Retrospective, Multicenter, Observational Study to Evaluate Clinical Real World Outcomes of Lorlatinib After Alectinib in ALK-Positive NSCLC Japanese Patients
Conditions: ALK-positive Non-small-cell Lung Cancer
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Retrospective, Multicenter, Observational 
Study to Evaluate Clinical Real World
Outcomes of Lorlatinib After Alectinib in 
ALK-Positive NSCLC Japanese Patients 
Protocol number
B7461038
Protocol version identifier
Version 2
Date 
15Apr 2021
Active substance
Lorlatinib
Medicinal product
Lorlatinib (LORBRENA®)
Research question and objectives
To evaluate the clinical real world outcomes 
of lorlatinib in 2ndsecond /later line setting 
as ALK TKI-TKI sequence treatment after 
failure of alectinib as a first-line treatment in 
Japanese ALK+ NSCLC patients
Author
MSc
Medical Manager, Medical Affairs, Pfizer 
Oncology Japan
PhD
Statistician, Clinical Statistics Group 1,
Development Japan
 PhD
Medical Affairs, Pfizer Oncology Japan
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................5
3. PRINCIPAL INVESTIGATOR(S) OF THE PROTOCOL...................................................6
4. ABSTRACT...........................................................................................................................6
5. AMENDMENTS AND UPDATES.......................................................................................6
6. MILESTONES.......................................................................................................................7
7. RATIONALE AND BACKGROUND..................................................................................8
8. RESEARCH QUESTION AND OBJECTIVES ...................................................................9
8.1. Primary objective ......................................................................................................9
8.2. Secondary objectives.................................................................................................9
9. RESEARCH METHODS ......................................................................................................9
9.firstudy design...............................................................................................................9
9.1.1. Primary endpoint ........................................................................................10
9.1.2. Secondary endpoint ....................................................................................10
9.1.3. Definition of endpoint.................................................................................11
9.1.4. Study flow...................................................................................................11
Setting............................................................................................................................12
9.2...................................................................................................................................12
9.2.1. Inclusion criteria .........................................................................................12
9.2.2. Exclusion criteria........................................................................................12
9.3. Variables..................................................................................................................13
9.3.1. Patient characteristics at baseline ...............................................................13
9.3.2. Time to treatment (TTF).............................................................................16
9.3.3. Objective Response ....................................................................................16
9.3.4. 3rd-line/later line regimen after lorlatinib or pretreatment regimen
before lorlatinib treatment................................................................................16
9.3.5. Combined TTF............................................................................................16
9.4. Data sources ............................................................................................................16
9.5. Study size ................................................................................................................16
9.6. Data management....................................................................................................17

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9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record........................................................................................................17
9.6.2. Record retention..........................................................................................17
9.6.3. Record disposal...........................................................................................18
9.7. Data analysis ...........................................................................................................18
9.7.1. Analysis Methods .......................................................................................18
9.8. Quality control.........................................................................................................18
9.9. Limitations of the research methods .......................................................................19
9.10. Other aspects .........................................................................................................19
9.10.1. Report to the chief executive of the study site..........................................19
10. PROTECTION OF HUMAN SUBJECTS ........................................................................19
10.1. Patient information................................................................................................19
10.2. Patient consent.......................................................................................................20
10.2.1. Subjects who are alive and visit the study site .........................................20
10.2.2. Subjects who are alive and had been transferred to another hospital.......21
10.2.3. Subjects who have died ............................................................................21
10.3. Patient withdrawal.................................................................................................22
10.3.1. Subjects who are alive and visit the study site, or subjects who are 
alive and had been transferred to another hospital...........................................22
10.3.2. Subjects who have been died....................................................................22
10.4. Institutional review board (IRB)/Independent ethics committee (IEC)................22
10.5. Ethical conduct of the study..................................................................................22
10.6. Predictable risks and benefits................................................................................22
10.6.1. Risk...........................................................................................................22
10.6.2. Benefits.....................................................................................................22
10.7. Conflicts of interest ...............................................................................................23
10.8. Registration and publication of study....................................................................23
10.9. Secondary use of specimens and information obtained from subjects..................23
10.10. Responding to consultations from subjects and other related parties .................23
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS .....................................................................................................................23
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........24

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13. REFERENCES ..................................................................................................................25
14. LIST OF TABLES.............................................................................................................25
15. LIST OF FIGURES ...........................................................................................................25
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................26
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................26
ANNEX 3. ADDITIONAL INFORMATION.........................................................................26

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AEM
adverse event monitoring 
ALK
anaplastic lymphoma kinase
BMI
body mass index
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CSA
clinical study agreement
DCF
Data Clarification Form
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EDC
electronic data capture
ENCEPP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
IEC
independent ethics committee
IQR
interquartile range
IRB
institutional review board
MHLW
Ministry of Health, Labour and Welfare
NIS
non-interventional study
NR
not reached
NSCLC
non-small cell lung cancer
PD
progressive disease
PFS
progression-free survival
Ph1 / Ph2 / Ph3
Phase1 / Phase2 / Phase3
PR
partial response
RECIST
Response Evaluation Criteria In Solid Tumors
SAP
statistical analysis plan
SD
stable disease
TKI
tyrosine kinase inhibitor
TNM
Tumor, Node and Metastasis
TTF
time-to-treatment failure
UMIN-CTR
University Hospital Medical Information Network - Clinical Trials Registry

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
List of Principal Investigators in this study will be prepared as Annex1.
4. ABSTRACT
Not applicable
5. AMENDMENTS AND UPDATES
None

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6. MILESTONES
Milestone
Planned date
Start of data collection 
02 Aug 2021
End of data collection
31 Oct 2021
Analytical dataset lock
30 Nov 2021
Completion of Analysis
31 Dec 2021

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7. RATIONALE AND BACKGROUND
Based on the results of J-ALEX/ALEX studies 1), 2), alectinib granted the highest 
recommendation in the Japanese Lung Cancer Treatment Guideline (2020) 3), and is broadly 
prescribed in the actual clinical setting in the first line setting and optimal subsequent therapy
is one of the clinical question for the anaplastic lymphoma kinase (ALK) tyrosine kinase 
inhibitor (TKI) treatment strategy.
In the 2020 clinical practice guideline for lung cancer in Japan, lorlatinib is recommended as 
a subsequent therapy option for select patients with ALK-positive (ALK+) NSCLC whose 
disease has progressed after any ALK-TKIs treatment (Recommendation level 2). Alectinib, 
brigatinib and ceritinib is also recommended as a subsequent therapy option for the patients 
with ALK+ NSCLC whose disease has progressed after ALK-TKI treatment (Alectinib :
Recommendation level 1, Brigatinib: Recommendation level 2, Ceritinib: Recommendation 
level 2).
The third-generation ALK-TKI, lorlatinib was approved (September 2018) in the
second/later line setting in Japan. It has good central nervous system (CNS) penetration and 
inhibits a broad range of ALK resistance mutations that develop after treatment with first
(crizotinib)- and second-generation ALK inhibitors (alectinib, ceritinib). Lorlatinib in Exp 2-
3A of Ph2 trial (patients treated with previous crizotinib only or patients treated with
previous crizotinib and chemotherapy) showed the median progression-free survival (PFS)
(not reached (NR) months [95% confidence interval (CI) 12.5–NR]). Lorlatinib in Exp 3B of
Ph2 trial (patients treated with one second-generation ALK-TKI) showed the median PFS
(5.5 months [95% CI 2.7–9.0]) 4).
Brigatinib in ALTA trial (patients with ALK+ NSCLC previously given crizotinib) showed
the median PFS (12.9 months [95% CI 11.1–NR]) 5) and J-ALTA trial (patients with ALK+
NSCLC previously given alectinib±crizotinib) demonstrated clinical benefit in the median 
PFS (7.3 months [95% CI 3.7–9.3]) 6).
Ceritinib in ASCEND-5 trial (patients with ALK+ NSCLC previously given
chemotherapy and crizotinib) showed a significant improvement in median PFS compared 
with chemotherapy (5.4 months [95% CI 4.1–6.9] for ceritinib vs 1.6 months [95% CI 1.4–
2.8] for chemotherapy; hazard ratio 0.49 [95% CI 0.36–0.67]; p<0·0001) 7). Ceritinib in 
ASCEND-9 trial (patients with ALK+ NSCLC previously given alectinib) also demonstrated
clinical benefit (median PFS: 3.7 months) 8) .
Although there is various evidence for the treatment sequence of ALK-TKI followed by 
another ALK-TKI in clinical trials as above mention, chemotherapy as subsequent treatment 
after failure of alectinib is widely accepted in Japan without robust evidence from clinical 
trials.
There is a paucity of information on the real-world utilization of lorlatinib and clinical

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outcomes among patients with ALK+ NSCLC for ALK TKI-TKI sequence treatment
including lorlatinib as the second /later line in Japan, although the results of lorlatinib,
brigatinib and ceritinib after alectinib in the clinical trial were as described above with the
same level of recommendation in the guideline in ALK+ NSCLC. Based on favorable
efficacy data on lorlatinib from clinical trials, this study is designed to collect the information 
on utilization of lorlatinib in an ALK+ NSCLC patients in a real-world clinical setting in 
Japan. In addition, this study will also describe characteristics and clinical outcomes of these 
patients. Findings from the study will help in addressing the knowledge gaps of lorlatinib.
8. RESEARCH QUESTION AND OBJECTIVES
To evaluate the clinical real world outcomes of lorlatinib in second /later line setting as ALK
TKI-TKI sequence treatment after failure of alectinib as a first-line treatment in Japanese 
ALK+ NSCLC patients.
8.1. Primary objective
The primary objective is to describe the demographic characteristics of patients with ALK+
NSCLC patients treated with lorlatinib as the second/later-line therapy in a real-world 
clinical setting, describe clinical usage and observed effectiveness of lorlatinib.
8.2. Secondary objectives
The secondary objectives are as follows:

To describe treatments received including alectinib as a first-line treatment prior to
lorlatinib

To describe treatment pattern after lorlatinib as a second/later-line treatment
9. RESEARCH METHODS
9.1. Study design
This study is a post-approval, company-sponsored, observational study. This study is a 
multicenter, non-interventional, retrospective, chart review of patients with ALK+ NSCLC 
patients treated using lorlatinib as the second/later line therapy in Japan after failure of 
alectinib treatment as the first line therapy from 20 November 2018.
All decisions regarding clinical management and treatment of the participating patients were 
made by an investigator as part of standard care in real-world clinical setting and were not
contingent upon the patient’s participation in the study. Data will be collected if available per
study site. Patients in this study are those who started treatment with lorlatinib from 1 May
2019 to 31 December, 2020 in clinical practice..
Observation period : From start date of alectinib to 15 Oct 2021

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9.1.1. Primary endpoint
ʀ Description of patient characteristics at baseline (at the timing of alectinib initiation date)
and at lorlatinib initiation date
̄ Age
̄ Sex
̄ Body mass index (BMI)
̄ Eastern Cooperative Oncology Group Performance Status (ECOG PS)
̄ NSCLC histopathological subtype
̄ Number and site of metastases
̄ Complications/medical history (related to history of treatment for ALK+ NSCLC)
̄ Smoking history
̄ ALK test result (ALK testing method, date of test result/diagnosis and test result)
̄ # of treatment regimens administered to the target disease prior to the start of
lorlatinib treatment
̄ Time-to-treatment failure (TTF) for lorlatinib as the second line and the 3rd/later line
(see Section 9.3.2. for definition)
9.1.2. Secondary endpoint
̄ Reason for discontinuation of each treatment line therapy
̄ Objective response of lorlatinib as the second line and the 3rd/later line
̄ TTF of alectinib and subsequent therapy except for lorlatinib 
̄ Objective response of alectinib
̄ Combined TTF; combined TTF will be defined as the sum of alectinib and 
subsequent therapy including TTF of lorlatinib 

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9.1.3. Definition of endpoint
9.1.3.1. TTF and Objective response
TTF is defined as the following:
Endpoint
Start date
Event (whichever occurs
earlier)
Censored
TTF
Date of first
treatment
Date of any-cause treatment
discontinuation including 
disease progression, 
treatment toxicity, and 
death.
Date of last treatment or 
end of observation period
Objective response is defined as the following:
Complete or partial response as the best adjudication result (complete response [CR] > partial 
response [PR] > stable disease [SD] > progressive disease [PD], unknown) in a method
complies with RECIST version. 1.1 tumor assessment as closely as possible in clinical 
practice by investigator’s judgment.
9.1.4. Study flow
The study flow is shown below (Figure 1 and Figure 2)
9.1.4.1. Patients who are alive and visit the study site upon enrollment in this
study
1. Investigators will check whether the patient meets the eligibility criteria. Patients will
then be included in this study.
2. Investigators will explain the study and obtain written informed consent from patients.
3. Data of these patients will be collected at each study site.
Figure1Study flow for patients who are alive and visit the study site

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9.1.4.2. firstPatients who have died
1. Investigators will check whether the patient meets the eligibility criteria, and patients will 
then be included in this study.
2. The details of the study will be disclosed to the patient’s legal representative must be 
guaranteed the opportunity to refuse participation or continuation in the study.
Information about this study must be easy for the patient’s legal representative to find:
posted on a website or displayed in a location where patient’s legal representative can 
check it.
3. The data of these patients will be collected at each study site.
Figure 2 Study flow for patients who have died
9.2. Setting
9.2.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Histologically or cytologically confirmed NSCLC, with any TNM stage.
2. Confirmed ALK gene rearrangement by any validated test.
3. Confirmed the treatment with alectinib in the first line setting as systemic therapy in the 
medical record.
4. Confirmed the start treatment with lorlatinib as the second/later-line therapy from 1st May
2019 to 31st December 2020. 
5. Availability of clinical information from medical record.
6. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects
of the study.
(1) Written consent is not required for patients who were transferred to a hospital, and 
registration with verbal consent is acceptable.(2) Opt-out enrollment is allowed for 
patients who have already died.
9.2.2. Exclusion criteria
Patients meeting any of the following criteria will not be included in this study:

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1. Participating on any clinical trials of which final results has not yet been reported during 
the study period.
9.3. Variables
9.3.1. Patient characteristics at baseline
All included cases will be treated with lorlatinib (exposure). Variables for patient 
characteristics, treatment and outcomes are presented in Table 1
Variables planned at the baseline will be collected at the time of obtaining the informed 
consent as much as possible.

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Table 1 Key variables of interest and data collection timepoints.
Role
Variable
Timepoint
Baseline
Initiation of 
lorlatinib
Subsequent 
follow-up 
visits
End of 
observati
on period
Patient 
characteristics
Age
X
Sex
X
Weight
X
(X) c
Height
X
(X) c
Smoking status (Current 
smoker, Former smoker, 
Never smoker)
X
Brinkman index
X
ECOG PS (Grades 0 to 5) a
X
X
X
Date of initial NSCLC
diagnosis
X
Date of advanced NSCLC 
(TNM stage IIIb-IV) 
diagnosis 
X
NSCLC histopathological 
subtype
X
Clinical NSCLC staging 
(based on Tumor, Node and
Metastasis, TNM) b
X
X
Presence and location of 
metastasis (including central 
nervous system, CNS) at 
initial diagnosis and 
lorlatinib initiation
X
X
X
Complications/medical 
history (related to history of 
treatment for ALK+ 
NSCLC)
X
Date of ALK testing
X
X
Method of ALK testing
X
X
Alectinib initiation date
X
Alectinib discontinuation 
date
X
Presence and location of 
metastasis (including central 
nervous system, CNS) 
during Alectinib treatment 
X
Presence of treatment for 
some metastasis (including 
X

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Role
Variable
Timepoint
Baseline
Initiation of 
lorlatinib
Subsequent 
follow-up 
visits
End of 
observati
on period
CNS) during Alectinib 
treatment, and type of 
treatment(i.e. Radiation 
Therapy)
Reason for alectinib
discontinuation
X
second-line treatment start/
end date and drug name, 
reason for the 
discontinuation, if lorlatinib 
is 3rd line treatment
X
Treatment
Line for lorlatinib
X
Lorlatinib initiation date
X
Dose of lorlatinib
X
X d
Lorlatinib discontinuation 
date
X
Reason for lorlatinib
discontinuation
X
Third-line or later treatment 
start and end dates, if 
lorlatinib is second or later 
line treatment.
X
Reason for Third-line or later 
discontinuation, if lorlatinib 
is second or later line
treatment.
X
Outcomes
TTF for lorlatinib
X
TTF for alectinib
X
If anticancer drug other than 
lorlatinib is used as 2nd line: 
TTF of anti-cancer treatment
X
If anticancer drugs are used 
after 2nd line lorlatinib: TTF 
of anti-cancer treatment
X
Tumor response to lorlatinib 
based on the RECIST
X
Tumor response to alectinib 
and second/3rd line 
treatment based on the
RECIST
(X) c
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; CNS, central nervous system; 
NSCLC, non-small cell lung cancer; ALK, anaplastic lymphoma kinase; TNM, Tumor Node Metastasis; RECIST, Response
Evaluation Criteria In Solid Tumors; TTF, time-to-treatment failure.

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a See Annex 3A for more information. 
b See Annex 3B and C for more information.
c Not mandatory, but if available.
dat the date of discontinuation
9.3.2. Time to treatment (TTF)
Definitions of TTF is defined in Section 9.1.3.The following lorlatinib treatment data will be 
collected: initial date of administration, actual dosage at the date of discontinuation, the date 
and the reason for discontinuation.
9.3.3. Objective Response
Definitions of objective response are defined in Section 9.1.3. The following data will be 
collected: tumor response, and date of tumor response assessment.
Best objective response will be assessed based on reported overall responses at different 
evaluation time points from each initiation of treatment therapy until discontinuation.
9.3.4. 3rd-line/later line regimen after lorlatinib or pretreatment regimen before 
lorlatinib treatment
The following 3rd/later-line regimen data will be collected, if lorlatinib treatment is the
second line setting: medication, initial date of administration, and reason for discontinuation.
The following second-line regimen data will be collected, if lorlatinib treatment is 3rd/later-
line setting: medication, initial date of administration, and reason for discontinuation.
9.3.5. Combined TTF
Definitions of Combined TTF is the sum of alectinib and subsequent therapy including TTF 
of lorlatinib and other treatment.
9.4. Data sources
As this is a retrospective study, all data will be collected from medical records at the 
participating study site.
9.5. Study size
This study is descriptive study which aims to describe the demographic characteristics of 
patients who were treated with lorlatinib in the second/later line treatment for ALK+ NSCLC 
patients, rather than testing any pre-defined hypothesis. Therefore, calculation of sample size 
and statistical power are not relevant.
The expected number of patients will be approximately 50 patients treated with loratinib in 
total (# of patients for the second line lorlatinib treatment will be approximately 30).  
However, the number should be considered flexible.

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9.6. Data management 
Investigators will fill out relevant CRFs based on source documents (e.g., patients’ medical
charts) by EDC. After the completion of the CRFs, the investigator will promptly submit 
them.
When receiving a query from the sponsor on the completed CRF (i.e., Data Clarification
Form [DCF]), investigators will reconfirm the information on source documents, fill out the 
DCF as required, and submit the DCF.
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete,
consistent, legible, timely (contemporaneous), enduring, and available when required.  The
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
The source documents are the hospital or the physician's chart. In these cases, data collected
on the CRFs must match those charts. 
9.6.2. Record retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients
(sufficient information to link records, e.g., CRFs and hospital records), all original signed 
informed consent, copies of all CRFs, safety reporting forms, source documents, detailed 
records of treatment disposition, and adequate documentation of relevant correspondence 
(e.g., letters, meeting minutes, and telephone call reports). The records should be retained by 
the investigator according to local regulations or as specified in the clinical study agreement
(CSA), whichever is longer.  The investigator must ensure that the records continue to be 
stored securely for so long as they are retained.

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If the investigator becomes unable for any reason to continue to retain study records for the
required period (e.g., retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless Pfizer have expressly agreed to a different period of retention via a separate
written agreement.  Record must be retained for longer than 15 years if required by 
applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
9.6.3. Record disposal
Study records must be disposed of appropriately according to each site regulation.
9.7. Data analysis
Detailed methodology for summary and statistical analyses of data collected in this study will
be documented in a statistical analysis plan (SAP), which will be dated, filed and maintained
by the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment.
9.7.1. Analysis Methods
Characteristics, treatment patterns and outcomes of ALK+ NSCLC patients treated with 
lorlatinib will be described in SAP . 
Continuous variables will be summarized using n, means, standard deviations, medians, 
IQRs, minimums and maximums. Categorical variables will be summarized using
frequencies (counts) and percentages. For the time-to-event endpoints, e.g. TTF, the Kaplan-
Meier estimates (product-limit estimates) will be presented together with a summary of 
associated statistics including the median TTF with 2-sided 95% CIs using Brookmeyer and 
Crowley method. Censoring rule is shown in Section 9.1.3.1. These endpoint will also be
displayed graphically.
Exploratory analyses using Cox proportional hazards model may be performed to examine 
the association between time-to-event outcomes and independent variables such as baseline 
patient, disease characteristics (e.g. age, sex, line of lorlatinib therapy, ECOG performance 
status, CNS metastasis, etc), and the reason for discontinuation of lorlatinib.
9.8. Quality control
The sponsor will train investigators and study site staff with an onsite training visit or web-
training on the protocol, CRFs, and any applicable study processes. Any new information 

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relevant to the performance of this study will be forwarded to the investigator and study site 
staff during the study. Remote data monitoring will be conducted during the life of the study 
to ensure timely reporting of data, data integrity, and consistency. CRFs for all included
patients will be made available to the remote data monitor for review. The study sites will be 
queried and managed to request resolution to any issues that may arise during the course of 
the study.
9.9. Limitations of the research methods
•
Because this study is retrospective in nature, only existing data reported in patient 
records will be available. Variables that are often missing may affect estimation
accuracy.
•
High-volume centers will be preferentially selected in this study, so site selection and 
outcome reporting bias may be included. For this reason, the study results may not 
reflect all Japanese clinical outcomes.
•
Evaluation of disease response may differ at each site, and measurement errors may be 
included in the estimated value.
9.10. Other aspects
9.10.1. Report to the chief executive of the study site
Each study site’s investigator shall report the following to the chief executive of the study
site in writing:
1˅ points to be revised in the protocol;
2˅ progression of the study
3˅ termination, discontinuation, and interruption of the study.
10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic form and will be
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster. In the event of a potential personal data breach, the
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 

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code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.2. Patient consent
10.2.1. Subjects who are alive and visit the study site
The investigator explains participation to patients using the reviewed and approved patient 
information sheet. An informed consent form is then used to obtain written consent from
fully informed patients. The investigator explains that participation in the research is
completely voluntary and that subjects are free to withdraw their consent at any time, even 
after providing consent form. In addition, the attending physician have to take necessary
measures to ensure that subjects’ rights to self-determination and treatment choice are not 
limited and that they would not be penalized for refusing or withdrawing consent from 
participation in the study. The informed consent form will then be revised after institutional 
review board (IRB)/independent ethics committee grants approval, and written consent will
be obtained from each subject. 
࡮Information to be provided to subjects
1)
Title of the study and the fact that approval of the chief executive of the study site has 
been given concerning its implementation. 
2)
Names of the study site and the principal investigator (including names of the 
collaborative study site(s) and principal investigators of such collaborative study 
site(s), when the study is conducted collaboratively with other study site(s));
3)
Objectives and significance of the study;
4)
Method and time period of the study (including purpose of utilization of specimens or 
information acquired from the subject);
5)
Reasons why asked to be enrolled in the study;
6)
Burdens to be caused on the subjects and predictable risks and benefits;
7)
The fact that subjects, etc. may withdraw their consent at any time even after they
have given consent with regard to the study being commenced or continued (when it 
can be difficult to take measures that follow the withdrawal made by the study
subject, etc., a statement to that effect and the reason for the difficulty). 
8)
The fact that the refusal or withdrawal of consent by a study subject, etc., with regard
to the study is to be commenced or continued does not cause any disadvantage to such 
subject, etc.
9)
Means to make information on the study public;

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10)
The fact that subjects, etc. can request and obtain or read the study protocol and 
documents concerning method of the study, to the extent it does not interfere the
protection of personal information, etc. of other subjects, etc. or the originality of the 
study, as well as the procedure to obtain or read such protocols and documents;
11)
Handling of personal information, etc. (including process of anonymization, when 
anonymization is conducted);
12)
Means for storage and disposal of specimens and information;
13)
Status of study-related conflicts of interest of the study site, such as study fund 
resources as well as study-related conflicts of interest of each investigator, such as 
his/her individual income. 
14)
Response to consultation, etc. made by subjects, etc. and other individuals concerned.
15)
When the study involves any financial expenditure on or remuneration for the subject, 
etc., a statement to that effect and details of such;
16)
When the study involves any invasiveness, whether compensation will be offered for 
study-related injury and details of such compensation. 
17)
With respect to specimens and information acquired from the subject, when any of 
those may be utilized or provided to other study site(s) for future study that is not 
identified at the time of obtaining consent from the study subject, etc., a statement to 
that effect and the contents of utilization assumed at the time of obtaining consent; or
18)
When the study involves any invasiveness (not including minor invasiveness) and 
intervention, the fact that the monitor(s), the auditor(s), and the ethical review 
committee will be granted direct access to the specimens and information acquired 
from the subjects to the extent necessary, without violating the confidentiality of the 
subjects.
10.2.2. Subjects who are alive and had been transferred to another hospital
It is not always necessary to obtain written informed consent when existing information is 
provided to another hospital, but the individual providing existing information must obtain 
oral informed consent.
10.2.3. Subjects who have died
Because the study is retrospective, informed consent could not be obtained from subjects 
who had died or had failed to visit the study site. Instead of informed consent, the 
investigator must provide the legal representatives of the subjects an opportunity to refuse
participation in the study. The following information must be made public:
1)
purpose for which the information will be used;
2)
item of collected information;

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3)
person responsible for information management;
4)
organization that will be provided information;
5)
how to manage refusal—if the subject refuses participation in the study, their data 
cannot be used. 
10.3. Patient withdrawal
10.3.1. Subjects who are alive and visit the study site, or subjects who are alive and had 
been transferred to another hospital
During the course of this study, the subject can withdraw his/her consent at any time. In any 
circumstance, every effort should be made to document patient outcomes, if possible. If the 
patient withdraws from the study and withdraws consent for disclosure of future information, 
no further evaluations should be performed and no additional data should be collected. The 
sponsor may retain and continue to use any data collected before withdrawal of consent.
10.3.2. Subjects who have been died
When the legal representatives of subjects refuse to participate in the study during the study 
period, all of their data must be excluded from the analysis dataset. If the results of this study 
are disclosed on paper or conference at the time of refusal, the subject’s data cannot be 
excluded.
10.4. Institutional review board (IRB)/Independent ethics committee (IEC)
There must be prospective approval of the study protocol, protocol amendments, and other
relevant documents (e.g., informed consent forms if applicable) from the relevant IRBs/IECs.  
All correspondence with the IRB/IEC must be retained.  Copies of IRB/IEC approvals must
be forwarded to Pfizer.
10.5. Ethical conduct of the study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in the Ethical Guidelines for Medical and Health Research Involving Human 
Subjects issued by the Ministry of Health, Labor and Welfare (MHLW).
10.6. Predictable risks and benefits
10.6.1. Risk
The subjects’ data will be collected retrospectively in this study, so there is no added risk to 
any individual subject.
10.6.2. Benefits
For individual subjects, there is no particular benefit because the study had a retrospective 
study design.

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10.7. Conflicts of interest
This study will be performed with funding from Pfizer Inc. The investigators will review any
conflicts of interests that may affect the planning of this study or the interpretation of results 
by the IRB/IEC or the Conflicts of Interest Committee, according to the regulations of the 
study site. When the results of the study are published, accurate information will be disclosed 
by self-reporting in compliance with the guidelines of the academic society or journal used 
for publishing the results of the study.
10.8. Registration and publication of study
Prior to implementation, this study and a summary were registered in the public database of 
UMIN-CTR and clinicaltrials.gov. Registered content will be properly updated without 
delay.
10.9. Secondary use of specimens and information obtained from subjects
The data obtained from this study may be used in other studies with different purposes. Such
use will only be possible if another protocol is developed and approved by the IRB/IEC.
10.10. Responding to consultations from subjects and other related parties
The principal investigator will set up a helpline for handling consultations about this study 
from subjects and other related parties. Information about each site helpline is included in the 
informed consent form and document related to opt-out.
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol). Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows:
Ь All serious and non-serious AEs with explicit attribution to any Pfizer drug that appear in 
the reviewed information must be recorded on the <data collection tool (e.g., chart 
abstraction form)> nd reported, within 24 hours of awareness, to Pfizer Safety using the NIS 
AEM Report Form.

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Ь Scenarios involving drug exposure, including exposure during pregnancy, exposure during 
breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy, and 
occupational exposure associated with the use of a Pfizer product must be reported, within 24 
hours of awareness, to Pfizer Safety using the NIS AEM Report Form.
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted.
ĀAll the demographic fields on the NIS AEM Report Form may not necessarily be 
completed, as the form designates, since not all elements will be available due to privacy 
concerns with the use of secondary data sources. While not all demographic fields will be 
completed, at the very least, at least one patient identifier (e.g., gender, age as captured in the 
narrative field of the form) will be reported on the NIS AEM Report Form, thus allowing the 
report to be considered a valid one in accordance with pharmacovigilance legislation. All 
identifiers will be limited to generalities, such as the statement “A 35-year-old female...” or
“An elderly male...” Other identifiers will have been removed.
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month /year of occurrence in the day/month/year 
(DD/MMM/YYYY ) format.”>
All research staff members must complete the following Pfizer training requirements:
ĀYRR Training for Vendors Working on Pfizer Studies (excluding interventional clinical 
studies and non-interventional primary data collection studies with sites/investigators)”.
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format. Copies of all signed training certificates must be provided to Pfizer.
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.  

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The results of this study are not part of any regulatory submission. The results of this study 
will be submitted for abstracts and publications. The final output will be filed in Pfizer’s 
Global Document Management System upon final study completion. 
13. REFERENCES
1) Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with 
ALK-positive non-small-cell lung cancerقJ-ALEXك: an open-label, randomised 
phase 3 trial. Lancet. 2017; 390ق10089ك: 29-39.
2) 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; 377ق9ك: 829-38.
3) https://www.haigan.gr.jp/guideline/2020/1/2/200102070100.html#cq59
4) Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-
small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018; 19
ق12ك: 1654-67.
5) Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory 
anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, 
multicenter phase ⋜trial. J Clin Oncol. 2017; 35ق22ك: 2490-8.
6) Nishio M, Yoshida T, Kumagai T, et al. Brigatinib in Japanese Patients With
ALK-Positive NSCLC Previously Treated With Alectinib and Other Tyrosine Kinase 
Inhibitors: Outcomes of the Phase 2 J-ALTA Trial. JTO. 2020 Nov 25; S1556-
0864(20)31026-1.
7) Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients with 
ALK-rearranged non-small-cell lung cancer previously given chemotherapy and
crizotinibقASCEND-5ك: a randomised, controlled, open-label, phase 3 trial. 
Lancet Oncol. 2017; 18ق7ك: 874-86.
8) Hida T, Seto T, Horinouchi H, et al. Phase Ⅱ study of ceritinib in alectinib-pretreated 
patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung 
cancer in Japan: ASCEND-9. Cancer Sci. 2018; 109ق9ك: 2863-72.
14. LIST OF TABLES 
Table 1 Key variables of interest and data collection timepoints.
15. LIST OF FIGURES
Figure firstudy flow for patients who are alive and visit the study site
Figure 2 Study flow for patients who have died

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ANNEX 1. LIST OF STAND ALONE DOCUMENTS
Number
Document reference 
number
Date
Title
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable
ANNEX 3. ADDITIONAL INFORMATION
Annex 3A. Description of the Eastern Cooperative Oncology Group (ECOG) Performance
Status. 
Grade
Description
Grade 0  
Fully active, able to carry on all pre-disease performance without restriction.
Grade 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work.
Grade 2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours.
Grade 3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours.
Grade 4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair.
Grade 5 
Dead
Reference:  Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol. 1982; 5:649-655.
Annex 3B. Definitions for Tumor, Node and Metastasis (TNM) descriptors. 
Grade
T (primary tumor)
T0
No primary tumor
Tis
Carcinoma in situ (squamous or adenocarcinoma)
T1
T1mi
T1a
T1a
T1b
T1c
Tumor ≤3cm
Minimally invasive adenocarcinoma
Superficial spreading tumor in central airways
Tumor ≤1cm
Tumor >1 but ≤2cm
Tumor >2 but ≤3cm
T2
T2a
T2b
Tumor >3 but ≤5cm or tumor involving: visceral pleura, main bronchus (not 
carina), atelectasis to hilum
Tumor >3 but ≤4cm
Tumor >4 but ≤5cm

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T3
Tumor >5 but ≤7cm or invading chest wall, pericardium, phrenic nerve; or separate 
tumor nodule(s) in the same lobe
T4
Tumor >7cm or tumor invading: mediastinum, diaphragm, heart, great vessels, 
recurrent laryngeal nerve, carina, trachea, esophagus, spine; or tumor nodule(s) in a 
different ipsilateral lobe
N (regional lymph nodes)
N0
No regional node metastasis
N1
Metastasis in ipsilateral pulmonary or hilar nodes
N2
Metastasis in ipsilateral mediastinal or subcarinal nodes
N3
Metastasis in contralateral mediastinal, hilar, or supraclavicular nodes
M (distant metastasis)
M0
No distant metastasis
M1a
Malignant pleural or pericardial effusion or pleural or pericardial nodules or 
separate tumor nodule(s) in a contralateral lobe
M1b
Single extrathoracic metastasis
M1c
Multiple extrathoracic metastases (1 or >1 organ)
Reference:  Rami-Porta R, Asamura H, Travis WD, Rusch VW. Lung cancer: Major changes in the American Joint 
Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):138-155.
Annex 3C. Lung cancer stage grouping based on Tumor, Node and Metastasis (TNM) 
grades. 
T/M
Subcategory
N0
N1
N2
N3
T1
T1a
IA1
IIB
IIIA
IIIB
T1b
IA2
IIB
IIIA
IIIB
T1c
IA3
IIB
IIIA
IIIB
T2
T2a
IB
IIB
IIIA
IIIB
T2b
IIA
IIB
IIIA
IIIB
T3
T3
IIB
IIIA
IIIB
IIIC
T4
T4
IIIA
IIIA
IIIB
IIIC
M1
M1a
IVA
IVA
IVA
IVA
M1b
IVA
IVA
IVA
IVA
M1c
IVB
IVB
IVB
IVB
Reference:  Rami-Porta R, Asamura H, Travis WD, Rusch VW. Lung cancer: Major changes in the American Joint 
Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):138-155.

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