Lorlatinib in Patients With Advanced Non-Small Cell Lung Cancer Who Progress on First- and Second- Generation Tyrosine Kinase Inhibitor: A Real-world Evidence Among Taiwanese Population, Non-Interventional Study
Conditions: Non-Small Cell Lung Carcinoma
Sponsor: Pfizer

L orlati ni b  
B 7 4 6 1 0 2 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Fi nal , Ver 1. 0, 1 1 Dec  2 0 1 9   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  1. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n 
St u dy  1 5 -A u g -2 0 1 8   
P a ge 1  of 2 3  
 
St u d y i nf or m ati o n  
Title  
L orl ati ni b i n Patie nts wit h  A d va nce d N o n -
S mall Cell L u n g Ca n cer W h o Pr o gress o n  
First - a n d 
Sec o n d - G e nerati o n T yr osi ne 
Ki nase I n hi bit or : A  R eal-w orl d 
E vi de nce  
a m o n g  
Tai w a nese  
P o p ulati o n , 
N o n -
Inter ve nti o nal S t u d y 
Pr ot oc ol n u m ber  
B 7 4 6 1 0 2 8  
Pr ot oc ol ve rsi o n i de ntifier  
1. 0  
D ate  
1 1 Dec 2 0 1 9  
Acti ve s u bst a nce  
P F -0 6 4 6 3 9 2 2  
Me dici n al pr o d uct  
L orl ati ni b  
Rese arc h q uesti o n a n d o bjecti ves  
T he pri mar y o bjecti ve of t his st u d y is t o  
e val uate 
real -w orl d 
s yste mic 
treat me nt 
patter ns 
a n d 
cli nical 
o utc o me 
a m o n g 
a d va nce d 
n o n -s mall 
cell 
l u n g 
ca n cer 
( N S C L C) p atie nts treate d i n L orlati ni b  w h o 
were pr o gresse d o n c he m ot hera p y, first- a n d 
sec o n d- ge n erati o n T KI   
A ut h or  
 
 
 
P P D
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Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 2 of 23 
1. TABLE OF CONTENTS 
 
 
1. TABLE OF CONTENTS ....................................................................................... 2 
2. LIST OF ABBREVIATIONS ................................................................................ 4 
3. RESPONSIBLE PARTIES .................................................................................... 6 
4. AMENDMENTS AND UPDATES ..................................................................... 10 
5. MILESTONES ..................................................................................................... 11 
6. RATIONALE AND BACKGROUND ................................................................ 11 
7. RESEARCH QUESTION AND OBJECTIVES ................................................. 12 
8. RESEARCH METHODS .................................................................................... 13 
8.1. Study design ............................................................................................ 13 
8.2. Setting ...................................................................................................... 13 
8.2.1. Inclusion criteria ......................................................................... 14 
8.2.2. Exclusion criteria ........................................................................ 14 
8.3. Variables .................................................................................................. 15 
8.4. Data sources ............................................................................................ 16 
8.5. Study size ................................................................................................ 16 
8.6. Data management .................................................................................... 16 
8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record ........................................................................................ 17 
8.6.2. Record retention .......................................................................... 17 
8.7. Data analysis ........................................................................................... 18 
8.8. Quality control ......................................................................................... 18 
8.9. Limitations of the research methods ....................................................... 19 
8.10. Other aspects ......................................................................................... 19 
9. PROTECTION OF HUMAN SUBJECTS .......................................................... 19 
9.1. Patient information .................................................................................. 19 
9.2. Patient consent ......................................................................................... 19 
9.3. Patient withdrawal ................................................................................... 20 
9.4. Institutional review board (IRB)/Independent ethics committee (IEC) .. 20 
9.5. Ethical conduct of the study .................................................................... 20 
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Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 3 of 23 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ...................................................................................................... 21 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ........................................................................................................... 21 
12. REFERENCES .................................................................................................. 22 
13. LIST OF TABLES ............................................................................................. 22 
14. LIST OF FIGURES ........................................................................................... 22 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS ......................................... 22 
ANNEX 2. ADDITIONAL INFORMATION ......................................................... 23 
 
 
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Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 4 of 23 
2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AEM 
Adverse Event Monitoring 
ADR 
Adverse Drug Reaction 
ALK 
Anaplastic Lymphoma Kinase 
ATP 
Adenosine Triphosphate 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSA 
Clinical Study Agreement 
CR 
Complete Response 
CUP 
Compassionate Use Program 
DCT 
Data Collection Tools 
EC 
Ethics Committee 
EML4 
Echinoderm Microtubule-Associated Protein-
Like 4  
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practices 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
NIS 
Non-interventional Study 
NSCLC 
Non-Small-Cell Lung Cancer 
090177e1a53d4f42\Approved\Approved On: 05-Jan-2026 12:56 (GMT)

Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 5 of 23 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
ROS-1 
Receptor Tyrosine Kinase C-Ros Oncogene I 
PR 
Partial Response 
RTK 
Receptor Tyrosine Kinase 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
TKI 
Tyrosine Kinase Inhibitor 
TTF 
Time to Treatment Failure 
YRR 
Your Reporting Responsibilities 
 
 
 
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L orlati ni b  
B 7 4 6 1 0 2 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Fi nal , Ver 1. 0, 1 1 Dec  2 0 1 9   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  1. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n 
St u dy  1 5 -A u g -2 0 1 8   
P a ge 6  of 2 3  
3.  R E S P O N SI B L E P A R TI E S  
T he c o nta ct details of all mai n res p o nsi ble parties a n d t he list of all i n vesti gat ors will be 
ke pt i n a sta n d -al o ne d o c u me nt a n d liste d i n A n ne x 1.  
Pri nci p al I n vesti g at or (s) of t he Pr ot oc ol  
  
N a me, de gree(s)  
J o b Title  
Affili ati o n  
A d dress  
 M D 
 
 
 
  
 
  
  
 
 
 
 
P P D
P P D
P P D
P P D
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L orlati ni b  
B 7 4 6 1 0 2 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Fi nal , Ver 1. 0, 1 1 Dec  2 0 1 9   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  1. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n 
St u dy  1 5 -A u g -2 0 1 8   
P a ge 7  of 2 3  
A B S T R A C T  
St u d y Title: L orl ati ni b  i n Patie nts wit h A d va nce d N o n-S mall Cell L u n g C a ncer 
W h o 
Pr o gress o n First - a n d Sec o n d - Ge n erati o n T yr osi ne Ki nase I n hi bit or: A Real -w orl d 
E vi de nce a m o n g T ai wa n ese P o p ulati o n, N o n -I nter ve nti o nal St u d y 
R ati o n ale a n d B ac k gr o u n d:  
N o n -s mall cell l u n g ca ncer ( N S C L C; 8 0 – 8 5 % of all l u n g ca ncers) re mai ns t he m ost 
c o m m o n ca use of ca ncer -relat e d m ortalit y gl o ball y, m ost ofte n dia g n ose d i n a d va nce d 
sta ges. Tar gete d dr u gs are c urre ntl y t he m ost oft e n use d t hera pies f or a d va nce d N S C L C  
patie nts  t hat har b or 
m olecular alterati o ns, i ncl u di n g t he ec hi n o der m 
micr ot u b ule -
ass ociate d pr otei n li ke 4 ( E M L 4) -a na pl astic l y m p h o ma ki nase ( A L K) tra nsl ocati o n  [ 1]. F or 
A L K -p ositi ve N S C L C  p atie nts , criz oti ni b, ceriti ni b, alecti ni b, a n d bri gati ni b, are t he first- 
a n d sec o n d -ge n erati o n t yr osi ne ki nase i n hi bit ors ( T KIs). Alt h o u g h t he be n efit of t he m has 
bee n de m o nstrate d  i n series of pi v otal cli nical trials , m ost patie nts w h o i nitiall y deri v e t he 
be nefit lat terl y de v el o p resista nce d ue t o sec o n d ar y m utati o ns [ 2, 3]. L orl ati ni b, a t hir d-
ge n erati o n i n hi bit or, is a T KI of A L K a n d R ece pt or T yr osi ne Ki n ase C -R os O nc o ge n e I  
(R O S -1 ). It is als o a p ote nt T KI t hat is effecti vel y a gai nst k n o w n resista nt m uta nts t hat 
me diate resista nce t o first - a n d sec o n d -ge nerati o n A L K -T KIs  [ 2, 4]. Des pite t he effica c y 
a n d safet y dat a deri v e d fr o m t he pi v otal p hase 1/ 2 cli nical trial , t here are li mite d data 
descri bi n g t he use of l orl ati ni b a n d its o utc o mes i n real -w orl d practice s etti n gs o utsi de t he 
hi g hl y c o ntr olle d e n vir o ns of cli nical trials. T he o bjecti ve of t his st u d y is t heref ore t o 
e val uate real -w orl d s yst e mic treat me nt p atter ns, cli nical o utc o me, t h era p e utic effect, safet y 
pr ofile of L orlati ni b i n a d va nce d N S C L C p atie nts, a n d als o fact ors ass ociate d wit h cli nical 
o utc o me i n t h ose L orlati ni b treate d patie nts.  
R ese arc h Q uesti o n a n d O bjecti ves: 
Pri mar y O bj ecti ve  
⚫ 
T o e val uate real -w orl d s yste mic treat me nt patter ns a m o n g a d v a nce d n o n -s m all 
cell l u n g ca ncer ( N S C L C)  patie nts tr eate d wit h 
L orlati ni b  w h o 
were 
pr o gresse d o n c he m ot h era p y, first - a n d s ec o n d - ge n erati o n T KI a m o n g 
Tai wa nes e p o p ulati o n.  
Sec o n dar y O bj ecti ve  
⚫ 
T o s u m marize t he t hera pe utic effect a n d safet y pr ofile of L orl ati ni b -treate d 
patie nts wit h a d va nce d N S C L C  
 
⚫ 
 
 
S t u d y Desi g n 
T his is a retr o- a n d pr os p ecti ve, m ulti -ce nter, o bs er vati o nal st u d y.  
C CI
C CI
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Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 8 of 23 
Population 
All subjects will be enrolled from Lorlatinib Compassionate Use Program (CUP) and 
should be entered into this observational study at the physician’s discretion.   
Variables 
Variable 
Role 
Operational definition 
Demographic 
characteristics 
Baseline 
characteristics  
Gender, age, smoking history, Hepatitis B 
Virus (HBV)/Hepatitis C Virus (HCV) 
infection status, prescription and diagnose 
record for NSCLC history and etc. at first 
dose of Lorlatinib used. 
NSCLC History 
Baseline 
Characteristics, 
study outcome 
NSCLC diagnose from initial diagnose to 
current status and NSCLC related gene 
mutation. 
Treatment of NSCLC 
TKI Exposure 
Treatment 
Duration 
Study outcome 
CT/TKI exposure, treatment duration and 
persistence by standard of care medical 
practice. 
Tumor assessment for 
NSCLC 
Study outcome 
1) Best response of pre-Lorlatinib NSCLC 
treatment will be presented as four ORR 
categories by physician clinical 
judgement  
2) NSCLC related gene mutation status 
before and after Lorlatinib Treatment 
3) ORR in intracranial, extracranial and 
overall response of Lorlatinib. 
4) OS, PFS, 1-year OS rate and Time to 
Treatment Failure (TTF) of each 
treatment and TTF of Lorlatinib. 
Lorlatinib 
related 
adverse drug reaction 
(ADR) 
Study outcome 
Lorlatinib related ADR to be recorded from 
first dose of Lorlatinib until study closed. For 
any ongoing Lorlatinib related ADR at the 
end of study, the reporting process will 
follow 
local 
regulations 
and 
Pfizer 
Spontaneous reporting related SOPs and the 
data will not be included in study data pool. 
Drug and non-drug 
treatment from first 
dose of Lorlatinib to 
study completion 
Study outcome 
Medications and procedures for NSCLC, 
comorbidities/complications and Lorlatinib 
ADR 
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Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 9 of 23 
 
Data Source 
The data will be collected through medical record review including the followings: 
 
- 
Subject demographic characteristics 
- 
HBV and HCV infection status 
- 
Prescription and diagnose record for NSCLC  
- 
NSCLC related gene examination result 
- 
Prescription and diagnose record for Lorlatinib related ADR 
- 
Tumor Assessment for NSCLC from initial diagnose. 
 
Study Size 
Given this is an observational study rather than a clinical research of comparison, the 
sample size is limited by actual patients fulfill the inclusion criteria and without any 
situation listed in exclusion criteria treated in Taiwan during the data collection period;  
calculated sample number is not applicable for present setting. However, attempt will be 
made to ensure around 90 subjects with comprehensive data can be enrolled to provide 
valuable clinical information. 
Data Analysis 
Kaplan-Meier estimates of survival curves will compute for overall survival (OS) 
progression free survival (PFS), 1-year OS rate, time to treatment Failure (TTF) and will 
be analyzed by the log rank test. Multivariate analyses will be carried out and variables 
include sex, smoking status, pathology, stage, and the potential interactions of any two 
factors used by fitting multiple Cox’s proportional hazard models to predict patient’s 
hazard rates of duration of response. In statistical testing, two-sided P ≦ 0.05 was 
considered statistically significant. 
Milestones 
Milestone 
Planned date 
Completion of feasibility assessment 
31 Aug 2019 
Start of data collection   
31 May 2020 
End of data collection  
30 Sep 2020 
Final study report 
31 Dec 2020 
 
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Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 10 of 23 
4. AMENDMENTS AND UPDATES 
 
Amendment 
number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 
NA 
 
 
 
 
 
 
 
 
 
 
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Lorlatinib 
B7461028 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, Ver 1.0, 11 Dec 2019  
 
 
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF02 1.0 Non-Interventional Study Protocol Template For Secondary Data Collection 
Study 15-Aug-2018  
Page 11 of 23 
5. MILESTONES 
 
Milestone 
Planned date 
Completion of feasibility assessment 
31 Aug 2019 
Start of data collection   
31 May 2020 
End of data collection  
30 Sep 2020 
Final study report 
31 Dec 2020 
 
6. RATIONALE AND BACKGROUND 
Non-small cell lung cancer (NSCLC; 80–85% of all lung cancers) remains the most 
common cause of cancer-related mortality globally, most often diagnosed in advanced 
stages. Platinum-based chemotherapy, with or without radiotherapy or immunotherapy, 
used to be the main treatment method for advanced NSCLC. With the development of gene 
sequencing technology, molecular target therapy has become a first-line treatment option 
for populations with therapy-sensitive mutations in lung cancer driver gene. [1]. The most 
common targeted drugs are tyrosine kinase inhibitors (TKIs) which act by binding and 
inhibiting receptor tyrosine kinases (RTKs) and thus lead to inhibition of signaling 
pathways that induce abnormal growth and proliferation of tumor cells. Although targeted 
therapies have been successfully used in the treatment for NSCLC, the 3-year overall 
survival is only about 11.3% and 14.9% for advanced-stage NSCLC patients who received 
TKIs as first-line and second-line treatments [5]. The unsatisfactory results highlight the 
need for novel therapies and treatment regimens. 
Targeted therapies work differently from the specificity of molecular targets, 
consequently it often works for patients with specific driven mutation only. For anaplastic 
lymphoma kinase (ALK)-positive NSCLC, crizotinib is the first approved TKI and it is 
also one of the first-line agents in current clinical practice. For most ALK-positive NSCLC 
patients (90%), the benefit from crizotinib has been shown both in clinical studies and real-
world reports [6, 7]. Regardless of the satisfaction, some ALK-positive NSCLC patients 
have limited benefit from the treatment (intrinsic resistance), as well as most patients who 
initially derive the benefit latterly develop resistance (acquired resistance) due to secondary 
mutations in ALK [2, 3]. In response to the failure of crizotinib treatment, next-generation 
ALK-TKIs are developed.  
The second-generation ALK-TKIs includes ceritinib, alectinib, and brigatinib, which 
have demonstrated their activity in a crizotinib refractory or resistant treatment setting and 
have shown the potential for even greater activity in treatment-naïve patients [8-10]. 
However, ALK resistance mutation were present in over one-half of patients progressing 
on second-generation ALK inhibitors while ALK G1202R is the most notably resistance 
mutation after treatment with second-generation ALK inhibitor [2, 4]. 
Lorlatinib, a selective, brain-penetrant and new generation TKI, is reversible, potent 
adenosine triphosphate (ATP)-competitive small molecule inhibitor of ALK and Receptor 
Tyrosine Kinase C-Ros Oncogene I (ROS-1) and is also a potent ALK-TKI that is 
090177e1a53d4f42\Approved\Approved On: 05-Jan-2026 12:56 (GMT)

L orlati ni b  
B 7 4 6 1 0 2 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Fi nal , Ver 1. 0, 1 1 Dec  2 0 1 9   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  1. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n 
St u dy  1 5 -A u g -2 0 1 8   
P a ge 1 2  of 2 3  
effecti vel y a gai nst all k n o w n resista nt m uta nts, i ncl u di n g certai n m utati o ns t hat are t he 
m ost diffic ult t o i n hi bit  s uc h as t he A L K G 1 2 0 2 R  m utati o n . T he p ote ntial of l orlati ni b t o 
i m pr o ve pro gressi o n -free s ur vi val ( P F S) of t he treat me nt-n aï ve a d va nce d A L K -p ositi ve 
N S C L C patie nts a n d p atie nts w h o ha d pr o gresse d o n criz oti ni b a n d sec o n d -ge nerati o n 
A L K -T KIs  h as de m o nstrate d b y cli nical trials [ 1 1, 1 2]. T he br oa d c o verage a n d t he 
mec ha nis m of l orlati ni b a gai nst all k n o w n si n gle p oi nt m utati o ns t hat me diate resista nce t o 
first- a n d sec o n d -ge n erati o n A L K -T KIs is als o el uci date d b y trials a n d st u dies [ 2, 4].  
C urre ntl y , t here are li mite d data des cri bi n g t he use of l orlati ni b a n d its o utc o mes i n 
real-w orl d practice s etti n gs o utsi de t he hi g hl y c o ntr olle d e n vir o ns of cli nical trials. T he 
o bjecti ve of t his st u d y is t heref ore t o e val uat e real -w orl d s yste mic treat me nt patter ns, 
cli nical o utc o me, t hera p e utic effect, safet y pr ofile of L orlati ni b i n a d v a nce d N S C L C 
patie nts, a n d als o fact ors ass ociate d wit h cli nical o utc o me i n t h ose L orlati ni b treate d 
patie nts . 
 
7.  R E S E A R C H Q U E S TI O N A N D O B J E C TI V E S  
7 . 1 St u d y O bjecti ve 
 
Pri mar y O bj ecti ve  
◼ 
T o e val uate real -w orl d s yste mic treat me nt patter ns a m o n g a d va nce d 
N S C L C patie nts treate d i n L orl ati ni b w h o were pr o gresse d o n 
c he m ot hera p y, first - a n d sec o n d - ge n erati o n T KI a m o n g Tai w a nese 
p o p ulati o n.  
Sec o n dar y O bj ecti ve  
◼ 
T o s u m marize t he cli nical o utc o me  a n d safet y pr ofile of L orlati ni b 
patie nts wit h a d va nce d N S C L C  
 
◼ 
 
 
7 . 2 St u d y E n d p oi nt 
 
Cli nical Effe ct E n d p oi nt  
◼ 
T he treat me nt patter n fr o m i nitial dia g n ose t o c urre nt L orlati ni b 
treat me nt 
◼ 
O bjecti ve res p o ns e rat e ( O R R), O verall S ur vi val ( O S), P F S, 1 -year O S  
rate, Ti me t o Treat me nt Fail ure ( T T F) f or all N S C L C treat me nt a n d 
T T F of L orlati ni b  base d o n i n vesti gat or’s fi nal assess me nt  
 
Safet y E n d p oi nt  
C CI
C CI
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L orlati ni b  
B 7 4 6 1 0 2 8  N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Fi nal , Ver 1. 0, 1 1 Dec  2 0 1 9   
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  1. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n 
St u dy  1 5 -A u g -2 0 1 8   
P a ge 1 3  of 2 3  
◼ 
T he cli nical nat ure, i nci d e nce, d urati o n, a n d se v erit y of L orlati ni b 
relate d a d v erse dr u g reacti o n; o utc o me a n d p ossi ble ca usalit y will be 
rec or de d. 
 
 
◼ 
 
 
8.  R E S E A R C H M E T H O D S  
8. 1.  St u d y d esi g n   
T his is a retr o- a n d pr os pecti ve, m ulti -ce nter, o bser vati o nal st u d y wit h p atie nts w h o are 
treate d b y L orlati ni b f or a d va nce d N S C L C after fail ure of c he m ot hera p y, first- or sec o n d - 
ge n erati o n  T KI . A p pr o xi matel y 9 0 patie nts fr o m L orl ati ni b c o m passi o nat e use pr o gra m 
( C U P), w h o 1) a p pr o ve d j oi ni n g L orlati ni b C U P o n / bef ore 3 1  J ul 2 0 1 9 ; 2) i nitiate 
L orl ati ni b  treat me nt b ef ore 3 0 Se p 2 0 1 9, are e x pecte d t o be e nr olle d i n t he st u d y i n Tai w a n. 
Pri or t o st u d y e ntr y, eac h eli gi ble patie nt s hall pr o vi de his/ her writte n i nf or me d c o nse nt , 
e x ce pt  retr os pecti ve pati e nts w h o die d  bef ore t his st u d y a p pr o ve d  b y I nstit uti o nal Re vie w 
B oar d (I R B) . 
All e nr olle d s u bjects will be f oll o we d u ntil st u d y c o m pleti o n  o n 3 0 Se p 2 0 2 0  t o ma ke s ure 
all s u bjects are f oll o we d at least 1 year fr o m first d ose of L orlati ni b. T h e dat a t o b e ca pt ure d 
fr o m t his gr o u p of p atie nts i ncl u des a d v a nce d N S C L C dia g n osis , ge n e m utati o n stat us,  
t u m or assess me nt, L orlati ni b A d verse Dr u g Reacti o n  ( A D R) a n d prescri pti o n rec or ds 
d uri n g usa ge of L orlati ni b.  
T he list bel o w is t he i nf or mati o n, pri or t he first d ose of L orlati ni b , t o be ca pt ure d as disease 
hist or y . 
1.  Prescri pti o n a n d dia g n os e rec or d of  N S C L C  fr o m i nitial N S C L C dia g n ose 
2.  He patitis B Vir us ( H B V) a n d He patitis C Vir us ( H C V) i nfecti o n stat us  
3.  N S C L C relate d ge ne e x a mi nati o n res ult , 
4.  Best t u m or res p o nse i n f o ur cate g ori es , i ncl u di n g c o m plete res p o nse ( C R), partial 
res p o nse ( P R), sta ble disease ( S D) a n d pr o gressi o n disease ( P D), f or all pre-L orlati ni b  
N S C L C treat me nt 
8. 2.  Setti n g  
A d va nce d N S C L C patie nts  e nr olle d fr o m L orlati ni b C U P  after fail ure of  c he m ot hera p y,  1 st 
an d 2 n d ge nerati o n T KI.  
T he site staff will c ollect patie nt data fr o m me dical rec or d acc or di n g t o t he s c he d ule b el o w.  
C CI
C CI
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Procedure/ Assessment  
Baseline visit  
(V1) 
Follow-up 
Data 
Collection 
Day 
D1 
Every 12 to 14 weeks 
until 30 Sep 2020 
Informed consent 
X* 
 
Inclusion/Exclusion Criteria 
X 
 
Demographic data 
X 
 
HBV/HCV Infection Status 
 
 
NSCLC Related Genetic Examination 
Result 
 
 
NSCLC specific medical/ treatment 
history 
X 
 
Primary diagnose at Lorlatinib prescription X 
 
Tumor assessment record 
X 
X 
Lorlatinib related ADR 
X 
→ 
Drug and non-drug treatment from fist dose 
Lorlatinib to study completion 
X 
→ 
* Informed consent process will be waived for subjects who died before the study approved 
by IRB. 
The investigator may schedule clinic visits in addition to those listed in the schedule of 
activities table according to clinical standard of care practice. 
8.2.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1. Age ≥ 20 years old 
2. Patients who were approved to join Lorlatinib CUP on or before 31 Jul 2019 while 
initiate Lorlatinib treatment before 30 Sep 2019,  
i. 
Joining in Lorlatinib CUP, or 
ii. 
Ever joined in Lorlatinib CUP since Mar 2018 
3. 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. 
*For retrospective subjects, the informed consent process is not required for patients 
who died before the study approved by IRB. 
8.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. Patient treated Lorlatinib other than CUP. 
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8.3. Variables 
Variable 
Role 
Data source(s) 
Operational definition 
Demographic 
characteristics 
Baseline 
characteristics  
Medical records  Gender, 
age, 
smoking 
history, 
HBV/HCV 
infection status and etc. at 
first dose of Lorlatinib used. 
NSCLC History 
Baseline 
Characteristics, 
study outcome 
Medical records 
NSCLC 
diagnose 
from 
initial diagnose to current 
status and NSCLC related 
gene mutation. 
Treatment 
of 
NSCLC 
Chemotherapy 
(CT) Exposure 
TKI Exposure 
Treatment Duration 
Study outcome 
Medical records 
CT/TKI exposure, treatment 
duration and persistence by 
standard of care medical 
practice. 
Tumor assessment 
for NSCLC 
Study outcome 
Medical records  1) Best response of pre-
Lorlatinib NSCLC 
treatment will be 
presented as four ORR 
categories by physician 
clinical judgement  
2) NSCLC related gene 
mutation status before 
and after Lorlatinib 
Treatment 
3) ORR in intracranial, 
extracranial and overall 
response of Lorlatinib. 
4) OS, PFS, 1-year OS rate 
of and TTF of each 
treatment and TTF of 
Lorlatinib. 
Lorlatinib 
related 
ADR 
Study outcome 
Medical records 
Lorlatinib related ADR to 
be recorded from first dose 
of Lorlatinib until study 
closed. For any ongoing 
Lorlatinib related ADR at 
the end of study, the 
reporting process will 
follow local regulations and 
Pfizer Spontaneous 
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reporting related SOPs and 
the data will not be included 
in study data pool. 
Drug and non-drug 
treatment from first 
dose of Lorlatinib 
to study completion 
Study outcome 
Medical records 
Medications and procedures 
for NSCLC, comorbidities/ 
complications and 
Lorlatinib ADR 
 
Detailed instruction regarding the variables will be included in Case Report Form (CRF) 
and statistical analysis plan. 
8.4. Data sources  
The data will be collected through medical record review.  
All demographic information, HBV/HCV Infection status, NSCLC related genetic 
examination result, NSCLC related medical history, Lorlatinib related ADR, Pre-Lorlatinib 
NSCLC drug/non-drug treatment, tumor assessment, Lorlatinib concurrent drug/non-drug 
treatment and post-Lorlatinib drug/non-drug treatment will be collected from medical 
record to Case Report Form.  
The demographic characteristic as baseline information will collect the data at the time of 
first dose of Lorlatinib administered. The Lorlatinib related ADR, Lorlatinib concurrent 
drug/non-drug treatment and post-Lorlatinib drug/non-drug treatment will be record from 
first dose of Lorlatinib until end of data collection. 
8.5. Study size 
This is a descriptive study rather than a clinical research of comparison. The sample size is 
limited by actual patients fulfill the inclusion criteria and without any situation listed in 
exclusion criteria in Taiwan during the specific period. A calculated sample number is not 
applicable for present setting. 
According to current Lorlatinib CUP in Taiwan, the estimated recruiting number is 90. All 
eligible subjects who signed and agree to the informed consent or not available to provide 
the informed consent will constitute the cohort to be analyzed for this observational study. 
8.6. Data management  
Study data will be collected via medical record review, the source documents are the subject 
medical records at study sites. Data collected on the CRFs must match the data in the source 
documents. 
The collected data will be entered into a validated database. Pfizer/CRO data management 
will be responsible for data processing, in accordance with the data management procedure. 
Database lock will occur once quality assurance procedures have been completed. 
 
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8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
As used in this protocol, the term CRF[/DCT] 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[/DCT] is required and should be completed for each included patient.  The 
completed original CRFs[/DCTs] 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[/DCTs] are securely stored at the study site in paper 
form and will be secured in a locked room 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[/DCTs] 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[/DCTs] must be signed by the investigator or by an authorized staff 
member to attest that the data contained on the CRFs[/DCTs] are true.  Any corrections to 
entries made in the CRFs[/DCTs] 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[/DCTs] must match those charts.  
8.6.2. 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[/DCTs] and hospital records), all original 
signed informed consent/assent documents, copies of all CRFs[/DCTs], 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. 
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. 
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8.7. Data analysis  
Descriptive statistics will be used to summarize the proportion of gene mutations in all 
patients, demographics, smoking history, clinical characteristics, treatments pattern, as well 
as response rate and duration of response under different treatment pattern.  
The treatment pattern will be analyzed into following subpopulations:  
1) Lorlatinib treatment after one prior ALK TKI different from crizotinib in ALK gene 
mutation subject;  
2) Lorlatinib treatment after two prior ALK TKI in ALK gene mutation subject;  
3) Lorlatinib treatment after at more than two prior ALK TKI in ALK gene mutation 
subject;  
4) Lorlatinib treatment in ROS-1 gene mutation subject with any pretreatment. 
Key outcome variables include OS, PFS, 1-year OS rate, and TTF for all NSCLC treatment 
and TTF of Lorlatinib will be summarized by using Kaplan-Meier method and analyzed by 
the log rank test. Multivariate analyses will be carried out and variables include first-line 
ALK TKI prescribed, sex, pathology, stage, and the potential interactions of any two factors 
used by fitting multiple Cox’s proportional hazard models to predict patient’s hazard rates 
of treatment response. 
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. 
8.8. Quality control 
Pfizer or its agent will conduct monitoring visits during study conduct for studies conducted 
at investigator sites, to ensure that the protocol and Good Clinica Practice (GCPs) and/or 
Good Pharmacoepidemiology Practices (GPP), as relevant, are being followed. The 
monitors may review source document to confirm that the data recorded on CRFs[/DCTs] 
are accurate. The investigator and institution will allow Pfizer monitors/ auditors or its 
agents and appropriate regulatory authorities direct access to source documents to perform 
this verification. This verification may also occur after study completion. 
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/Ethics Committee (EC). It is important that the investigator(s) and their 
relevant personnel are available during the monitoring visits and possible audits and that 
sufficient time is devoted to the process. 
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8.9. Limitations of the research methods 
As the study only to describe the real-world treatment pattern and treatment outcome, the 
size of sample might not guarantee to ensure a representative distribution of the Taiwanese 
advanced NSCLC population. 
The secondary limitation of the research is related to subject population. Subject who die 
after IRB approval but before clinic visit to join this study will not be able to be enrolled. 
IRB will only approve to waive informed consent process for subject who die before IRB 
approve the study. 
8.10. Other aspects 
Not applicable 
9. PROTECTION OF HUMAN SUBJECTS 
9.1. 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 paper form and will be 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, 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 
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. 
 
9.2. Patient consent 
Informed consent is required per IRB requirements and local regulation and below 
requirements should be followed: 
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The informed consent form must be in compliance with local regulatory requirements and 
legal requirements. 
The informed consent form used in this study, and any changes made during the course of 
the study, must be prospectively approved by both the IRB/Independent Ethics Committee 
(IEC) and Pfizer before use. 
The investigator must ensure that each study patient, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. The investigator, or a person designated by the 
investigator, will obtain written informed consent from each patient or the patient’s legally 
acceptable representative before any study-specific activity is performed. The investigator 
will retain the original of each patient’s signed consent form.  
For patients completed Lorlatinib treatment before study start and not able to be contacted, 
the informed consent process will be waived. Only retrospective data will be collected from 
this group of patients. 
9.3. Patient withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons. In any circumstance, every effort should be made to document 
subject outcome, if possible. The investigator should inquire about the reason for 
withdrawal and follow-up with the subject regarding any unresolved adverse events.  
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
 
9.4. 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.  
9.5. 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 Good practices for real‐world data studies of treatment and/or comparative 
effectiveness: Recommendations from the joint ISPOR‐ISPE Special Task Force on 
real‐world evidence in health care decision making. 
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639372/). 
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10. 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: 
• All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the paper Case Report 
Form and reported, within 24 hours of awareness, to Pfizer Safety using the NIS 
AEM Report Form. 
• 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. 
 
All research staff members must complete the following Pfizer training requirements:    
•  “YRR 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.  
 
11. 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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12. REFERENCES 
1. 
Chan, B.A. and B.G. Hughes, Targeted therapy for non-small cell lung cancer: 
current standards and the promise of the future. Transl Lung Cancer Res, 2015. 4(1): 
p. 36-54. 
2. 
Gainor, J.F., et al., Molecular Mechanisms of Resistance to First- and Second-
Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov, 
2016. 6(10): p. 1118-1133. 
3. 
Casaluce, F., et al., Resistance to Crizotinib in Advanced Non-Small Cell Lung 
Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies 
and New Targeted Therapies. Curr Clin Pharmacol, 2016. 11(2): p. 77-87. 
4. 
Johnson, T.W., et al., Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-
oxo-10,15,16,17-tetrahydro-2H-8,4-(m 
etheno)pyrazolo[4,3-h][2,5,11]-
benzoxadiazacyclotetradecine-3-carbonitrile 
(PF-06463922), 
a 
macrocyclic 
inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with 
preclinical brain exposure and broad-spectrum potency against ALK-resistant 
mutations. J Med Chem, 2014. 57(11): p. 4720-44. 
5. 
Shi, Q., et al., Survival analysis of patients with advanced non-small cell lung 
cancer receiving tyrosine kinase inhibitor (TKI) treatment: A multi-center 
retrospective study. Thorac Cancer, 2018. 9(2): p. 278-283. 
6. 
Davis, K.L., et al., Real-world outcomes in patients with ALK-positive non-small 
cell lung cancer treated with crizotinib. Curr Oncol, 2018. 25(1): p. e40-e49. 
7. 
Solomon, B.J., et al., First-line crizotinib versus chemotherapy in ALK-positive 
lung cancer. N Engl J Med, 2014. 371(23): p. 2167-77. 
8. 
Chabner, B.A., Approval after phase I: ceritinib runs the three-minute mile. 
Oncologist, 2014. 19(6): p. 577-8. 
9. 
Gadgeel, S.M., et al., Safety and activity of alectinib against systemic disease and 
brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-
cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 
study. Lancet Oncol, 2014. 15(10): p. 1119-28. 
10. 
Gettinger, S.N., et al., Activity and safety of brigatinib in ALK-rearranged non-
small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 
trial. Lancet Oncol, 2016. 17(12): p. 1683-1696. 
11. 
Akamine, T., et al., Spotlight on lorlatinib and its potential in the treatment of 
NSCLC: the evidence to date. Onco Targets Ther, 2018. 11: p. 5093-5101. 
12. 
Solomon, B.J., et al., Lorlatinib in patients with ALK-positive non-small-cell lung 
cancer: results from a global phase 2 study. Lancet Oncol, 2018. 19(12): p. 1654-
1667. 
13. LIST OF TABLES  
Not applicable 
14. LIST OF FIGURES 
Not applicable 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
  
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Number 
Document reference 
number 
Date 
Title 
B7461028-001 
Contact 
Detail 
of 
Study Personnel 
 
 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable 
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