF-06463922 - Lorlatinib) Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 4.0 Statistical Analysis Plan Template 01-Nov-2018 
PFIZER CONFIDENTIAL  
Page 1 
TMF Doc ID: 98.03 
 
 
 
Protocol B7461027 
 
 
 
 
Single-Arm Study of Lorlatinib in Participants with Anaplastic Lymphoma Kinase 
(ALK)-Positive Non-Small Cell Lung Cancer (NSCLC) Whose Disease Progressed 
After One Prior Second-Generation ALK Tyrosine Kinase Inhibitor (TKI) 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
1 
 
Date:  
11 Oct 2019 
 
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Protocol B7461027 (PF-06463922 - Lorlatinib) Statistical Analysis Plan 
 
 
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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................4 
APPENDICES ...........................................................................................................................4 
1. VERSION HISTORY ............................................................................................................5 
2. INTRODUCTION .................................................................................................................5 
2.1. Study Objectives, Endpoints, and Estimands ............................................................5 
2.1.1. Primary Estimand .........................................................................................8 
2.1.2. Secondary Estimands ....................................................................................9 
2.2. Study Design ...........................................................................................................11 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................12 
3.1. Primary Endpoint ....................................................................................................12 
3.1.1. Confirmed OR by ICR ................................................................................12 
3.2. Secondary Endpoints ...............................................................................................12 
3.2.1. Confirmed OR by INV ...............................................................................12 
3.2.2. Confirmed IC-OR by ICR/INV ..................................................................12 
3.2.3. TTR by ICR/INV ........................................................................................13 
3.2.4. IC-TTR by ICR/INV ...................................................................................13 
3.2.5. DoR by ICR/INV ........................................................................................13 
3.2.6. IC-DoR by ICR/INV ...................................................................................13 
3.2.7. PFS by ICR/INV .........................................................................................13 
3.2.8. TTP by ICR/INV ........................................................................................13 
3.3. Other Endpoints .......................................................................................................14 
3.4. Baseline Variables ...................................................................................................14 
3.5. Safety Endpoints .....................................................................................................14 
3.5.1. Adverse Events ...........................................................................................14 
3.5.2. Vital Signs – Weight ...................................................................................15 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................15 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................15 
5.1. Hypotheses and Decision Rules ..............................................................................16 
5.1.1. Hypotheses and Sample Size ......................................................................16 
5.1.2. Decision Rules ............................................................................................16 
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5.2. General Methods .....................................................................................................16 
5.2.1. Data handling after the cut-off date ............................................................16 
5.2.2. Definition of study day ...............................................................................16 
5.2.3. Definition of Cycle and Cycle Day ............................................................16 
5.2.4. Date of last contact .....................................................................................17 
5.2.5. Measurable Disease ....................................................................................18 
5.2.6. TumorAssessment Date ..............................................................................18 
5.2.7. Sum of Lesion Diameters ...........................................................................18 
5.2.8. Adequate Baseline Tumor Assessment ......................................................19 
5.2.9. Adequate Post Baseline Tumor Assessment...............................................19 
5.2.10. Unscheduled Assessments ........................................................................19 
5.2.11. Standard Derivations and Reporting Conventions ...................................19 
5.2.12. Analyses for Binary Endpoints .................................................................19 
5.2.13. Analyses for Continuous Endpoints .........................................................20 
5.2.14. Analyses for Categorical Endpoints .........................................................20 
5.2.15. Analyses for Time-to-Event Endpoints ....................................................20 
5.3. Methods to Manage Missing Data ..........................................................................20 
5.3.1. Missing Dates .............................................................................................20 
5.3.2. Missing Toxicity Grade of Adverse Events ................................................23 
6. ANALYSES AND SUMMARIES ......................................................................................24 
6.1. Primary Endpoint ....................................................................................................24 
6.1.1. Confirmed OR by ICR ................................................................................24 
6.2. Secondary Endpoints ...............................................................................................26 
6.2.1. Confirmed OR by INV ...............................................................................26 
6.2.2. Confirmed IC-OR by ICR/INV ..................................................................26 
6.2.3. TTR by ICR/INV ........................................................................................26 
6.2.4. IC-TTR by ICR/INV ...................................................................................26 
6.2.5. DoR by ICR/INV ........................................................................................27 
6.2.6. IC-DoR by ICR/INV ...................................................................................27 
6.2.7. PFS by ICR/INV .........................................................................................28 
6.2.8. TTP by ICR/INV ........................................................................................30 
6.3. Other Endpoint(s) ....................................................................................................32 
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6.4. Subset Analyses .......................................................................................................32 
6.5. Baseline and Other Summaries and Analyses .........................................................32 
6.5.1. Baseline Summaries ....................................................................................32 
6.5.2. Study Conduct and Participant Disposition ................................................34 
6.5.2.1. Participant Disposition ..............................................................34 
6.5.2.2. Protocol Deviations ...................................................................34 
6.5.3. Study Treatment Exposure .........................................................................35 
6.5.3.1. Exposure to lorlatinib ................................................................35 
6.5.3.2. Dose Reductions and Interruptions ...........................................35 
6.5.4. Concomitant Medications and Nondrug Treatments ..................................36 
6.5.5. Subsequent Anti-Cancer Therapies/Procedures .........................................37 
6.6. Safety Summaries and Analyses .............................................................................37 
6.6.1. Adverse Events ...........................................................................................37 
6.6.1.1. Basic Results .............................................................................39 
6.6.1.2. Adverse Events of Special Interest ............................................39 
6.6.2. Deaths .........................................................................................................39 
6.6.3. Vital Signs – Weight ...................................................................................39 
7. INTERIM ANALYSES .......................................................................................................40 
7.1. Introduction .............................................................................................................40 
7.2. Interim Analyses and Summaries ............................................................................40 
8. APPENDICES .....................................................................................................................41 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ..............................................................................................5 
Table 2. 
Outcome and event dates for PFS analyses ..........................................................29 
Table 3. 
Censoring Reasons and Hierarchy for PFS analyses ............................................29 
Table 4. 
Outcome and event dates for TTP analyses ..........................................................31 
Table 5. 
Censoring Reasons and Hierarchy for TTP analysis ............................................32 
 
APPENDICES 
Appendix 1. List of Abbreviations...........................................................................................41 
 
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1. VERSION HISTORY 
Table 1. 
Summary of Changes  
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
XX Sep 2019 
Original 
31 Jul 2019 
NA 
NA 
 
2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B7461027.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment. 
The analyses of this study will include all data up to a data cut-off date after End of Trial, 
defined as 12 calendar months after the “last patient first visit” (LPFV) date in the study. 
All summaries and analyses will include all data pertaining to visits/assessments performed 
up to and including the data cut-off date. 
2.1. Study Objectives, Endpoints, and Estimands 
Study B7461027 is a post-authorization efficacy study (PAES) requested by EMA in order to 
obtain additional data on the activity of lorlatinib for the treatment of patients with 
ALK-positive metastatic non-small-cell lung cancer whose disease has progressed after 
alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy. 
The study focuses mainly on evaluation of antitumor activity, with analysis of safety data 
limited to Adverse Events.   
Objectives 
Estimands 
Endpoints 
Primary 
 
 
• To assess Overall and 
Intracranial Response 
Rate of single-agent 
lorlatinib in participants 
with advanced ALK-
positive NSCLC whose 
disease has progressed on 
alectinib or ceritinib as 
the first ALK tyrosine 
kinase inhibitor (TKI) 
therapy 
• The primary estimand is 
the treatment effect of 
lorlatinib by independent 
central review (ICR) from 
time of first dose until 
progression is met or 
subsequent anti-cancer 
therapy is administered 
for all participants who 
receive at least one dose 
of lorlatinib without 
regard to discontinuation 
from treatment; all 
• Confirmed Objective 
Tumor Response assessed 
by Response Evaluation 
Criteria in Solid Tumor 
(RECIST) version 1.1 per 
ICR 
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response assessments 
regardless of gaps in 
tumor assessments are 
considered 
Secondary 
 
 
• To assess secondary 
measures of clinical 
efficacy  
• The estimand for 
Objective Response (OR) 
by investigator (INV) 
follows the estimand 
specified for the primary 
endpoint except that the 
treatment effect is based 
on INV 
• The estimand for 
Intracranial (IC) response 
is the Intracranial 
treatment effect (ie in 
brain lesions) of lorlatinib 
from time of first dose 
until Intracranial 
progression is met or 
subsequent anti-cancer 
therapy is administered 
for all participants who 
receive at least one dose 
of lorlatinib without 
regard to discontinuation 
from treatment; all 
response assessments 
regardless of gaps in 
tumor assessments are 
considered 
• The estimand for Time to 
Tumor Response (TTR) is 
the treatment effect from 
the time of first dose to 
the first date of response 
that is subsequently 
confirmed for all 
participant who are 
responders to lorlatinib 
• Every endpoint assessed by 
RECIST version 1.1 
• Confirmed Objective 
Tumor Response assessed 
per INV 
• Confirmed Intracranial 
tumor response assessed per 
ICR/INV 
• TTR per ICR/INV 
• DOR per ICR/INV 
• Duration of Intracranial 
response (IC-DOR) per 
ICR/INV 
• PFS per ICR/INV  
• TTP per ICR/INV 
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• The estimand for 
Duration of Response 
(DOR) is the treatment 
effect from the first date 
of OR that is 
subsequently confirmed 
for all participant who are 
responders to lorlatinib 
until progression or death, 
without regard to 
discontinuation from 
treatment unless new 
anti-cancer therapy is 
initiated or extended gap 
in tumor assessment is 
present prior to 
progression or death 
• The estimand for IC-DOR 
follows the estimand 
specified for the DOR, 
but limited to intracranial 
lesions 
• The estimand for 
Progression Free Survival 
(PFS) is the treatment 
effect from the time of 
first dose for all 
participants who receive 
at least one dose of 
lorlatinib until 
progression or death, 
without regard to 
discontinuation from 
treatment unless new anti-
cancer therapy is initiated 
or an extended gap in 
tumor assessment is 
present prior to 
progression or death 
• The estimand for Time to 
Tumor Progression (TTP) 
is the treatment effect 
from the time of first dose 
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for all participants who 
receive at least one dose 
of lorlatinib until 
progression, without 
regard to discontinuation 
from treatment unless 
participant dies, new anti-
cancer therapy is initiated 
or extended gap in tumor 
assessment is present 
prior to progression 
• To confirm the safety and 
tolerability of lorlatinib 
• The estimand for safety is 
the incidence of Adverse 
Events from the time of 
first dose to 28 days post 
last dosing date or the 
date of initiation of a new 
anti-cancer therapy for all 
participants who receive 
at least one dose of 
Lorlatinib 
• Adverse Events as 
characterized by type, 
frequency, severity (as 
graded by National Cancer 
Institute Common 
Terminology Criteria for 
Adverse Events [NCI 
CTCAE] v.4.03), 
seriousness, and 
relationship to study 
therapy 
 
2.1.1. Primary Estimand 
The primary estimand is the treatment effect of Lorlatinib from the time of first dose until 
progression is met, death or subsequent anti-cancer therapy is administered regardless of 
tolerability or duration on treatment.  It includes the following 4 attributes:  
• Population: Participants with Anaplastic Lymphoma Kinase (ALK)-Positive Non-
Small Cell Lung Cancer (NSCLC) Whose Disease Progressed After One Prior 
Second-Generation ALK Tyrosine Kinase Inhibitor (TKI), as defined by the inclusion 
and exclusion criteria, and who receive at least one dose of lorlatinib 
• Variable: Confirmed Objective Response according to RECIST 1.1 per ICR, defined 
as CR or PR from the date of first dose until PD, death, or start of new anticancer 
therapy 
• Intercurrent event: All data after the intercurrent event “start of subsequent anti-
cancer therapy treatment” will be excluded; non adherence to treatment is not an 
intercurrent event; assessments are considered regardless of gaps in assessments 
• Population-level summary:  ORR, ie percentage of participants with confirmed 
complete response [CR] or confirmed partial response [PR] and associated exact CI  
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2.1.2. Secondary Estimands 
A secondary estimand is the treatment effect of Lorlatinib from the time of first dose until 
progression is met, death or subsequent anti-cancer therapy is administered regardless of 
tolerability or duration on treatment.  It includes the following 4 attributes:  
• Population: Participants with Anaplastic Lymphoma Kinase (ALK)-Positive Non-
Small Cell Lung Cancer (NSCLC) Whose Disease Progressed After One Prior 
Second-Generation ALK Tyrosine Kinase Inhibitor (TKI), as defined by the inclusion 
and exclusion criteria, and who receive at least one dose of lorlatinib 
• Variable: Confirmed Objective Response according to RECIST 1.1 per INV, defined 
as PR or CR from the date of first dose until PD, death, or start of new anticancer 
therapy 
• Intercurrent event: All data after the intercurrent event “start of subsequent anti-
cancer therapy treatment” will be excluded; non adherence to treatment is not an 
intercurrent event; assessments are considered regardless of gaps in assessments 
• Population-level summary:  ORR, ie percentage of participants with confirmed 
complete response [CR] or confirmed partial response [PR] and associated exact CI 
A secondary estimand is the durability of treatment effect of Lorlatinib from the time of first 
response until progression is met, death or subsequent anti-cancer therapy is administered 
regardless of tolerability or duration on treatment for participants showing a confirmed OR 
per ICR/INV.  It includes the following 4 attributes:  
• Population: Participants meeting same criteria of Primary estimand and showing a 
confirmed OR per ICR/INV 
• Variables: DoR /DoR censoring status 
• Intercurrent event: All data after the intercurrent event “start of subsequent anti-
cancer therapy treatment” will be excluded; non adherence to treatment is not an 
intercurrent event; assessments are considered regardless of gaps in assessments 
• Population-level summary: Kaplan-Meier Median of DOR and associated CI 
Another secondary estimand is the intra-cranial treatment effect of Lorlatinib from the time 
of first dose until intra-cranial progression is met per ICR/INV, death or subsequent anti-
cancer therapy is administered regardless of tolerability or duration on treatment.  It includes 
the following 4 attributes:  
• Population: Participants meeting same criteria of Primary estimand and having CNS 
metastases at study entry 
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• Variable: Confirmed IC-OR according to RECIST 1.1 per ICR/INV, defined as intra 
cranial PR or CR from the date of first dose until PD, death, or start of new anticancer 
therapy 
• Intercurrent event: All data after the intercurrent event “start of subsequent anti-
cancer therapy treatment” will be excluded; non adherence to treatment is not an 
intercurrent event; assessments are considered regardless of gaps in assessments 
• Population-level summary:  IC-ORR, ie percentage of participants with confirmed 
intra-cranial complete response [CR] or confirmed intra-cranial partial response [PR] 
and associated exact CI 
Another secondary estimand is the durability of intra-cranial treatment effect of Lorlatinib 
from the time of first intra-cranial response until intra-cranial progression is met, death or 
subsequent anti-cancer therapy is administered regardless of tolerability or duration on 
treatment for participants showing a confirmed IC-OR per ICR/INV.  It includes the 
following 4 attributes:  
• Population: Participants meeting same criteria of Primary estimand, having CNS 
metastases at study entry and showing a confirmed IC-OR per ICR/INV 
• Variable: IC-DOR according to RECIST 1.1 per ICR/INV 
• Intercurrent event: All data after the intercurrent events “start of subsequent anti-
cancer therapy treatment” or “extended gap in tumor assessment prior to progression 
or death”; non adherence to treatment is not an intercurrent event; assessments are 
considered regardless of gaps in assessments 
• Population-level summary: Kaplan-Meier Median of IC-DOR and 95% CI 
Another secondary estimand is the time to effect of Lorlatinib from the time of first dose 
until response is met for participants showing a confirmed OR per ICR/INV.  It includes the 
following 4 attributes:  
• Population: Participants meeting same criteria of Primary estimand and showing a 
confirmed OR per ICR/INV 
• Variable: Time To Response per ICR/INV 
• Intercurrent event: All data after the intercurrent event “start of subsequent anti-
cancer therapy treatment” will be excluded; non adherence to treatment is not an 
intercurrent event; assessments are considered regardless of gaps in assessments 
• Population-level summary: median of TTR observed on participants using descriptive 
statistics  
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Another secondary estimand is  the treatment effect of Lorlatinib from the time of first dose 
until progression per ICR/INV or death is observed or subsequent anti-cancer therapy is 
administered regardless of tolerability or duration on treatment.  It includes the following 4 
attributes: 
• Population: Participants meeting same criteria of Primary estimand 
• Variable: PFS /PFS censoring status (per ICR/INV) 
• Intercurrent event: All data after the intercurrent events “start of subsequent anti-
cancer therapy treatment” or “extended gap in tumor assessment prior to progression 
or death” will be excluded; non adherence to treatment is not an intercurrent event 
• Population-level summary: Kaplan-Meier Median of PFS and 95% CI 
Another secondary estimand is the treatment effect of Lorlatinib from the time of first dose 
until progression per ICR/INV is observed or subsequent anti-cancer therapy is administered 
regardless of tolerability or duration on treatment..  It includes the following 4 attributes: 
• Population: Participants meeting same criteria of Primary estimand 
• Variable: TTP /TTP censoring status (per ICR/INV) 
• Intercurrent event: All data after the intercurrent events “start of subsequent anti-
cancer therapy treatment” or “extended gap in tumor assessment prior to progression” 
will be excluded; non adherence to treatment is not an intercurrent event 
• Population-level summary: Kaplan-Meier Median of TTP and 95% CI  
2.2. Study Design 
This is a Phase 4 open-label, multi-center, multi-national, non-randomized, prospective, 
single arm study of lorlatinib in adult participants with ALK-positive NSCLC who 
progressed on alectinib or ceritinib as first line of treatment for metastatic disease.  
Approximately 85 participants will be screened to achieve 70 participants assigned to study 
intervention.   
Participants will take lorlatinib at the approved dose of 100 mg QD.  Participants will be 
treated until disease progression per RECIST 1.1, participant refusal/lost to follow-up, or 
unacceptable toxicity. 
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An independent core imaging laboratory will be used in this study for ICR. All sites will be 
required to submit images for ICR as soon as they are performed at the site so that imaging 
scans may be read in real time. 
After treatment discontinuation participants will be followed for short term follow-up up to 
35 days from discontinuation. No long-term follow up will be collected for the study. 
The End of Trial is defined as 12 calendar months after the “last patient first visit” (LPFV) 
date in the study.  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint 
3.1.1. Confirmed OR by ICR 
Objective Response (OR) based on ICR assessment is defined as complete response (CR) or 
partial response (PR) according to RECIST v1.1 from date of first dose until documented PD 
or start of new anti-cancer therapy without regard to discontinuation from treatment. Both 
CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after 
the criteria for response are first met. 
Participants without a CR or PR or with death prior to first post-baseline assessment, 
inadequate baseline assessment, new anti-cancer therapy started prior to first post-baseline 
assessment, and all post-baseline disease assessments missing will be considered as non-
responders. 
3.2. Secondary Endpoints 
3.2.1. Confirmed OR by INV  
Defined as OR by ICR but evaluated according to INV.  
3.2.2. Confirmed IC-OR by ICR/INV 
Intra-Cranial Objective Response (OR) based on ICR/derived investigator assessment is 
defined as Intra-Cranial complete response (CR) or partial response (PR) according to 
RECIST v1.1 from date of first dose until documented IC-PD or start of new anti-cancer 
therapy without regard to discontinuation from treatment. Both IC-CR and IC-PR must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met. 
Participants without IC-CR or IC-PR or death prior to first post-baseline assessment, 
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inadequate baseline assessment, new anti-cancer therapy started prior to first post-baseline 
assessment, and all post-baseline disease assessments missing will be considered as non-
responders. 
3.2.3. TTR by ICR/INV 
Time to Response (TTR) based on ICR/derived investigator assessments is defined, for 
participants with a confirmed objective response, as the time from the date of first dose to the 
first documentation of objective response (CR or PR) which is subsequently confirmed. For 
participants whose OR proceeds from PR to CR, the onset of PR is taken as the onset of 
response.   
3.2.4. IC-TTR by ICR/INV 
Time to Intra-Cranial Response (IC-TTR) based on ICR/derived investigator assessments is 
defined, for participants with a confirmed intra-cranial objective response, as the time from 
the date of first dose to the first documentation of objective intra-cranial response (CR or PR) 
which is subsequently confirmed. For participants whose IC-OR proceeds from PR to CR, 
the onset of PR is taken as the onset of response.   
3.2.5. DoR by ICR/INV 
Duration of Response (DoR) based on ICR/ derived investigator assessment is defined, for 
participants with a confirmed objective response, as the time from first documentation of 
objective response (CR or PR whichever is earlier) to the date of first documentation of PD 
or death due to any cause, whichever occurs first. The censoring rules for DOR are identical 
to those presented for PFS in section 6.2.7. 
3.2.6. IC-DoR by ICR/INV 
Duration of Intra-Cranial Response (IC-DoR) based on ICR/ derived investigator assessment 
is defined, for participants with a confirmed objective intra-cranial response, as the time from 
first documentation of objective intra-cranial response (CR or PR whichever is earlier) to the 
date of first documentation of PD in brain or death due to any cause, whichever occurs first. 
The censoring rules for DOR are identical to those presented for PFS in section 6.2.7. 
3.2.7. PFS by ICR/INV 
Progression Free Survival (PFS) is defined as the time from date of first dose to the date of 
the first documentation of PD (per RECIST v1.1 based on ICR/derived investigator 
assessment) or death due to any cause, whichever occurs first.  Refer to section 6.2.7 for 
details on censoring rules. 
3.2.8. TTP by ICR/INV 
Time To Progression (TTP) is defined as the time from date of first dose to the date of the 
first documentation of PD (per RECIST v1.1 based on ICR/derived investigator assessment).  
Refer to section 6.2.8 for details on censoring rules. 
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3.3. Other Endpoints 
Not Applicable 
3.4. Baseline Variables 
The date of first dose (start date) of study treatment is the earliest date of non-zero dosing of 
the study drug. The date of last dose of study treatment is the latest date of non-zero dosing 
of the study drug. 
No windowing will be applied when defining baseline, except as noted in Section 5.2.8 for 
tumor assessments. Any deviations from the protocol specified window will be documented 
as protocol deviations.  A separate definition of adequate baseline will be provided for tumor 
assessment related efficacy endpoints. 
For efficacy analyses and baseline characteristics associated with tumor assessments the last 
assessment prior to treatment start date will serve as the baseline assessment. 
For Adverse Events the last assessment performed on or prior to date of the first dose of 
study treatment will serve as the baseline assessment. If there are no observations meeting 
these criteria, then baseline is considered missing. 
3.5. Safety Endpoints 
Safety endpoints in this study will be limited to Adverse Events and maximum Weight 
increase from baseline. 
3.5.1. Adverse Events 
Adverse Events will be summarized based on the on-treatment period unless otherwise 
specified. 
On-treatment is defined as the time from the first dose of study treatment through end of 
safety follow-up period, ie at least 28 days, and no more than 35 days after discontinuation of 
treatment, or start of new anti-cancer therapies (follow up systemic therapy, follow up 
radiation therapy or follow-up surgery ), whichever occurs first. Adverse events occurring on 
the same day as the first dose of study treatment will be considered to have occurred during 
the on-treatment period.  
Adverse events collected outside the on-treatment period as described above will be listed 
but not summarized. All adverse events with onset date on or after start of a new anti-cancer 
drug therapy will also be listed on a separate display. 
An adverse event is considered treatment emergent (TEAE) when the onset date is greater or 
equal to the treatment period start date.  
All Adverse Events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The investigator will classify the severity of AEs using the CTCAE 
v4.03.  
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Adverse Events of Special Interest (AESI) 
AESIs include events such as HYPERCHOLESTEROLEMIA and 
HYPERTRIGLYCERIDEMIA, EDEMA, PERIPHERAL NEUROPATHY, COGNITIVE 
EFFECTS, MOOD EFFECTS, SPEECH EFFECTS, Weight gain, VISION DISORDER, 
Liver tests increased, QT interval prolongation, Interstitial lung disease/Pneumonitis, 
Atrioventricular (AV) block, and Pancreatitis. These events will be defined based on a list of 
MedDRA Preferred Terms specified in the Safety Review Plan for lorlatinib. A final list will 
be provided to programming prior to database release. 
3.5.2. Vital Signs – Weight 
Weight will be summarized based on the on-treatment period. 
Assessments of weight which occur on the same day as the first dose of study treatment will 
be considered baseline assessments (see section 3.4 for the definition of baseline).  
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled  
All participants who sign the ICF 
Intent to Treat 
(ITT)/Safety 
All enrolled participants who take at least 1 dose of lorlatinib 
Per Protocol Population: 
Participants with CNS 
metastases based on ICR 
Subset of the ITT analysis set including only participants with 
CNS metastases at study entry (i.e. with Lesions having 
Disease Site=Brain) according to ICR 
Per Protocol Population: 
Participants with CNS 
metastases based on 
Investigator Assessment 
Subset of the ITT analysis set including only participants with 
CNS metastases at study entry (i.e. with Lesions having 
Disease Site=Brain) according to Investigator Assessment 
 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures. 
5. GENERAL METHODOLOGY AND CONVENTIONS 
The primary analysis of objective tumor response based on ICR assessment will be 
performed at study participant data set release after 12 calendar months after the LPFV date 
in the study (as per End of Trial protocol definition). 
Participants who still experience clinical benefit at the End of Trial will discontinue from the 
study and continue treatment per standard of care.  
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The study will be reported using CDISC. 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and Sample Size 
According to literature, platinum-based doublet chemotherapy in participants with ALK + 
NSCLC refractory to second generation TKIs has an objective response rate of 
approximately 30%. Setting as target for lorlatinib a response rate of about 43% (as observed 
in cohort EXP-3B of phase 2 portion of study B7461001), a sample size of 60 participants 
would result in an exact two-sided 95% CI of the ORR with lower limit of the CI greater than 
30%.  In order to compensate for a potential 15% drop out rate (participants with death prior 
to first post-baseline assessment, inadequate baseline assessment, new anti-cancer therapy 
started prior to first post-baseline assessment, post-baseline disease assessments missing), the 
overall sample size for the study is set to 70 participants. 
5.1.2. Decision Rules 
The study will be considered to have met its primary endpoint if the lower limit of the 95% 
confidence interval around the estimated ORR excludes 30%. 
5.2. General Methods 
5.2.1. Data handling after the cut-off date 
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations 
5.2.2. Definition of study day 
Start day of study treatment is the day of the first dose of study treatment. 
The study day for assessments occurring on or after the first dose of study treatment (eg, 
adverse event onset) will be calculated as: 
Study day = Date of the assessment/event - start date of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as: 
Study day = Date of the assessment/event –start date of study treatment. 
For efficacy endpoints and for tumor assessment the study day will be calculated with respect 
to the date of study treatment start.  
The study day will be displayed in all relevant data listings. 
5.2.3. Definition of Cycle and Cycle Day 
Cycle start and end dates are derived per patient. Treatment will be dispensed at the 
beginning of every 21-day cycle. 
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• For Cycle X, the actual cycle start date for each subject is the earliest start date of dosing 
(dose>0 at that visit) in Cycle X visit CRF exposure page 
• For all but the last cycle, 
• actual cycle stop date is calculated as the start date of the next cycle minus one day. 
• actual cycle duration is calculated from Day 1 of a cycle to the day prior to Day 1 of 
the next cycle, as follows: Actual Cycle Duration (weeks) = (cycle stop date – cycle 
start date + 1) / 7 
• For the last cycle, actual cycle duration is calculated as follows: 
• Actual Cycle Duration (weeks) = (last date of study treatment– cycle start date + 1) /7 
The cycle day will be calculated as: 
• Cycle day = Date of the assessment/event – cycle start date + 1. 
5.2.4. Date of last contact 
The date of last contact will be derived for patients not known to have died at the data cutoff 
date using the latest complete date (i.e. imputed dates will not be used in the derivation) 
among the following: 
• All patient assessment dates e.g. tumor assessments 
• Start and stop dates of concomitant therapies including non-drug treatments or 
procedures 
• Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation including systemic therapy, radiation, and surgeries, 
• AE start and end dates 
• Date of first and last dose 
• Vital sign – weight assessment dates  
• Date of discontinuation on disposition CRF pages (do not use if reason for 
discontinuation is lost to follow-up or death). 
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the dates data 
were entered into the CRF will not be used.  
Assessment dates after the data cutoff date will not be applied to derive the last contact date. 
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5.2.5. Measurable Disease 
A patient will be considered to have measurable disease if there is at least one target lesion 
identified at baseline meeting the following criteria: 
• Non lymph node lesions with longest diameter ≥ 10 mm by CT scan, 
• Non lymph node lesions with longest diameter ≥ 10 mm caliper measurement by clinical 
exam, 
• CNS lesions with longest diameter ≥5 mm provided by gadolinium contrast enhanced 
MRI perfomed with contingent slices of 1 mm, or 
• Lymph nodes with short axis ≥ 15 mm when assessed by CT. 
5.2.6. TumorAssessment Date 
Tumor assessment dates will be assigned differently for ICR assessment and for 
investigator’s assessment of tumor data. 
For analyses of ICR assessments, the date of tumor assessments will be determined based on 
the radiologist assessments at each nominal timepoint and will be provided on listings as the 
associated date of response/progression at nominal timepoints. These dates will also be used 
for censoring in time to event analyses; however, the date of progression and response as 
provided by ICR will be used in time to event endpoint analyses as the independent 
oncologist provided an overall assessment of best response and date of progression based on 
a review of each nominal timepoint and additional clinical information available for the 
determination of the date of response/progression. 
For analyses based on investigator’s assessment when response/progression are derived 
programmatically from the target lesions measurements, non-target lesions status, and new 
lesions recorded on the CRF, the date of tumor assessment should be derived as the earliest 
scan/assessment date. Since tumor assessments are captured on a log CRF page, a clustering 
algorithm for grouping scans will be used: 
• Each cluster represents an actual unique assessment date. For each patient, the number of 
clusters is equal to the maximum number of unique assessment dates available among all 
target, non-target, new lesions and investigator overall assessment dates. SAS procedure, 
Proc Fastclus, is applied to a variable that represents the days from the date of treatment 
start to the date of the scan for each lesion/investigator overall assessment (date of scan – 
date of treatment start +1). Then the assessments of target and non-target lesions that 
occurred close to each other in time will be assigned to the same cluster 
5.2.7. Sum of Lesion Diameters 
For lesions that are assessed as ‘too small to measure’, 5 mm will be imputed and used in the 
calculation of the sum of the lesion diameters 
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5.2.8. Adequate Baseline Tumor Assessment 
Adequate baseline is defined using the following criteria: 
• All baseline assessments must be within 28 days prior to and including the date of first 
dose. 
• All documented lesions must have non-missing assessments (ie, non missing 
measurements for target lesions and non missing lesions status at baseline for non-target 
lesions). 
• Measurable disease at baseline (see Section 5.2.5 for the definition of measurable 
disease) 
5.2.9. Adequate Post Baseline Tumor Assessment 
An adequate assessment is defined as an assessment where a response of CR, PR, SD, non-
CR/non-PD, or PD has been provided by ICR or can be programmatically derived based on 
investigator’s assessment of tumor data for the analyses by ICR or investigator, respectively. 
Timepoints where the response is not evaluable or no assessment was performed will not be 
used for determining the censoring date. 
5.2.10. Unscheduled Assessments 
Unless otherwise specified, unscheduled assessments will not be displayed in summary tables 
by nominal visit/timepoint. Unscheduled assessments will be used when deriving baseline 
and worst case on-treatment for Adverse Events. Additionally, unscheduled tumor 
assessments will be used for efficacy analyses (eg, defining date of progression/censoring, 
best overall response). 
5.2.11. Standard Derivations and Reporting Conventions 
The following conversion factors will be used to convert days into weeks, months or years:  
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Percentages will be reported to one decimal place. The rounding will be performed to closest 
integer / first decimal using the common mid-point between the two consecutive values. 
Eg,5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be rounded to an integer 
of 6.  
5.2.12. Analyses for Binary Endpoints 
Binary endpoints will be summarized by percentage rates along with two-sided 95% CI using 
the Clopper-Pearson method (exact CI for a binomial proportion). Waterfall plots will be 
used to visualize best %change vs baseline in sum of baseline target lesion diameters, Spider 
plots to visualize %change from baseline in sum of baseline target lesion diameters across 
visits.  
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5.2.13. Analyses for Continuous Endpoints 
Continuous variables will be summarized using descriptive statistics i.e., number of non-
missing values and number of missing values [i.e., n (missing)], mean, median, standard 
deviation (std), minimum, maximum, first and third quartile (Q1 and Q3), InterQuartile 
Range.  
In case the analysis refers only to certain visits, percentages will be based on the number of 
participants with an assessment at that visit, unless otherwise specified. 
5.2.14. Analyses for Categorical Endpoints 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of 
participants with an assessment at that visit, unless otherwise specified. 
5.2.15. Analyses for Time-to-Event Endpoints 
Time to event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically when appropriate.  Graphs will describe the 
number of participants at risk over time.  The median, quartiles, and probabilities of an event 
at particular points in time will be estimated by the Kaplan-Meier method.  Confidence 
intervals for medians and quartiles are based on the Brookmeyer-Crowley method.  
Confidence intervals for the estimated probability of event at a particular timepoint will be 
generated using the log(-log) method with back transformation to a confidence interval on 
the untransformed scale. Summaries of the number and percentages of participants with an 
event will also be provided on summary tables and figures. 
5.3. Methods to Manage Missing Data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used. 
Any imputations will occur at the analysis dataset level.  Additionally, in all patient data 
listings imputed values will be presented and flagged as imputed. 
Missing statistics, e.g. when they cannot be calculated, should be presented as ‘ND’ for not 
done, ‘NR’ for not reached or ‘NA’ for not applicable.  For example, if N=1, the measure of 
variability cannot be computed and should be presented as ‘ND’ or ‘NA’. 
5.3.1. Missing Dates 
For purposes of data listings, dates will reflect only the information provided by the 
investigator on the CRF. 
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If start dates for adverse events or concomitant medications are completely missing, a worst-
case approach will be taken whereby the events will be considered treatment emergent and 
the medications will be considered concomitant.  If only partial information is available (e.g. 
only a month and year or only a year), and the partial information provides sufficient 
information to indicate the dates are prior to the start of study treatment (e.g. month/year less 
than month/year of first dose), then these will be considered to have started prior to 
treatment; otherwise a similar worst case approach will apply and these will be considered to 
have started after treatment. 
Date of Last Dose of Study Treatment 
No imputation will be done for first dose date.  Date of last dose of study treatment, if 
unknown or partially unknown, will be imputed as follows: 
• If the last date of study treatment is completely missing and there is no End of Treatment 
(EOT) CRF page and no death date, the participant should be considered to be ongoing 
and use the data cutoff date for the analysis as the last dosing date; or 
• If the last date of study treatment is completely or partially missing and there is EITHER 
an EOT CRF page OR a death date available (on or prior to the data cutoff date), then 
impute this date as the last dose date: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death 
date), 
= Last day of the month, if both Year and Month are available and Year = Year of 
min (EOT date, death date) and Month < the month of min (EOT date, death date), or 
= min (EOT date, death date), for all other cases. 
Missing or Partial Death Dates 
Missing or partial death dates will be imputed based on the last contact date: 
• If the entire date is missing it will be imputed as the day after the date of last contact (see 
derivation of date of last contact in section 5.2.4); or 
• If the day or month is missing, death will be imputed to the maximum of the full (non-
imputed) day after the date of last contact and the following: 
o Missing day: 
1st day of the month and year of death, or 
o Missing day and month:  January 1st of the year of death. 
Date of Start of New Anti-cancer Therapy  
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Anti-cancer therapies will be collected in short term follow up only (up to 35 days after 
treatment discontinuation) 
Incomplete dates for new anti-cancer therapy will be imputed as follows and will be used to 
determine censoring dates for efficacy analyses: 
• The end date of new anti-cancer therapy will be included in the imputation for start date 
of new anti-cancer therapy.  If the end data of new anti-cancer therapy is: 
o completely missing then it will be ignored in the imputations below,  
o partially missing with only year available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy, or 
o partially missing with only month and year available then the imputations below 
will consider the last day of the month for MMMYYYY as the end date of the 
new anti-cancer therapy. 
• For participants who have not discontinued study treatment at the time of the data cutoff 
date, last dose of study treatment is set to the data cutoff date in the imputations below. 
• If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is: 
= 31DECYYYY, if only Year is available and Year < Year of min [max (PD date + 1, 
last dose of study treatment + 1), end date of new anti-cancer therapy] 
= Last day of the month, if both Year and Month are available and  
Year = Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  
Month < Month of min [max (PD date + 1 day, last dose of study treatment + 
1 day), end date of new anti-cancer therapy] 
= min [max (PD date + 1, last dose of study treatment + 1), end date of new anti-
cancer therapy], for all other cases. 
AE Onset Date 
The following imputation rules apply if the event is unique for a participant or it is the first of 
a series of similar events; otherwise, the AE Onset Date will not be imputed: 
• If the AE Collection Date is not missing, is less than the Date of First Exposure to 
Treatment, and is less than the AE Stop Date, then AE Onset Date is set to the Date of 
AE Collection. 
• If the Previous Visit Date is greater than the Date of First Exposure to Treatment and less 
than the AE Stop Date, the AE Start Date is set to the previous visit date. 
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• If the Date of First Exposure to Treatment is greater than the previous visit date and less 
than the AE Stop Date, the AE Onset Date is set to the Date of First Exposure to 
Treatment. 
• Otherwise AE Onset date is set to the AE Stop date. 
AE Stop Date 
Ongoing events will have the AE Stop Date set to one of the following values: 
• Date of Death, if the participant died and a date of death exists. 
• Maximum of (Participant Withdrawal date, AE Onset Date, AE Collection Date) if the 
participant withdrew from the study and a date of withdrawal exists. 
• Maximum of (AE Onset Date, Subject Summary Collection Date, AE Collection Date) if 
the Subject Summary CRF page exists but a date of withdraw does not exists. 
• Maximum of (Last Treatment Date, AE Onset Date) if no Subject Summary page exits. 
Imputation will only occur if event is unique for the participant, or it is the last of a series of 
similar events; otherwise the Stop Date will not be imputed.  Adverse Events are deemed 
similar if they have the same verbatim term. 
Resolved events will have the AE Stop Date set to the maximum of the AE collection date 
and the AE Onset date. 
Other Missing or Partial Dates 
Imputation methods for other partial dates are as follows:  
• If the day of the month is missing for a start date used in a calculation, the first day of the 
month will be used to replace the missing date.  
• If both the day and month are missing, the first day of the year is used.  
• For stop dates, the last day of the month, or last day of the year is used if the day or day 
and month are missing, respectively.  
• If the date is completely missing, no imputation will be performed. 
5.3.2. Missing Toxicity Grade of Adverse Events 
Prior to Study Treatment: If no toxicity grade is available or the grade is reported as 
unknown for an adverse event prior to the first study treatment, then Grade 1 will be assumed 
for purposes of defining a baseline grade.  
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In summaries which present maximum toxicity grade, the maximum of non-missing grades 
will be displayed.  Missing grade will only be displayed for cases where a participant 
reported only one event and the grade is missing.  
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoint 
6.1.1. Confirmed OR by ICR 
Analysis set: ITT:  All enrolled participants who take at least 1 dose of Lorlatinib 
Analysis methodology:   
• Objective Response Rate (ORR) defined as the percentage of patients with a confirmed 
best overall response (BOR) of CR or PR according to RECIST v1.1  
BOR will be determined based on reported overall responses at different evaluation 
timepoints by the independent radiologist from the date of treatment start until 
documented disease progression or start of new anti-cancer therapy, according to the 
following rules: 
• CR = at least two determinations of CR at least 4 weeks apart and documented before 
progression and start of new anti-cancer therapy 
• PR = at least two determinations of PR or better (and not qualifying for a CR) at least 
4 weeks apart and before progression and start of new anti-cancer 
• SD (for patients with at least one measurable lesion at baseline) = at least one SD 
assessment (or better and not qualifying for CR or PR) ≥ 6 weeks after date of 
treatment start and before progression and the start of new anti-cancer therapy 
• Non-CR/Non-PD (for patients with only non-target disease at baseline) = at least one 
Non-CR/Non-PD assessment (or better and not qualifying for CR or PR) ≥ 6 weeks 
after date of treatment start and before progression and the start of new anti-cancer 
therapy 
• PD = progression ≤ 14 weeks after date of treatment start and not qualifying for CR, 
PR or SD 
• Not Evaluable (NE) = all other cases. 
Clinical deterioration will not be considered as documented disease progression. 
• patients without documented CR or PR will be considered as non-responders 
• Exact CI for a binomial proportion for ORR using the Clopper-Pearson method  
• best % changes vs baseline as defined below under Summaries used for Reporting 
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• % change vs baseline across visits as defined below under Summaries used for Reporting 
Intercurrent events and missing data:  
• data on response after subsequent anti-cancer therapy is administered will be excluded 
• participants with death prior to first post-baseline assessment, inadequate baseline 
assessment, new anti-cancer therapy started prior to first post-baseline assessment, and all 
post-baseline disease assessments missing will also be considered as non-responders. 
Summaries used for reporting:  
• The frequency (number and percentage) of patients with BOR of CR, PR, SD, PD, non-
CR/non-PD (applicable only to patients with non-measurable disease at baseline), and NE 
(not-evaluable) 
• ORR estimated by dividing the number of patients with OR (CR or PR) by the number of 
patients in the ITT population  
• corresponding exact 2-sided 95% CIs  
• Waterfall plots of best %change vs baseline  
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-
nodal lesions and short axis for nodal lesions from baseline will be created. These plots 
will display the best percentage change from baseline in the sum of the diameter of all 
target lesions for each patient with measurable disease at baseline and at least one valid 
post-baseline assessment. The best percent change from baseline will be calculated from 
start of study treatment up to first visit with disease progression or to the last visit 
available prior to the start of new anti-cancer therapy (for patients who start new anti-
tumor therapy prior to progression or who are progression-free patients at the time of 
analysis) 
• Spider Plots of %change from baseline across visits  
A spider plot of %change from baseline across visits in the sum of longest diameter for 
non-nodal lesions and short axis for nodal lesions from baseline will be presented. These 
plots will display the % change from baseline in the sum of the diameter of all target 
lesions for each patient with measurable disease at baseline and at least one valid post-
baseline assessment. The % change from baseline will be calculated from start of study 
treatment to each visit up to first visit with disease progression or to the last visit 
available prior to the start of new anti-tumor therapy (for patients who start new anti-
tumor therapy prior to progression or who are progression-free patients at the time of 
analysis). 
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6.2. Secondary Endpoints 
6.2.1. Confirmed OR by INV 
The primary analysis performed on OR by ICR will be repeated on OR based on INV 
applying the same rules. 
6.2.2. Confirmed IC-OR by ICR/INV 
IC-OR by ICR 
Analysis set: Participants with CNS metastases based on ICR 
IC-OR by INV 
Analysis set: Participants with CNS metastases based on Investigator Assessment 
Analysis methodology:   
The IC-OR, based on ICR/INV, will be summarized similar to OR (as described above in 
section 6.1 and 6.2), in Per Protocol Population Participants with CNS metastases based on 
ICR/INV. Surgery or radiotherapy of extracranial lesions will not affect the determination of 
IC-OR. 
6.2.3. TTR by ICR/INV  
Analysis set: Subsets of Participants with confirmed objective response by ICR/INV 
Analysis methodology:       TTR (months) = [first date of CR/PR which is subsequently 
confirmed-date of first dose+1]/30.4375 
For participants whose OR proceeds from PR to CR, the onset of PR is taken as the onset of 
response. 
Intercurrent events and missing data:  data on response after subsequent anti-cancer 
therapy is administered will be excluded. 
Summaries used for reporting: TTR will be summarized based on both ICR/INV 
assessment using simple descriptive statistics (mean, std, median, min, max, Q1, Q3, IQR). 
6.2.4. IC-TTR by ICR/INV  
Analysis set: Subsets of Participants with confirmed Intra-Cranial objective response by 
ICR/INV 
Analysis methodology:       IC-TTR (months) = [first date of CR/PR in brain lesions which 
is subsequently confirmed-date of first dose+1]/30.4375 
For participants whose IC-OR proceeds from PR to CR, the onset of PR is taken as the onset 
of response. 
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Intercurrent events and missing data:  data on response after subsequent anti-cancer 
therapy is administered will be excluded. 
Summaries used for reporting: IC-TTR will be summarized based on both ICR/INV 
assessment using simple descriptive statistics (mean, std, median, min, max, Q1, Q3, IQR). 
6.2.5. DoR by ICR/INV  
Analysis set: Subsets of Participants with confirmed objective response by ICR/INV 
Analysis methodology:  
DoR will be calculated on every participant showing OR as follows:  
      DoR (months) = [first date of PD or death/censoring – first date of CR/PR  subsequently 
confirmed+1]/30.4375 
Censoring for DOR will be identical to the censoring rules presented for PFS.  
Participants with an event more than 14 weeks after the last adequate tumor assessment will 
be censored on the date of the last adequate tumor assessment prior to the gap that 
documented no progression. If a new anti-cancer therapy starts prior to an event, the 
participant will be censored on the date of the last adequate tum or assessment that 
documented no progression prior to start of the new anti-cancer therapy.  
Intercurrent events and missing data:  data on response after subsequent anti-cancer 
therapy is administered will be excluded 
Summaries used for reporting:  Kaplan-Meier estimates (product-limit estimates) will be 
presented together with a summary of associated statistics including the median DR time 
with two-sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer 
and Crowley. 
When the number of participants with PD after a confirmed CR or PR is small, the use of 
Kaplan‑Meier method is limited due to high number of censored observation, so the DOR 
will be summarized using number (%) of participants with events and of participants 
censored with DOR in the following categories: less than 6 months, ≥6 - <9 ,≥9-<12, ≥12-
<15, ≥15-<18, ≥18-<21, ≥21-<24, and ≥24 months 
6.2.6. IC-DoR by ICR/INV  
Analysis set: Subsets of Participants with confirmed Intra-Cranial objective response by 
ICR/INV 
Analysis methodology: IC-DoR (months) = [first date of PD in brain lesions or 
death/censoring – first date of IC OR (CR/PR  subsequently confirmed)+1]/30.4375 
For participants whose IC-OR proceeds from PR to CR, the onset of PR is taken as the onset 
of response. 
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Censoring for DOR will be identical to the censoring rules presented for PFS. 
Intercurrent events and missing data:  data on response after subsequent anti-cancer 
therapy is administered will be excluded. 
Summaries used for reporting: The IC-DoR, based on ICR/INV, will be summarized 
similar to DoR (as described above in section 6.2.5), in Per Protocol Population Participants 
with CNS metastases based on ICR/INV. Surgery or radiotherapy of extracranial lesions will 
not affect the determination of IC-OR. 
6.2.7. PFS by ICR/INV  
Analysis set: ITT:  All enrolled participants who take at least 1 dose of Lorlatinib 
Analysis methodology:   
PFS is defined as the time from date of first dose to the date of the first documentation of PD 
per RECIST v1.1 as assessed by ICR/INV or death due to any cause, whichever occurs first 
and will be summarized in months: 
PFS (months) = [date of event or censoring–date of treatment start +1]/30.4375. 
PFS data will be censored as follows: 
• For participants who start a new anti-cancer therapy prior to an event, censoring will be at 
the last adequate tumor assessment (see Section 5.2.9) prior to the start of new anti-
cancer therapy. Note: if date of progression occurs on the same date as the start of new 
anti-cancer therapy, the progression will be counted as an event. 
• For participants with documented progression or death after two or more missing tumor 
assessments, censoring will occur at the last adequate tumor assessment prior to the 
missing assessments. In this study antitumor activity will be assessed through 
radiological tumor assessments conducted at screening and every 6 weeks until disease 
progression regardless of initiation of subsequent anti-cancer therapy. The allowable time 
window for disease assessments is ±1week while on treatment and whenever disease 
progression is suspected (eg, symptomatic deterioration). Therefore time without 
adequate assessment is defined as 98 days (12 weeks plus 2 weeks). 
• For participants who do not have an adequate baseline tumor assessment or who do not 
have any post-baseline tumor assessments, censoring will occur on the date of first dose 
unless death occurred on or before the time of the second planned tumor assessment (ie, 
on or before day 98) in which case the death will be considered an event. Note for 
participants who died without any post baseline assessments and meet the definition of 
two or more missing assessment the reason for censoring will be documented as two or 
more missed assessments and censoring will occur on the date of first dose. 
• All other participants alive without objective progression will be censored on the date of 
the last adequate tumor assessment.  
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The date of tumor response at each nominal timepoint based on the ICR/INV assessments 
will be used for determining the dates of last adequate assessment for censoring purposes. 
The censoring and event date options to be considered for the PFS analysis are presented in 
Table 2. 
Table 2. 
Outcome and event dates for PFS analyses 
 
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment 
date of first dose 
Censored a 
Progression or death ≤ 98 days after last 
adequate tumor assessment or ≤ 98 days after 
date of first dose 
Date of progression or death 
Event 
 
Progression or death > 98 days after the last 
adequate tumor assessment b 
Date of last adequate 
assessment b documenting no 
PD prior to anti-cancer 
therapy or missed assessments 
Censored 
 
No progression 
New anti-cancer therapy given prior to PD 
a if the participant dies ≤ 98 days after date of first dose the death is an event on the death date 
b if there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose; if the criteria were met the censoring will be on the 
start date. 
 
Summaries used for reporting:   
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median PFS time with two-sided 95% CIs. The PFS rate 
at 12 months will be estimated with corresponding two-sided 95% CIs. The CIs for the 
median will be calculated according to Brookmeyer and Crowley and the CIs for the survival 
function estimates at the timepoints defined above will be derived using the log(-log) method 
according to Kalbfleisch and Prentice (conftype=loglog default option in SAS Proc 
LIFETEST). The estimate of the standard error will be computed using Greenwood’s 
formula. 
Frequency (number and percentage) of participants with each event type (PD or death) and 
censoring reasons will be presented along with the overall event and censor rates. 
Reasons for censoring will be summarized according to the categories in Table 3. If a 
participant meets multiple definitions for censoring the list will be used to define the 
hierarchy. 
 
Table 3. 
Censoring Reasons and Hierarchy for PFS analyses 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment 
No adequate baseline assessment 
2 
Start of new anti-cancer therapy before event.  
Start of new anti-cancer therapy 
3  
Event more than 98 days from last adequate 
post-baseline tumor assessment/start date 
Event after missing assessments a 
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4 
No event and  
withdrawal of consent date ≥ start date  
OR  
End of study (EOS) = Subject refused further 
follow-up  
Withdrawal of consent 
5 
No event and lost to follow-up in any disposition 
page  
Lost to follow-up 
6 
No event and EOS page present and no adequate 
post-baseline tumor assessment  
No adequate post-baseline tumor 
assessment 
7  
No event and none of the conditions in the prior 
hierarchy are met  
Ongoing without an event 
a more than 98 days after last adequate tumor assessment.    
 
The PFS time or censoring time and the reasons for censoring will also be presented in a 
participant listing. 
6.2.8. TTP by ICR/INV  
Analysis set: ITT:  All enrolled participants who take at least 1 dose of Lorlatinib 
Analysis methodology:   
TTP is defined as the time from date of first dose to the date of the first documentation of PD 
per RECIST v1.1 as assessed by ICR/INV and will be summarized in months: 
TTP (months) = [date of PD or censoring–date of treatment start +1]/30.4375. 
TTP data will be censored as follows: 
• For participants who start a new anti-cancer therapy prior to an event, censoring will be at 
the last adequate tumor assessment (see Section 5.2.9) prior to the start of new anti-
cancer therapy. Note: if date of progression occurs on the same date as the start of new 
anti-cancer therapy, the progression will be counted as an event. 
• For participants with documented progression or death after two or more missing tumor 
assessments, censoring will occur at the last adequate tumor assessment prior to the 
missing assessments. In this study antitumor activity will be assessed through 
radiological tumor assessments conducted at screening and every 6 weeks until disease 
progression regardless of initiation of subsequent anti-cancer therapy. The allowable time 
window for disease assessments is ±1week while on treatment and whenever disease 
progression is suspected (eg, symptomatic deterioration). Therefore time without 
adequate assessment is defined as 98 days (12 weeks plus 2 weeks). 
• For participants who do not have an adequate baseline tumor assessment or who do not 
have any post-baseline tumor assessments, censoring will occur on the date of first dose 
unless death occurred on or before the time of the second planned tumor assessment (ie, 
on or before day 98) in which case the death will be considered an event. Note for 
participants who died without any post baseline assessments and meet the definition of 
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two or more missing assessment the reason for censoring will be documented as two or 
more missed assessments and censoring will occur on the date of first dose. 
• All other participants alive without objective progression will be censored on the date of 
the last adequate tumor assessment.  
The date of tumor response at each nominal timepoint based on the ICR/INV assessments 
will be used for determining the dates of last adequate assessment for censoring purposes. 
The censoring and event date options to be considered for the TTP analysis are presented in 
Table 4. 
Table 4. 
Outcome and event dates for TTP analyses  
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment 
date of first dose 
Censored  
Progression ≤ 98 days after last adequate 
tumor assessment or ≤98 days after date of 
first dose 
Date of progression  
Event 
 
Death ≤ 98 days after last adequate tumor 
assessment or ≤ 98 days after date of first 
dose 
Date of death 
Censored 
 
Progression or death > 98 days after the last 
adequate tumor assessment a 
Date of last adequate 
assessment b documenting no 
PD prior to anti-cancer 
therapy or missed assessments 
Censored 
 
No progression 
New anti-cancer therapy given prior to PD 
a if there are no adequate post-baseline assessments prior to PD or death, then the time without adequate assessment 
should be measured from the date of first dose; if the criteria were met the censoring will be on the start date. 
 
Summaries used for reporting:   
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median TTP time with two-sided 95% CIs. The TTP rate 
at 12 months will be estimated with corresponding two-sided 95% CIs. The CIs for the 
median will be calculated according to Brookmeyer and Crowley and the CIs for the survival 
function estimates at the timepoints defined above will be derived using the log(-log) method 
according to Kalbfleisch and Prentice (conftype=loglog default option in SAS Proc 
LIFETEST). The estimate of the standard error will be computed using Greenwood’s 
formula. 
Frequency (number and percentage) of participants with PD and each censoring reasons will 
be presented along with the overall event and censor rates. 
Reasons for censoring will be summarized according to the categories in Table 5. If a 
participant meets multiple definitions for censoring the list will be used to define the 
hierarchy. 
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Table 5. 
Censoring Reasons and Hierarchy for TTP analysis  
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment 
No adequate baseline assessment 
2 
Start of new anti-cancer therapy before event.  
Start of new anti-cancer therapy 
3  
Event more than 98 days from last adequate 
post-baseline tumor assessment/start date 
Event after missing assessments a 
4 
No event and  
withdrawal of consent date ≥ start date  
OR  
End of study (EOS) = Subject refused further 
follow-up  
Withdrawal of consent 
5 
No event and lost to follow-up in any disposition 
page  
Lost to follow-up 
6 
No event and EOS page present and no adequate 
post-baseline tumor assessment  
No adequate post-baseline tumor 
assessment 
7 
No event and Death recorded in any disposition 
page or Notice of Death 
Patient died 
8  
No event and none of the conditions in the prior 
hierarchy are met  
Ongoing without an event 
a more than 98 days after last adequate tumor assessment.    
 
The TTP time or censoring time and the reasons for censoring will also be presented in a 
participant listing. 
6.3. Other Endpoint(s) 
Not Applicable 
6.4. Subset Analyses 
Primary endpoint OR by ICR will be reported also by: 
• prior ALK inhibitor (Alectinib or Ceritinib) 
• prior Chemotherapy (Yes/No) 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
• Demographic and Physical Characteristics  
The following demographic and baseline characteristics will be summarized by number and 
percentage: 
• Gender(male, female) 
• Age (18-<45; 45- <65; ≥65) . 
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• Race (white, black, Asian, other)  
• Eastern Cooperative Oncology Group (ECOG) Performance status  
will be summarized by category (number and percent). 
Age (continuous), weight (kg), will be summarized with descriptive statistics (mean, median, 
standard deviation, minimum, and maximum, inter quartile range).   
• Disease Characteristics  
The following baseline disease characteristics will be summarized by number and percentage 
according to both ICR/INV: 
• Measurable disease at baseline (yes/no) (see section 5.2.5) 
• Involved tumor sites at baseline. 
• Number of sites of disease at baseline (1, 2, ≥3) 
Time since diagnosis (months), defined as (date of first dose – date of diagnosis)/30.4375, 
will be summarized by descriptive statistics (mean, median, standard deviation, minimum, 
and maximum).   
Involved tumor sites at baseline will be derived from target and non-target lesions at 
baseline.  Each participant will be counted once per organ.  Similarly, number of sites of 
disease at baseline will be derived by counting the number of unique organ sites from target 
and non-target lesions at baseline.  “Other” will be counted as one organ site. 
• Medical History  
Medical history will be coded using the most current version of MedDRA and summarized 
by MedDRA’s System Organ Class (SOC) and PT.  Each participant will be counted only 
once within each PT or SOC.  Summaries will be ordered by primary SOC and PT in 
descending order of frequency.  Separate summaries will be provided for past and present 
conditions.  
 
• Prior Anti-Cancer Treatments  
Prior anti-cancer treatments include systemic therapy, radiation, and surgery. The number 
and percentage of participants in each of the following anti-cancer therapy categories will be 
tabulated: 
• Participants with at least one type of prior anti-cancer treatment; 
• Participants with at least one prior anti-cancer drug therapy; 
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• Participants with at least one prior anti-cancer radiotherapy; 
• Participants with at least one prior anti-cancer surgery. 
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of participants: 
• Number of prior anti-cancer therapy regimens: missing / 1 / 2 / 3 / ≥4; 
• Number of participants who received prior chemotherapy 
• Number of participants who received Alectinib/Ceritinib as Prior ALK Inhibitor  
The prior anti-cancer drugs will be coded in the WHO Drug coding dictionary.  
6.5.2. Study Conduct and Participant Disposition 
The study protocol consists of two different epochs: Study and Treatment. 
6.5.2.1. Participant Disposition 
A summary of the number of participants enrolled by country and site will be provided for 
the Enrolled population. 
Discontinuations from study will be summarized using the Enrolled set. 
Discontinuations from study treatment will be summarized using the ITT set  
Discontinuations from study treatment due to adverse events will be identified as either 
related or not related to study treatment. If causality is missing the event will be considered 
related to treatment.  If multiple events lead to study treatment discontinuation and at least 
one was considered related, discontinuation will be reported as related to study treatment.  
An additional summary to meet European Union Disclosure requirements will categorize 
discontinuations due to adverse events based on the following categories: 
• Adverse Event, not serious 
• Adverse event, serious non-fatal 
• Adverse event, serious fatal 
6.5.2.2. Protocol Deviations 
Protocol deviations will be compiled prior to database closure and will be summarized by 
category (n(%)) for the Enrolled Analysis Set.  Categories will be assigned by the study 
Clinician. 
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6.5.3. Study Treatment Exposure 
6.5.3.1. Exposure to lorlatinib  
Exposure will be summarized for the ITT/Safety analysis set. 
The summary of treatment exposure for lorlatinib will include the following information: 
• Treatment duration (days) 
• Cumulative dose (mg)  
• Dose intensity (mg/day) 
• Relative dose intensity (%).  
The duration of lorlatinib (in days) is defined as: 
Treatment duration (days) = (last dose date – first dose date + 1) 
The cumulative dose (mg) of lorlatinib is the sum of the actual dose levels that the participant 
received (i.e., total dose administered (mg)).  
The dose intensity (DI) and the relative dose intensity (RDI) of lorlatinib will be calculated 
for each participant during the study. The DI (mg/day) of lorlatinib during the study is 
defined as 
DI (mg/day) = [cumulative dose (mg)]/[treatment duration (days)] 
The RDI of lorlatinib is defined as the ratio of the DI and planned dose intensity d and 
expressed in % 
RDI (%) = 100× [DI (mg/day]/[d (mg/day)]. 
6.5.3.2. Dose Reductions and Interruptions 
A dose reduction is defined as a non-zero dose that is less than the prior dose. 
The number and percentage of participants with at least one dose reduction as well as a 
breakdown of dose reductions (1 / 2 / 3 / ≥4) will be summarized.   
Reasons for dose reductions will also be summarized.  Participants can contribute to more 
than one reason if multiple dose reductions occurred for different reasons, but will only be 
counted once per reason.  Percentages will be calculated based on the total number of 
participants in safety analysis set. 
An interruption is defined a 0 mg dose administered on one or more days.  (Note: A dose 
interruption is not considered a dose reduction). The number and percentage of participants 
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with dose interruptions and the corresponding reasons will be summarized.  Participants can 
contribute to more than one reason if multiple dose interruptions occurred for different 
reasons, but will only be counted once per reason.  Percentages will be calculated based on 
the total number of participants in safety analysis set. 
What follows defines how dose interruptions will be counted in the case of multiple dose 
interruptions: 
• If an interruption occurs consecutively for at least two days due to the same reason, then 
it will be counted only once. 
• If an interruption occurs consecutively for at least two days due to different reasons, then 
it will be counted for each reason.  
• If an interruption occurs for more than one day due to the same reason, but the days are 
not consecutive, i.e. there is at least one dosing day in between, then each dose 
interruption will be counted as a different occurrence.  
6.5.4. Concomitant Medications and Nondrug Treatments 
Concomitant medications and non-drug treatments received by participants during the study 
will be summarized for the Safety Analysis Set.   
Concomitant medications refer to all medications which started prior to first dose of study 
treatment and continued during the on-treatment period (see section 5.2) as well as those 
started during the on-treatment period.  Concomitant medications will be coded in the WHO 
Drug coding dictionary and  will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification level 2 and preferred term in descending order of frequency. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used.  A 
participant will be counted only once within a given drug class and within a given drug 
name, even if he/she received the same medication at different times.  Preferred Terms will 
be reported under each ATC class that it is included under within WHO Drug (no primary 
path is available in WHO Drug) 
Concomitant non-drug treatments refer to all non-drug treatments administered during the 
on-treatment period.  Non-drug treatments will be coded with the most current version of 
MedDRA and will be summarized by MedDRA’s SOC and PT in descending order of 
frequency.   
Participants will be counted only once per PT even if he/she received the same treatment 
multiple times. 
Any medications or non-drug treatments, aside from anti-cancer treatments described in 
section 6.5.1, which were only administered prior to treatment start will be listed but not 
summarized. 
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6.5.5. Subsequent Anti-Cancer Therapies/Procedures 
Subsequent Anti-Cancer Therapies and Procedures are defined as therapies entered on the 
short term follow up in the ‘Follow-up Cancer Therapy’, ‘Follow-up Radiation Therapy’, and 
‘Follow-up Surgery’ CRF pages.  The number and percentage of participants within each 
category (medication therapy, radiation therapy, and surgeries) will be provided.   
Medications will be coded using the WHO Drug coding dictionary and will be tabulated by 
preferred term in descending order of frequency.   
Analyses will be based on the ITT analysis set. 
6.6. Safety Summaries and Analyses 
Summaries of AEs and other safety parameters will be based on the Safety analysis set.  
6.6.1. Adverse Events 
All analyses will be based on treatment emergent events unless otherwise specified.  
Treatment emergent is defined in section section 3.5.1.   
High-level summaries of adverse events (both All Causality and Treatment Related) will 
include the number and percent of participants with: 
• Any Adverse Event; 
• Serious AE; 
• Adverse Events with CTCAE Grade 3-4; 
• Grade 5 events; 
• AEs leading to dose interruptions; 
• AEs leading to dose reductions; 
• AEs leading to withdraw;  
Additionally, the number of events reported for each of the categories above will be 
provided.  Each unique adverse event at the PT level for a participant is included in the 
count.  
Seriousness, relatedness, toxicity grade, action taken (interruption, reduction, and withdraw) 
are as reported by the investigator on the adverse event CRF. 
Summaries by System Organ Class  and PT in decreasing frequency will be provided for: 
• Treatment Emergent Events by Maximum Toxicity Grade (All Causality); 
• Treatment Emergent Events by Maximum Toxicity Grade (Treatment Related); 
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• Serious Treatment Emergent by Maximum Toxicity Grade Events (All Causality); 
• Serious Treatment Emergent by Maximum Toxicity Grade Events (Treatment Related);  
An event will be considered treatment related if the investigator considered the event related 
to the study drugs or this information is unknown. 
Clustered adverse events will be summarized by maximum CTCAE grade and causality (all-
causality and treatment-related) together with other adverse events. Adverse Events 
pertaining to each cluster will be summarized separately, by cluster. The clustered events are 
described in a list in the product’s Safety Review Plan maintained by the Sponsor. 
The following summaries will be provided by PT/Cluster Term (summaries will not include 
SOC) in decreasing frequency: 
• Treatment Emergent Events (All Causality) by Preferred Term and Maximum Toxicity 
Grade; 
• Treatment Emergent Grade 1-2, 3-5 Events (All Causality) by Preferred Term and 
Maximum Toxicity Grade; 
• Treatment Emergent Adverse Events Leading to Dose Interruptions (All Causality); 
• Treatment Emergent Adverse Events Leading to Dose Reductions (All Causality); 
• Treatment Emergent Adverse Events Leading to Permanent Withdrawal (All Causality); 
• Treatment Emergent Adverse Events Leading to Dose Interruptions (Treatment Related); 
• Treatment Emergent Adverse Events Leading to Dose Reductions (Treatment Related); 
• Treatment Emergent Adverse Events Leading to Permanent Withdrawal (Treatment 
Related); 
• Serious Treatment Emergent Events (All Causality). 
• Serious Treatment Emergent Events (Treatment Related). 
Each participant will be counted only once within each SOC, Cluster Term and PT.   
As described in section 5.3, in case a participant has events with missing and non missing 
toxicity grades, the maximum of the non-missing grade will be displayed.   Missing grade 
will only be displayed in the event that only one event has been reported for a participant and 
the grade is missing. 
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6.6.1.1. Basic Results 
For summaries required for basic results disclosures in the US and EU the follow additional 
summaries will be provided: 
• Treatment Emergent Non-Serious Adverse Events by SOC and PT in >5% of 
participants; 
• Treatment Emergent Non-Serious Adverse Events by SOC and PT; 
• Treatment Emergent Serious Adverse Events by SOC and PT; and  
• Fatal Adverse Events by SOC and PT. 
Each of the above summaries will include a count of the number of participants with all 
causality events and the number of participants with treatment related events. 
6.6.1.2. Adverse Events of Special Interest 
These analyses will be performed for treatment emergent AEs of special interest as specified 
in 3.5.1: 
• Treatment Emergent Events by Maximum Toxicity Grade (All Causality); 
• Treatment Emergent Events by Maximum Toxicity Grade (Treatment Related); 
6.6.2. Deaths 
The frequency (number and percentage) of participants in the safety analysis set who died 
and who died within 28 days after last dose of study treatment as well as the primary reason 
for death, will be tabulated based on information from the ‘Notice of Death’. 
The frequency (number and percentage) of participants in the safety analysis set who died 
within 30 days of first dose of study treatment will also be provided. 
Date and cause of death will be provided in individual participant data listing together with 
selected dosing information (date of first / last administration, dose). 
6.6.3. Vital Signs – Weight  
The number and percent of patients in each of the following maximum body weight 
categories will be presented: 
• Maximum change from baseline body weight (increase)  < 10% 
• Maximum change from baseline body weight (increase) ≥ 10% and < 20% 
• Maximum change from baseline body weight (increase) ≥ 20% 
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7. INTERIM ANALYSES 
7.1. Introduction 
Not applicable 
7.2. Interim Analyses and Summaries 
Not applicable 
 
 
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Protocol B7461027 (PF-06463922 - Lorlatinib) Statistical Analysis Plan 
 
 
DMB02-GSOP-RF02 4.0 Statistical Analysis Plan Template 01-Nov-2018 
PFIZER CONFIDENTIAL  
Page 41 
TMF Doc ID: 98.03 
8. APPENDICES 
Appendix 1. List of Abbreviations 
Abbreviatio
n 
Term 
AE 
adverse event 
AESI 
adverse event of special interest 
BOR 
best overall response 
CDARS 
Clinical Data Analysis and Reporting System (of US Food 
and Drug Administration) 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CTC 
common toxicity criteria 
DoR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
ICF 
informed consent form 
ICR 
independent central review 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 
ND 
Not Done 
NR 
Not Reached 
OR 
Objective Response 
ORR 
Overall Response Rate 
PD 
progressive disease/disease progression 
PFS 
Progression Free Survival 
PR 
Partial Response 
PT 
preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
std 
standard deviation 
SD 
Stable Disease 
SOC 
system organ class 
TTR 
time to response 
TEAE 
Treatment Emergent Adverse Event 
WHO  
World Health Organization 
 
090177e19216a097\Final\Final On: 17-Oct-2019 10:03 (GMT)