A Real-world Study to Explore Therapeutic Changing Mode of Locally Therapy During 1L Lorlatinib Treatment in Unresectable ALK+ NSCLC Patients
Conditions: Lung Cancer, Non-Small Cell
Sponsor: Peking University Cancer Hospital & Institute

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Investigation drug：LORBRENA       Trial phase：Investigator Initiated 
 
 
An Investigator Sponsored Research  
A real-world study to explore therapeutic changing mode of locally 
therapy during 1L lorlatinib treatment in unresectable ALK+ 
NSCLC patients 
 
Clinical Study Protocol 
 
 
Sponsor: Beijing Cancer Hospital 
Principal Investigator: Jun Zhao 
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Participating units 
Sponsor 
Name: Beijing Cancer Hospital 
Address: 52 Fucheng Road, Haidian District, Beijing 
Principal Investigator: Jun Zhao 
Contact information:86（010）88196456 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
I will be in accordance with the“Drug clinical trial management norms 
(GCP)” provisions, the implementation of the work entrusted by the sponsors 
and tasks. Agree to carry out the clinical study according to the design and 
regulation of this protocol. 
 
 
 
 
 
Sponsor：Beijing Cancer Hospital 
Principal Investigator: 
Date: 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
1. I will personally participate in and direct the clinical study.  
2. I have read the clinical trial protocol and agreed to conduct the study in 
accordance with the ethical and scientific principles of the Declaration of Helsinki 
and the GCP, modifications to the scheme are made only after notification to the 
sponsor and are subject to the consent of the ethics committee, unless urgent 
measures are required to protect the safety, rights and interests of the subject. 
3. I will ensure that all subjects sign a written informed consent form before 
entering the study as required by the GCP. 
4. I will be responsible for making medical decisions related to the trial and 
ensuring that participants receive appropriate treatment if adverse events occur 
during the trial. 
5. I will ensure that the data is recorded truthfully, accurately, completely and in 
a timely manner. I will be supervised and inspected by inspectors or inspectors 
from contract research organizations to ensure the quality of clinical trials.  
6. I promise to keep the subject information and related matters confidential, and 
I have been informed that I will be held liable for any breach of this promise. 
 
 
 
 
Research Unit： 
Principal Investigator: 
Date: 
 
 

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CONTENTS 
1. 
INTRODUCTION ........................................................................................................... 3 
2. STUDY OBJECTIVES ........................................................................................................ 6 
2.1. OBJECTIVES ..................................................................................................................... 6 
2.2. ENDPOINTS ...................................................................................................................... 7 
3. STUDY DESIGN .................................................................................................................. 8 
3.1 STUDY DESIGN.................................................................................................................. 9 
3.2 SAFETY PLAN ................................................................................................................. 17 
4. SUBJECT SELECTION ................................................................................................... 17 
4.1 INCLUSION CRITERIA  .................................................................................................... 14 
4.2 EXCLUSION CRITERIA .................................................................................................... 16 
5. TREATMENT .................................................................................................................... 18 
5.1 TREATMENT ADMINISTERED ......................................................................................... 18 
5.2 LORLATINIB DOSE MODIFICATION ................................................................................ 19 
6. STUDY PROCEDURES .................................................................................................... 24 
6.1 BASELINE ....................................................................................................................... 24 
6.2 STUDY PERIOD ............................................................................................................... 26 
6.2.1 Cycle 1 Day 1 ......................................................................................................... 26 
6.2.2 Cycle 1 Day 28 (±2 days) ....................................................................................... 26 
6.2.3 Day 1 of Subsequent Cycles (-4/+2 days) .............................................................. 26 
6.2.4 Local therapy .......................................................................................................... 27 
6.2.5 Imaging ................................................................................................................... 27 
6.2.6 End of Treatment Visit ............................................................................................ 27 
6.2.7 Post Treatment Follow-up Visit.............................................................................. 28 
6.2.8 Long-term Follow-up for Progression and Survival .............................................. 28 
7. ASSESSMENTS ................................................................................................................. 29 
7.1 TIMING OF ASSESSMENTS .............................................................................................. 29 
7.2 EFFICACY ASSESSMENTS ............................................................................................... 30 
7.2.1 Tumor Response Assessment .................................................................................. 30 
7.2.2 Blood Specimens for Circulating Tumor DNA (ctDNA) Profiling ......................... 31 
7.3 SAFETY ASSESSMENTS ................................................................................................... 31 
7.3.1 12 Lead ECG .......................................................................................................... 31 
7.3.2 Safety Laboratory Data .......................................................................................... 32 
7.3.3 Vital Signs ............................................................................................................... 33 
8. ADVERS`E EVENT REPORTING ................................................................................. 33 
8.1 REPORTING PERIOD ........................................................................................................ 34 
8.2 DEFINITION OF AN ADVERSE EVENT .............................................................................. 35 
8.3 ABNORMAL TEST FINDINGS ........................................................................................... 36 
8.4 SERIOUS ADVERSE EVENTS ........................................................................................... 36 
9. DATA ANALYSIS/STATISTICAL METHODS ............................................................ 37 

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9.1 SAMPLE SIZE DETERMINATION ...................................................................................... 37 
9.2 EFFICACY ANALYSIS ...................................................................................................... 37 
9.2.1 Analysis Populations .............................................................................................. 37 
9.2.2 Definition of Primary Endpoint .............................................................................. 38 
9.2.3 Analysis of Primary Endpoint ................................................................................ 38 
9.2.4 Definitions of Secondary Efficacy Endpoints ......................................................... 38 
9.2.5 Analysis of Secondary Endpoints ........................................................................... 39 
9.3 SAFETY ANALYSIS ......................................................................................................... 40 
10. STUDY ORGANISATION AND COMMITTEES ....................................................... 41 
10.1 STUDY COORDINATION ................................................................................................ 41 
10.2 TRIAL MANAGEMENT COMMITTEE .............................................................................. 41 
11. QUALITY CONTROL AND QUALITY ASSURANCE ............................................. 42 
12. DATA HANDLING AND RECORD KEEPING .......................................................... 43 
12.1 CASE REPORT FORMS/ELECTRONIC DATA RECORD .................................................... 43 
12.2 RECORD RETENTION .................................................................................................... 43 
13. ETHICS ............................................................................................................................. 44 
13.1 INSTITUTIONAL REVIEW BOARD /INDEPENDENT ETHICS COMMITTEE ....................... 44 
13.2 ETHICAL CONDUCT OF THE STUDY .............................................................................. 44 
13.3 SUBJECT INFORMATION AND CONSENT ....................................................................... 44 
13.4 SUBJECT RECRUITMENT ............................................................................................... 45 
13.5 REPORTING OF SAFETY ISSUES AND SERIOUS BREACHES OF THE PROTOCOL OR ICH 
GCP ...................................................................................................................................... 45 
14. PUBLICATION OF STUDY RESULTS ....................................................................... 46 
14.1 COMMUNICATION OF RESULTS BY THE SPONSOR ........................................................ 46 
14.2 PUBLICATIONS BY INVESTIGATORS ............................................................................. 46 
15. REFERENCES ................................................................................................................ 47 
APPENDIX 1   ECOG PERFORMANCE STATUS ....................................................... 49 
APPENDIX 2   MEDICATIONS WITH POTENTIAL PR INTERVAL 
PROLONGATION EFFECT ................................................................................................ 50 
APPENDIX 3   RECIST VERSION 1.1 ............................................................................ 51 
APPENDIX 4   PRO INSTRUMENT................................................................................ 55 
 
 
 
 

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1. INTRODUCTION 
Lung cancer is the most fatal malignancy in China, as estimated by National Cancer 
Center of China, 1 accounting for 828,100 new cases, and 657,000 deaths in 2016. Non-
small cell lung cancer (NSCLC), constituting 80%-85% of lung cancer, is most often 
diagnosed in advanced stages, where surgery and local radiotherapy are no longer 
curative or indicated. 2 Since the first anaplastic lymphoma kinase (ALK) tyrosine 
kinase inhibitors (TKI) approved in United States in 2011 and 2013 in China, the 
response and overall survival of ALK-positive NSCLC patients were significantly 
improved as compared with empiric chemotherapy.3 Subsequently, more second-
generation ALK TKIs emerged, including alectinib, brigatinib, ceritinib and ensartinib, 
4-8 with notably longer median progression free survival (mPFS) and higher intracranial 
response rate. However, drug resistance yet develops inevitably, mostly due to ALK 
resistant mutation (e.g., I1171N, L1196M and G1202R),9,10 and intracranial progression, 
a major cause of illness and death. 11-15  
Lorlatinib (Pfizer) is a novel third-generation ALK TKI that is more potent than second-
generation ALK TKIs in biochemical and cellular assays and has the broadest coverage 
of ALK resistance mutations that have been identified.9,16,17 Lorlatinib was designed to 
cross the blood–brain barrier in order to achieve high exposures in the central nervous 
system (CNS).18,19 In phase 1 and 2 studies, lorlatinib had potent antitumor activity after 
the failure of previous ALK TKIs (first-generation, second-generation, or both).19,20 In 
particular, lorlatinib had marked intracranial activity in previously treated patients with 
baseline CNS disease, including leptomeningeal disease.11,12,20 In an ongoing China 
only phase 2 study, lorlatinib exhibited highly consistent antitumor activity, intracranial 
efficacy and safety profile as global phase 2 study in patients with progression on ALK 
TKIs,21 reconfirming superior efficacy of lorlatinib in combating ALK resistance. 
The CROWN trial is a global, randomized, phase 3 trial comparing lorlatinib (n=149) 
with crizotinib (n=147; the standard-of-care first-line treatment at the time of trial 

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initiation) in patients with previously untreated advanced ALK-positive NSCLC.22 At 
the time of first data cutoff, the mPFS was not reached (NR; 95% confidence interval 
[CI], NR=NR) in the lorlatinib group, as compared with 9.3 months (95% CI, 7.6-11.1) 
in the crizotinib group by BICR. The percentage of patients who were alive without 
disease progression at 12 months was 78% in the lorlatinib group and 39% in the 
crizotinib group (hazard ratio, 0.28, 95% CI, 0.19-0.41); P<0.001, one-sided). The 
hazard ratio favored lorlatinib over crizotinib across all prespecified patient subgroups 
defined according to baseline characteristics and stratification factors. At the second 
data cutoff, the mPFS was yet NR (95% CI, NR-NR) in the lorlatinib group, as 
compared with 9.3 months (95% CI, 7.6-11.1 months) in the crizotinib group by 
BICR.22 24-month and 36-month PFS rate were distinctly higher in the lorlatinib group 
of 68.2% and 63.5%, as compared with 21.5% and 18.9% in the crizotinib group 
(hazard ratio, 0.27, 95% CI, 0.184-0.388). For patients with measurable brain 
metastases at baseline, lorlatinib achieved 72% intracranial complete response (CR) 
rate, and 83% intracranial objective response rate (ORR). Time to intracranial 
progression by BICR was remarkably longer with lorlatinib than crizotinib in the 
intention-to-treat population as well as in patients with and without baseline brain 
metastases, in which 8 out of 37 patients with baseline brain metastases and only 1 out 
of 112 patients without baseline brain metastases had intracranial progression after 
median follow-up over 36 months. This indicates that lorlatinib possesses the potential 
to clear existing brain metastases, meanwhile prevents new metastatic lesions in the 
brain. 
In consideration of high intracranial activity and 63.5% PFS rate and not reached mPFS 
after 36.7 months follow-up in the CROWN trial,22 ALK-positive NSCLC patients shall 
benefit most using lorlatinib in the first-line treatment in the clinical practice. 
Nevertheless, only 10 ALK+ NSCLC patients were randomized to the lorlatinib group 
in China mainland, and published data of clinical trials regarding first-line treatment of 
lorlatinib is still limited to CROWN trail. There is a vast vacancy of efficacy and safety 
regarding first-line lorlatinib treatment in China ALK-positive NSCLC patients. Further, 

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first-line resistance mechanism of lorlatinib is still ambiguous,23 the sequencing therapy 
after PD of first-line lorlatinib is far from definite, and how lorlatinib benefiting ALK-
positive NSCLC patients in clinical practice beyond CROWN criteria should be further 
explored. There is no clear answer so far to these clinically relevant questions. 
In addition, recent clinical studies have shown that continuation of TKI treatment 
beyond progression in patients with oligometastasis NSCLC can be an effective 
strategy to target tumor cells that still addicted to the EGFR pathway and prevent the 
disease flare observed after discontinuation of the targeted agent. 24,25Further more, for 
patients with oligometastases （means target lesions with residual disease ，definition 
a maximum of 3 organs, and no more than 5 lesions in total）, treatment should be 
considered in combination with local therapeutic approaches, such as surgery, local 
ablation or radiotherapy, to improve disease control and thereby long-term survival 
outcomes.26 However, no studies have yet reported whether patients with ALK+ 
NSCLC can also benefit from the above treatment mode. 
This real-word study is designed to prospectively explore whether local treatment 
(surgery, ablation, radiotherapy and others) can prolong the time to treatment 
discontinuation during 1L lorlatinib treatment in Chinese patients with unresectable 
ALK+  NSCLC. Since this is a non-interventional study (NIS) to observe the routine 
practice, there will not be any study required clinical interventions or laboratory 
assessments. Participation in this study is not intended to change the routine treatment 
received as determined by their attending physicians. Patients will be treated according 
to the routine medical practice in terms of visit frequency and types of assessments 
performed. 
This study will enroll patients with ALK-positive non-small cell lung cancer locally 
diagnosed in about 6 sites in China from study setup to about Oct 2025, as the target 
observation population. Patients’effectiveness and safety data of first line treatment 
with lorlatinib will be collected after their first dose until the 60th month or patient 
death, loss to follow-up, or withdrawal from the study for any reason. The visit schedule 

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during study is not mandatory and follow local routine clinical practice. 
 The study data will be generated from the attending physician's routine clinical 
assessment during standard care. The data source used for data collection will be from 
electronic medical records/medical records or medical charts or other approved data 
source. 
The database lock date is about Oct 2030 or the date of the death of the last enrolled 
patient. 
 
2. STUDY OBJECTIVES 
2.1. Objectives 
Primary Objective: 
• 
To evaluate the time-to treatment discontinuation (TTD) of lorlatinib with locally 
therapy in unresectable ALK-positive NSCLC patients who have received 1L lorlatinib 
in real-world settings; 
Secondary Objectives: 
• 
To evaluate the rwORR, rwDCR and real-world intracranial ORR, intracranial time to 
progression (IC-TTP) and TTP of 1L lorlatinib in real world setting ; 
• 
To explore the progression pattern in this therapeutic changing mode; 
• 
To evaluate 1/2/3/4/5-year overall survival (OS) rate and OS of in each treatment 
cohort; 
• 
To explore the association between the effectiveness of lorlatinib in first line for 
Chinese patients with ALK-positive locally advanced or metastatic NSCLC patients 
with baseline brain metastases (Yes or No) ，ALK Fusion Variants ([V1, V2, V3] and 

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TP53 mutation status [TP53 mutation, TP53 WT]) if data is available in medical 
records; 
• 
To evaluate the safety and tolerability of the therapeutic changing mode; 
• 
To explore the adverse events (AEs), the dose modification and the reason for 
interruption or discontinuation of lorlatinib in first line for Chinese ALK-positive 
locally advanced or metastatic NSCLC recorded in medical records; 
• 
To evaluate patient-reported outcomes (PROs) of health-related quality of life for 
this therapeutic mode; 
• 
To describe the demographic, clinicopathological and baseline co-mutation 
characteristics of enrolled patients.   
 
Exploratory Objectives: 
• 
To explore dynamic ctDNA change during lorlatinib treatment; 
•   To evaluate candidate biomarkers of sensitivity or resistance to lorlatinib in no-
prior ALK-TKIs treatment tumor tissue and peripheral blood if available in real world 
setting; 
 
2.2. Endpoints 
Primary Endpoint: 
• 
Time-to treatment discontinuation (TTD) is defined as the time from start of 
treatment to the date of discontinuation of these therapeutic methods. 
 Secondary Endpoints: 
• 
Effectiveness: Objective Response Rate (ORR), duration of response (DOR) and  
TTP based on investigator’s assessment; intracranial ORR (IC-ORR), IC-time to 
progression (IC-TTP), progression pattern ,1/2/3/4/5-year rwOS rate and OS; 
• 
Safety: To explore the adverse events (AEs), the dose modification and the reason 

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for interruption or discontinuation of lorlatinib in first line for Chinese patients with 
ALK-positive locally advanced or metastatic NSCLC recorded in medical records; 
◼ Adverse Events (AEs), as graded by NCI CTCAE (National cancer Institute 
Common Terminology Criteria for Adverse Events) v5.0; laboratory 
abnormalities (as graded by NCI CTCAE v5.0); vital signs (blood pressure, 
pulse rate) and body weight; electrocardiograms (ECGs); echocardiogram or 
MUGA (multigated acquisition) scan; ophthalmologic data; 
• 
PRO as assessed by EORTC (European Organization for Research and Treatment 
of Cancer) QLC-C30;  
• 
To describe the demographic, clinicopathological and baseline co-mutation 
characteristics of enrolled patients.   
 
Exploratory Endpoints: 
• 
Dynamic molecular response associated with lorlatinib treatment using ctDNA as 
measured by next-generation sequencing (NGS) if available in real world setting ; 
• 
Biomarkers of sensitivity or resistance to lorlatinib in no-prior ALK-TKIs treatment 
tumor tissue and peripheral blood if available in real world setting; 
3. STUDY DESIGN 
Figure 1.  Study Design 
 
 
 
 

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3.1 Study design 
This is a prospective，observational，multi-center, parallel-group, real world study to 
explore therapeutic changing mode of locally therapy after 1L lorlatinib treatment in 
unresectable ALK-positive Non-Small Cell Lung Cancer (NSCLC). Patients with 
unresectable NSCLC must have no previous systemic treatment for advanced (Stage 
IIIB/C not amenable for multimodality treatment) or metastatic (Stage IV) disease.All 
subjects must have tumors that test, positive for ALK rearrangement, with methods of 
Ventana ALK (D5F3), fluorescence in situ hybridization (FISH), polymerase chain 
reaction (PCR), or next generation sequencing (NGS), or circulating tumor DNA 
(ctDNA) for ALK rearrangement, with method of NGS. All tumors will be of histo- 
and/or cytopathology consistent with NSCLC, (e.g., adenocarcinoma, Squamous-cell 
carcinoma, or mixed), or its pathologically accepted variants.  
The study will collect and analyze effectiveness, safety, PRO of lorlatinib in first-line 
from approximately 100 ALK positive locally advanced or metastatic NSCLC patients 
from study beginning to last subject last visit across approximately 8 sites in the real-
world setting in China. 
Lorlatinib will be administered orally QD at approximately the same time of the day on 
a continuous daily dosing schedule, ie, without a break in dosing in the absence of drug-
related toxicity. Patients must swallow the study medication whole and must not 
manipulate or chew the medication prior to swallowing. A dosing card will be provided 
to the patients to provide guidance for the correct use of lorlatinib. Patients must be 
instructed that should they miss a dose or vomit any time after taking a dose, they must 
not “make it up” with an extra dose. Instead, resume the subsequent doses as originally 
prescribed. Any missed dose may be taken up to 6 hours prior to the next scheduled 
dose, otherwise it should be skipped and dosing resumed with subsequent doses as 
prescribed. The patient must be instructed to record all doses (including missed or 
vomited) in a dosing diary supplied by the site. If doses are missed or vomited, this 
must be indicated in the source documents and Case Record Forms (CRFs). 

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After lorlatinib treatment for 4 weeks, patients will receive an imaging assess. The 
patients who achieve PR or SD with oligometastasis (refer to target lesions with residual 
disease, a maximum of 3 organs, and no more than 5 lesions in total) should continue 
lorlatinib treatment and will receive imaging assess per 8-12 weeks. If target lesions 
indicate stable in 2 consecutive imaging, investigators will organize MDT and 
comprehensively evaluate patients’ will to decide and choose local therapy. The local 
therapy includes surgery, ablation and, radiotherapy et al. After local therapy, patients 
should continue taking lorlatinib. While those who achieve CR or with multiple 
metastasis will continue lorlatinib treatment without any local therapy. 
To dynamically monitor ctDNA changes in ALK + NSCLC patients during Lorlatinib 
treatment; to explore the correlation between ctDNA and Lorlatinib treatment 
efficacy .Patients need check the ctDNA-seq (10000x) in plamsa with NGS at 
baseline,4weeks after lorlatinib treatment and at disease progression. 
Subjects will be on lorlatinib therapy until disease progression or unacceptable toxicity, 
new systemic anticancer therapy instituted, withdrawal of consent, death, or 
investigator decision dictated by protocol compliance, whichever occurs first.  
Patients received continuous daily PO dosing of lorlatinib 100mg QD with/without 
locally therapy, from the date of first dosing (per the current protocol) or until one of 
the following criteria were met (whichever occurred first): disease progression; 
initiation of a new anti-cancer therapy; unacceptable toxicities; global deterioration of 
health-related symptoms; pregnancy; withdrawal of consent; loss to follow-up; death; 
investigator decision dictated by protocol non-compliance; or study termination. 
Patients who have progressive disease (PD) (per RECIST v1.1, by investigator review) 
and for whom the investigator believes it is in their best interest to continue lorlatinib 
treatment are allowed to continue lorlatinib therapy, at the discretion of the investigator, 
until any alternate or additional systemic anti-cancer therapy regimen was 
implemented. 
At the time of progression and termination of study treatment, the patients could receive 

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any therapy at the judgment of the investigator. This study will take 1 years to enroll 
subjects, and each subject will be followed up for survival status and subsequent cancer 
therapies up to 60 months from the date of first dosing.  
Participation in this study is not intended to change the routine treatment received as 
determined by their attending physicians. Patients will be treated according to the 
routine medical practice in terms of visit frequency and types of assessments performed. 
Upon site initiation, investigators will consecutively enroll eligible patients into this 
study after obtaining patients’ informed consent. The observation period for each 
patient is planned to be 60 months, starting from the patients who received lorlatinib 
enrolled in this study and ending at the earliest occurrence of the completion of 60 
months of follow-up, death, loss to follow-up, or withdrawal from the study. The study 
data will be generated from the attending physician's routine clinical assessment during 
standard care. The data source used for data collection will be from electronic medical 
records/medical records or medical charts or other approved data source. 
The study duration will be approximately 6 years. The enrollment period is planned to 
be about 12 months (from first site initiation, until the planned number of patients 
reached). The follow-up period per patient is up to 60 months from the time patients 
who received lorlatinib enrolled in this study. The interim analysis will be performed 
when half TTD events happen. The study is expected to be closed in about Oct 2030. 
Safety and effectiveness assessments were performed throughout the treatment period 
and at the end-of-study visit. Routine safety assessments included the collection and 
evaluation of AEs, concomitant medications, vital signs, and body weight. Particular 
attention was given to AEs consistent with the lorlatinib toxicity profile (including lipid 
elevation, cognitive and mood disorder, etc.). Additional safety assessments performed 
at selected visits included ECOG PS, clinical laboratory tests, ECGs, and LVEF 
imaging. Contrast-enhanced computed tomography (CT) or magnetic resonance 
imaging (MRI) was used for tumor assessment at screening,at baseline, 4 weeks after 
lorlatinib treatment and then every 8-12 weeks. For patients with brain metastases, 

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RANO-BM criteria was used for intracranial lesions. Gadolinum-enhanced brain MRI 
is recommended at baseline and 4 weeeks after lorlatinib treatment. 
A post-treatment follow-up visit for safety occurred at least 28 days, and no more than 
35 days, after discontinuation of treatment. All patients (regardless of the reason for 
discontinuation from study treatment) were to be followed for subsequent anti-cancer 
systemic therapies and survival status approximately every 6 months from the post-
treatment follow-up visit, for up to 60 months from the date of first dosing (per the 
current protocol).  Patients with no evidence of disease progression at the time of 
permanent treatment discontinuation were to be followed until disease progression; for 
these patients, repeat tumor assessments were suggested to occur approximately every 
8-12 weeks from the date of the CT/MRI at the end-of-study treatment. 
Subjects should be instructed to take their medication at approximately the same time 
every day. 
Throughout the study, there was no fixed schedule of visits and safety assessments and 
effectiveness assessments will follow local clinical routine. 
Data Source/Data Collection: 
 
Data will be collected from approximately 8 hospitals. The data is sourced from the 
hospital information system (HIS)/electronic medical record (EMR)/laboratory 
information system (LIS)/ picture archiving and communication system (PACS), and 
genetic testing report data. All data collection will be done using LinkDoc data 
management platform. All data are based on medical records or genetic testing reports 
if available. The investigators at the sites are responsible for ensuring that the required 
data is collected and entered into the LinkDoc data management platform. 
For each patient, the attending physician will document the clinical information during 
the initial visit, follow-up visits, and the final visit. The attending physician will 
document the baseline data (demographic and baseline disease characteristics) from 
medical records or through an interview at an initial visit. When patients who received 

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lorlatinib enrolled in this study, follow-up visits are performed by investigator to collect 
study-related data, including data on effectiveness, tumor status, and other study 
required variables. A final data collection will be performed at death, withdrawal of 
consent, loss to follow-up, or the end of the study which is the earliest occurrence. There 
is no fixed visit schedule; visits will follow local routine clinical practice. Data will be 
collected until the 60th month after patient enrolled in this study (last follow-up time) 
or the death of patients due to any cause, loss to follow-up or withdrawal from the study 
which is the earliest occurrence.    
 
Data type: 
 
The clinical data collected for this study include, but is not limited to: 
Collect patients' baseline demographic information (including age at diagnosis, gender, 
height, weight, physical examination, smoking status), ECOG score, past history, 
baseline disease characteristics (disease stage, molecular typing, pathological 
diagnosis), laboratory test results (blood routine, urine routine, blood biochemistry, 
coagulation function tests, electrocardiogram, echocardiography, vital signs), ALK 
genetic testing methods and results, test specimen types, imaging tests (tumor 
assessment[size, number, and location], medication treatment, adverse events, post-
resistance gene testing, dose modification regimens, reasons for lorlatinib dose 
modification, interruption or discontinuation, PRO (if data is available in clinical 
practice) and survival status. 
Collection and recording of SAEs and AEs will commence once the study participant 
has provided informed consent and terminate till 28 (and no more than 35) days after 
administration of the last dose of lorlatinib. After this period, only lorlatinib-related 
SAEs must be reported to the Pfizer. SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). All patients will be periodically contacted for survival and 
safety information unless the patient requests to be withdrawn from the study. Survival 
status is also encouraged to be confirmed through a telephone follow-up by the 
investigator or designee at the end of the study or withdrawal from the study. 

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3.2 Safety Plan 
The overall safety profile and toleration of lorlatinib and locally therapy will be based 
on AEs and laboratory abnormalities with regard to frequency, severity (in accordance 
with CTCAE v5.0), timing and relationship with study drug and treatment mode.  
Throughout the study, all patients treated with lorlatinib are followed for safety to 
assess the safety of lorlatinib, including AEs leading to dose modification, interruption 
or discontinuation of lorlatinib and other reasons for dose modification, interruption or 
discontinuation of lorlatinib in the medical records. 
4. SUBJECT SELECTION 
Subject eligibility should be reviewed and documented by an appropriately qualified 
member of the investigator’s study team before patients are included in the study. 
4.1 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment 
into the study: 
1. Diagnosis: 
a. Study Population: Patients with histologically or cytologically confirmed 
diagnosis of locally advanced [(Stage IIIB/C not amenable for multimodality 
treatment) or metastatic (Stage IV) by American Joint Committee on Cancer 
(AJCC) v 7.0] ALK-positive NSCLC where ALK status is determined by the 
Ventana ALK (D5F3) Companion Diagnostic (CDx) IHC test performed on the 
Ventana ULTRA or XT Platforms, FISH, PCR, or next generation sequencing 
(NGS), or circulating tumor DNA (ctDNA). 

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b. Tumor Requirements: At least 1 measurable target lesion per RECIST v. 1.1 that 
has not been previously irradiated. Brain metastases are allowed.  
2. No prior systemic treatment for advanced (Stage IIIB/C not amenable for 
multimodality treatment) or metastatic (Stage IV) disease.  
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, 2 or 3. 
4. Age ≥18 years. 
5. Adequate Liver Function, including: 
a. Total serum bilirubin ≤1.5 x ULN; 
b. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 
x ULN (≤5.0 x ULN in case of liver metastases). 
6. Life expectancy at least 6 months. 
7. Serum pregnancy test (for females of childbearing potential) negative at screening. 
Female patients of non-childbearing potential must meet at least 1 of the following 
criteria: 
a. Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or physiological 
cause (which may be confirmed with a serum follicle-stimulating hormone [FSH] 
level confirming the postmenopausal state if appropriate); 
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c. Have medically confirmed ovarian failure. 
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential. 

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8. 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. 
9. Willing and able to comply with scheduled visits, treatment plans, laboratory tests 
and other procedures. 
4.2 Exclusion Criteria 
Subjects presenting with any of the following characteristics/conditions will not be 
included in this clinical study: 
1. Major surgery within 4 weeks prior to randomization. Minor surgical procedures (e.g., 
port insertion) are not excluded, but sufficient time should have passed for adequate 
wound healing. 
2. Radiation therapy within 2 weeks prior to enrollment, including stereotactic or partial 
brain irradiation. Patients who complete whole brain irradiation within 4 weeks prior to 
randomization or palliative radiation therapy outside of the CNS within 48 hours prior 
to randomization will also not be included in the study. 
3. Gastrointestinal abnormalities, including inability to take oral medication; 
requirement for intravenous alimentation; prior surgical procedures affecting 
absorption including total gastric resection or lap band; active inflammatory 
gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease; treatment 
for active peptic ulcer disease in the past 6 months; malabsorption syndromes. 
4. Known prior or suspected severe hypersensitivity to study drugs or any component 
in their formulations. 
5. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial 
fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, 

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and pulmonary fibrosis. 
6. Evidence of active malignancy (other than NSCLC, non-melanoma skin cancer, or 
localized prostate cancer or any in situ cancer which does not currently require 
treatment) within the last 3 years prior to randomization. 
7. Concurrent use of any of the following food or drugs (consult the sponsor if in doubt 
whether a food or a drug fall into any of the above categories) within 12 days prior to 
the first dose of lorlatinib. 
a. Known strong CYP3A inhibitors (e.g., strong CYP3A inhibitors: grapefruit juice or 
grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], boceprevir, 
cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, ritonavir alone and 
with danoprevir or elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or 
dasabuvir or saquinavir or tipranavir, telaprevir, troleandomycin, and voriconazole. The 
topical use of these medications (if applicable), such as 2% ketoconazole cream, is 
allowed. 
b. Known CYP3A substrates with narrow therapeutic index, such as astemizole*, 
terfenadine*, cisapride*, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, 
alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, 
dihydroergotamine) (*withdrawn from US market). 
c. Known strong CYP3A inducers (e.g., carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s Wort). d. Known P-gp substrates with a narrow 
therapeutic index (e.g., digoxin). 
8. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study. 

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9. Participation in other studies involving investigational drug(s) within 2 weeks prior 
to study entry and/or during study participation. 
 
5. TREATMENT 
5.1 Treatment Administered 
A patient must sign an informed consent form (ICF) before being evaluated for study 
entry. Once a patient who has met inclusion and exclusion criteria has provided a signed 
ICF, will receive lorlatinib orally 100 mg QD, administered as 4 x 25 mg oral tablets, 
at approximately the same time of the day on a continuous daily dosing schedule, ie, 
without a break in dosing in the absence of drug-related toxicity. Patients must swallow 
the study medication whole and must not manipulate or chew the medication prior to 
swallowing. A dosing card will be provided to the patients to provide guidance for the 
correct use of lorlatinib. Patients must be instructed that should they miss a dose or 
vomit any time after taking a dose, they must not “make it up” with an extra dose. 
Instead, resume the subsequent doses as originally prescribed. Any missed dose may be 
taken up to 6 hours prior to the next scheduled dose, otherwise it should be skipped and 
dosing resumed with subsequent doses as prescribed. The patient must be instructed to 
record all doses (including missed or vomited) in a dosing diary supplied by the site. If 
doses are missed or vomited, this must be indicated in the source documents and Case 
Record Forms (CRFs). Lorlatinib will be administered from the date of first dosing 
(Cycle 1 Day 1 [C1D1]) or until 1 of the following criteria was met (whichever occurred 
first): disease progression; initiation of a new anti-cancer therapy; unacceptable 
toxicities; global deterioration of health-related symptoms; pregnancy; withdrawal of 
consent; loss to follow-up; death; investigator decision dictated by protocol compliance; 
study termination by the investigator.   
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lorlatinib can be administered with or without food. 
After lorlatinib treatment for 4 weeks, patients will receive an imaging assess.  The 
patients who achieve PR or SD with oligometastasis(A maximum of 3 organs, and no 
more than 5 lesions in total) should continue lorlatinib treatment and will receive 
imaging assess per 8-12 weeks. If target lesions indicate stable in 2 consecutive imaging, 
investigators will organize MDT and comprehensively evaluate patients’ will to decide 
and choose local therapy. The local therapy includes surgery, ablation and, radiotherapy 
et al. After local therapy patients should continue taking lorlatinib. While those who 
achieve CR or multiple metastasis will continue lorlatinib treatment without any local 
therapy. 
Subjects who receive local therapy must observe the therapeutic plan and complete the 
process under the direction of investigators. They shouldn’t use other drugs and 
methods that may influence the effects of investigational therapeutic mode. 
Patients need check the ctDNA-seq (10000x)in plamsa with NGS at baseline, 4 weeks 
after lorlatinib treatment, and at disease progression if available. 
 
5.2 Lorlatinib Dose Modification 
In case of adverse events, investigators are encouraged to employ best supportive care 
according to local institutional clinical practices or follow the guidance for selected 
adverse events provided in Table 1. 
 
Table 1. Lorlatinib Dose Modification 
Dose Levels 
Lorlatinib Dose 
0 
100 mg QD 
-1 
75 mg QD 
-2 
50 mg QD 
Dose reductions below dose level -2 are not allowed. 
 

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Patients will be monitored closely for toxicity, and the dose of lorlatinib may be 
adjusted as indicated in Table 3 below. dose reduction by 1 and, if needed, 2 dose levels 
will be allowed depending on the type and severity of toxicity encountered. 
If a patient has a significant toxicity from lorlatinib treatment which fails to recover 
within 42 days (6 weeks) or, in the opinion of the investigator, requires permanent 
discontinuation of the treatment based on the severity of the adverse event, then this 
patient should not be further treated with lorlatinib but should remain in the trial with 
ongoing tumor assessments until RECIST-defined disease progression by the 
investigator. 
Recommendations for lorlatinib dose modification for treatment-related non-
hematological and hematological toxicity, as well as for treatment-related toxicity of 
special interest, are provided in Table 2 below. 
Re-escalation is not allowed except if discussed with and approved by the sponsor’s 
medical contact. 
 
 
 

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Table 2. Lorlatinib Dose Modifications for Lorlatinib-Related Toxicities Non-Hematologic Toxicities 
Toxicity 
Grade 1** 
Grade 2** 
Grade 3 
Grade 4 
Pancreatitis 
NA 
If elevated enzymes (both amylase and lipase are Grade ≤2) are 
observed in the absence of radiological findings of pancreatitis: 
continue lorlatinib at the same dose level without dose hold. 
Repeat lipase and amylase and obtain pancreatic isoenzyme if 
possible. 
If radiologically confirmed pancreatitis: withhold lorlatinib dose. 
Repeat radiology and lipase and amylase weekly and obtain 
pancreatic isoenzyme.  If appropriate, resume lorlatinib treatment 
at one dose level lower if radiology has returned to baseline and 
lipase and amylase are Grade ≤2. 
Permanently 
discontinue lorlatinib. 
Permanently 
discontinue 
lorlatinib. 
Pneumonitis (in the 
absence of disease 
progression, 
pulmonary 
embolism, positive 
cultures or radiation 
effect)§. 
Asymptomatic, radiographic findings 
only: No need for lorlatinib dose 
adjustment.  Initiate appropriate 
monitoring. 
Withhold current lorlatinib dose until toxicity has returned to 
baseline. Rule out infection and consider initiating treatment with 
corticosteroids.  Then resume lorlatinib treatment at one dose 
level lower.  Discontinue lorlatinib permanently if pneumonitis 
recurs or if failure to recover after 6 weeks of study treatment hold 
and steroid treatment. 
Permanently 
discontinue lorlatinib. 
Permanently 
discontinue 
lorlatinib. 
Electrocardiogram 
QTc prolongation 
. 
Assess electrolytes and concomitant 
medications. Correct any electrolyte 
abnormalities, or 
hypoxia. 
Continue lorlatinib at the same dose 
level. 
Assess electrolytes and concomitant medications. 
Correct any electrolyte abnormalities, or hypoxia. 
Continue lorlatinib at the same dose level. 
Withhold lorlatinib dose. 
Assess electrolytes and 
concomitant medications. 
Correct any electrolyte 
abnormalities, or hypoxia. 
Upon recovery to 
Grade 1 resume lorlatinib 
treatment at one dose level 
lower. 
Permanently 
discontinue 
lorlatinib. 
LV Dysfunction 
CTCAE v5.0 does not report Grade 1. 
CTCAE v 5.0 does not report Grade 2. 
Permanently 
discontinue lorlatinib. 
Permanently 
discontinue 
lorlatinib. 
Non-Hematologic 
General 
Continue lorlatinib at the same dose 
level. 
Continue lorlatinib at the same dose level. 
Withhold lorlatinib dose 
until toxicity is 
Grade 1(or has returned 
to baseline) then reduce 
the dose by 1 level or 
rechallenge at the same 
dose.* 
Withhold dose 
until toxicity is 
Grade 1 (or 
has returned to 
baseline), then 
reduce the dose 
by 1 level* or 

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25 
 
 
discontinue at 
the discretion 
of the 
investigator. 
* Patients who develop asymptomatic Grade 4 hyperuricemia or Grade 3 hypophosphatemia may continue lorlatinib without dose modification at 
the discretion of the investigator. Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy to require lorlatinib 
dose modification . 
** In cases where no specific dose adjustments for Grade 1 or Grade 2 treatment-related toxicity are provided, investigators should always 
manage their patients according to their medical judgment which may include dose reduction or interruption based on the particular clinical 
circumstances. 
§ If a patient has a potential diagnosis of pneumonitis or drug-related lung injury the same evaluations/procedures provided 
should be considered to assist or exclude the diagnosis of pneumonitis during this period. 
 
 
Hematologic Toxicities 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematologic 
General 
Continue lorlatinib at 
the same dose level. 
Continue lorlatinib at the same dose level. 
Withhold lorlatinib dose 
until toxicity is 
Grade 1 (or has returned 
to baseline), then 
rechallenge at the same 
dose or reduce the dose by 
1 dose level. 
Withhold lorlatinib dose until 
toxicity is Grade 1 (or has 
returned to baseline) then 
rechallenge at the same dose or 
reduce the dose by 1 dose level. 
Lymphopenia 
Continue lorlatinib at 
the same dose level. 
Continue lorlatinib at the same dose level. 
If no evidence of infection 
or other clinically 
significant toxicity, 
continue lorlatinib at the 
same dose; otherwise, 
withhold dose until toxicity 
is Grade 1 (or baseline) 
then rechallenge at the 
same dose or reduce by 
1 level. 
If no evidence of infection or 
other clinically significant 
toxicity, continue lorlatinib at 
same dose; otherwise, withhold 
dose until toxicity is 
Grade 1 (or baseline), then 
rechallenge at the same dose or 
reduce the dose by 1 dose level. 
Lipid Elevation Toxicities 
Cholesterol 
Continue lorlatinib at 
the same dose. 
Consider introducing 
use of a statin or other 
lipid lowering agent as 
Introduce the use of a statin or other lipid 
lowering agent as appropriate, and continue 
lorlatinib at the same dose. 
Introduce the use of a statin 
or other lipid-lowering 
agent as appropriate, or 
increase the dose of the 
statin/lipid lowering agent 
Increase the dose of the statin or 
other lipid-lowering agents, or 
change to a new statin/lipid 
lowering agent. Withhold 
lorlatinib dose until toxicity is 

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26 
 
 
appropriate based on 
investigator’s medical 
judgment. 
or change to a new agent. 
Either continue lorlatinib at 
the same dose without 
interruption or withhold 
dose until toxicity is 
G d
2
d h
Grade ≤2 and then reduce the 
dose by 1 dose level or 
rechallenge at the same dose. 
Triglycerides 
Continue lorlatinib at 
the same dose. 
Consider introducing 
use of a statin or other 
lipid-lowering agent as 
appropriate based on 
investigator’s medical 
judgment. 
Introduce the use of a statin or other 
lipid-lowering agent as appropriate, and 
continue lorlatinib at the same dose. 
Introduce the use of a statin 
or other lipid-lowering 
agent as appropriate, or 
increase the dose of the 
statin/lipid-lowering agent 
or change to a new agent. 
Either continue lorlatinib at 
the same dose without 
Increase the dose of the statin or 
other lipid-lowering agents, or 
change to a new 
statin/lipid-lowering agents. 
Withhold lorlatinib dose until 
toxicity is Grade ≤2 and then 
reduce the dose by 1 dose level 
or rechallenge at the same dose. 
 
 
CNS Toxicities 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
CNS effectsβ 
Continue lorlatinib at 
the same dose or 
withhold dose until 
recovery to baseline. 
Continue lorlatinib at same dose or withhold 
dose until recovery to Grade ≤1.  Consider 
dose reduction or rechallenge at the same dose. 
Withhold lorlatinib dose 
until toxicity is Grade ≤1. 
Reduce dose to the next 
lower dose. 
Permanently 
discontinue lorlatinib. 
β Examples of CNS effects could include changes in speech, memory, sleep, cognition, or vision. 

ENGLISH 
 
27 
 
6. STUDY PROCEDURES 
All assessments and procedures during the study are detailed in the Schedule of 
Activities (Table 1). 
To allow for subject and investigator schedules, holidays, and weather or other 
emergencies requiring clinical facilities to be closed, all subject visits can be performed 
within -2/+2 weeks of the scheduled visit date. To allow for additional flexibility in 
scheduling subject visits and procedures, Screening and Baseline procedures may be 
completed on the same day. 
 
6.1 Baseline 
The following text outlines baseline assessments and procedures to be performed (see 
Schedule of Activities Table 1).   
Within 2 weeks prior to first study drug administration of lorlatinib, the following 
assessments will be performed. It is unnecessary to repeat assessment at baseline if 
screening assessment and all laboratory evaluation items for baseline were performed 
at screening and within 2 weeks prior to first study drug administration of lorlatinib 
(Pregnancy test result need to be known to be negative prior to study treatment: In case 
of serum sample, pregnancy test needs to be conducted within 72 hours prior to first 
day of lorlatinib administration. In case of urine sample, pregnancy test needs to be 
conducted on Day 1 of lorlatinib administration before study treatment is started.) and 
there is no clinical reason to believe the baseline has significantly changed:  
• Vital signs and body weight will be measured (see Section 7.3.3); 
• Demographics and medical history (relevant clinical events and conditions 
including tumor-related signs and symptoms); collection of subject reported 
weight loss over the past 6 months; history of smoking; 

ENGLISH 
 
28 
 
• Physical examination will be performed; 
• A 12-Lead ECG reading will be done. QTc must be less than CTCAE v5.0 Grade 
2 (≤480 msec) using Fridericia’s or Bazett’s correction formula with a manual 
reading by the investigator if required.  The ECG may be repeated for 
evaluation of eligibility after management of correctable causes for observed 
QTc prolongation (see Section 7.3.1). Subject whose heart rate <45 beats per 
minute in the presence of clinical symptoms (e.g., hypotension, evidence of 
hypoperfusion) will not start study treatment; 
• Blood samples will be collected (hematology, blood chemistry, coagulation and 
pregnancy test; see Section 7.3.2). Subject who does not have adequate organ 
function will not start study treatment in the CC cohort; 
a. Estimated creatinine clearance 30 mL/min (as determined by Cockcroft-
Gault formula or the study site’s standard formula); 
b. Absolute neutrophil count (ANC) ≥1500 cells/mm3; 
c. Platelets ≥100,000 cells/mm3; 
d. Hemoglobin ≥10.0 g/dL; 
e. Bilirubin  1.5 x ULN; 
f. 
AST (also known as SGOT) and ALT (also known as SGPT) 2.5 x ULN 
( 5.0 x ULN if hepatic metastases); 
• Prior/concomitant medication and SAE data will be collected and reviewed; 
• Blood collection for a retrospective analysis for the presence of ctDNA. 
Subjects who sign the informed consent, and successfully completed screening and 
baseline assessments will subsequently be assigned open label lorlatinib. Treatment 
must start within 3 days. 

ENGLISH 
 
29 
 
6.2 Study Period 
6.2.1 Day 1 of the first 4 weeks 
Day 1 procedures may be completed on the same day as Baseline procedures (see the 
Schedule of Activities, Table 1). The following assessments and procedures will be 
performed: 
⚫ Vital signs and body weight will be measured; 
⚫ ECOG PS (see Appendix 1); 
⚫ Concomitant medication and AE data will be collected and reviewed.  
Subjects will be instructed to avoid extended unprotected exposure to sunlight (e.g., 
sunbathing) or tanning for the duration of the study period and end of treatment visit 
(approximately 8 weeks after completion of study drug). 
6.2.2 Day 28 of the first 4 weeks (±2 days) 
• Check the ctDNA-seq (10000x) in plamsa with NGS 
6.2.3 Day 1 of Subsequent Cycles (-4/+2 days) 
Subjects will visit the investigator site on Day 1 (-1/+1 week) of each subsequent 
cycle for the following assessments: 
⚫ Vital signs and body weight will be measured; 
⚫ ECOG PS (see Appendix 1); 
⚫ Blood samples will be collected (hematology, blood chemistry, see Section 
7.3.3). Safety laboratory tests may be done up to 72 hours prior to the visit; 
⚫ Concomitant medication and AE data will be collected and reviewed; 
⚫ Tumor assessments will occur at the end of the first 4 weeks and then following 
per 8-12 weeks.  The assessment may be performed up to 7 days prior to the visit 
to facilitate availability of results to the investigator at the time of the clinic visit.  

ENGLISH 
 
30 
 
6.2.4 Local therapy 
⚫ Patients may be assigned to receive local therapy if stable of target lesions in 2 
consecutive imaging during lorlatinib treatment, and the specific treatment will 
be at the discretion of the investigator or patients willingness. 
6.2.5 Imaging 
Either a CT or MRI scan (whichever was used at screening) of the tumor area will be 
conducted at the first 4 weeks and following per 8-12 weeks. The scan is to include 
the chest, Brain, liver, adrenal glands and other applicable sites of disease.  
6.2.6 End of Treatment Visit 
If a subject comes off treatment for progression of disease, intolerance to study 
treatment, or subject withdrawal, etc., they should return to the study site as soon as 
possible for assessments of efficacy and safety as follows.  
⚫ Vital signs and body weight will be measured; 
⚫ ECOG PS (see Appendix 1); 
⚫ Blood and urine samples will be collected (hematology, blood chemistry, 
coagulation, pregnancy test [if required], urinalysis;). Safety laboratory tests may 
be done up to 72 hours prior to the visit; 
⚫ Concomitant medications and AE data collection and review; 
⚫ If tumor assessments have not been done within the last 4 weeks for patients who 
discontinue treatment for reasons other than disease progression, these will be 
obtained as soon as feasible; 
6.2.7 Post Treatment Follow-up Visit 
At least 28 days, and no more than 35 days, after discontinuation of treatment, 
subjects will return to the study site or other medical facilities and the following 
assessments will be performed. 

ENGLISH 
 
31 
 
In case subjects continue on therapy after progressive disease, assessments of safety 
and survival status at post treatment follow-up visit should be performed at least 28 
days, and no more than 35 days after end of treatment visit assessments. 
⚫ Vital signs and body weight will be measured; 
⚫ Subsequent cancer therapy; 
⚫ Concomitant medications and AE data collection and review. 
Subjects continuing to experience treatment-related toxicity at this point after 
discontinuation of treatment will continue to be followed at least every 4 weeks until 
resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected. 
6.2.8 Long-term Follow-up for Progression and Survival 
Subjects with no evidence of disease progression at the time of treatment 
discontinuation should be followed up until disease progression, regardless of any 
start of subsequent cancer therapy. Repeat tumor assessments are suggested 
approximately every 8-12 weeks from the date of CT/MRI at the end of study 
treatment. 
All subjects (including those who show disease progression) must be followed up for 
subsequent cancer therapies and survival status regardless of the reasons for 
discontinuation from study drug treatment approximately every 2-3 months from post 
treatment follow-up visit. Telephone contact or other means to obtain timely regular 
follow-up is recommended, including subjects who are subsequently followed by 
providers other than the investigator. The information for subsequent therapies 
collected and recorded on the LinkDoc should include enumeration of subsequent 
treatment, including drugs administered, date of initiation and discontinuation of each 
medication. Each subject will be followed up for survival status and subsequent 
cancer therapies up to 60 months from the date of first dosing of loraltinib. 

ENGLISH 
 
32 
 
7. ASSESSMENTS 
Every effort should be made to ensure that the study required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure 
the safety and well-being of the subject. When a study required test cannot be 
performed, the investigator will document the reason and any corrective and preventive 
actions which he/she has taken to ensure that normal processes are adhered to as soon 
as possible.  
7.1 Timing of Assessments 
All subjects being considered for the study must sign an informed consent within 28 
days of start of treatment, and prior to any study specific screening procedures.  
Baseline assessments must be performed within 14 days prior to commencing study 
treatment, except pregnancy test (if applicable). Pregnancy test result needs to be 
known to be negative prior to study treatment.  In case of serum sample, pregnancy 
test needs to be conducted within 72 hours prior to Cycle 1 Day 1.  In case of urine 
sample, pregnancy test needs to be conducted on Cycle 1 Day 1 before study treatment 
is started.   
On visits after Day 1 of the first 8 weeks, laboratory assessments may be performed up 
to 72 hours and tumor/imaging assessments up to 7 days prior to Day 1 of any cycle in 
order for results to be available for investigator review at time of subject visit. 

ENGLISH 
 
33 
 
7.2 Efficacy Assessments 
7.2.1 Tumor Response Assessment 
Objective tumor response will be measured using RECIST v1.1 (see Appendix 3) and 
assessed by the investigator (INV) in real world clinical practice . 
Imaging tumor assessments at screening are to be performed within 28 days prior to 
commencing study treatment. All measurements should be recorded in metric notation 
using a ruler or calipers.   
Investigators are encouraged to select greater than one lesion, representative and 
reproducible and to include the largest lesion, when identifying target lesions to be 
followed. 
Post-baseline tumor assessments will be performed at the end of the first 8 weeks 
then every cycle (within 7 days of the start of subsequent cycle including Day 1 of 
subsequent cycle), using the same method and technique used to characterize lesions 
identified at baseline. Imaging serves also as safety assessment to monitor/exclude 
pulmonary toxicity. 
Subjects with no evidence of disease progression at the time of treatment 
discontinuation, should be followed up until disease progression, regardless of the start 
of any new cancer therapy. Repeat tumor assessments are suggested approximately 
every 4 weeks from the date of CT/MRI at the end of study treatment in the appropriate 
setting.  
All subjects should be followed up for subsequent cancer therapies and survival status 
regardless of the reasons for discontinuation from study drug treatment. Telephone 
contact or other means to obtain timely regular follow-up is recommended. The 
information for subsequent therapies collected and recorded on the CRF should include 
enumeration of subsequent treatment, including drugs administered, date of initiation 

ENGLISH 
 
34 
 
and discontinuation of each drug. This may be conducted by telephone for unresponsive 
subjects. As per RECIST v1.1 guidelines, PR and CR do not need to be confirmed 
following initial response documentation. However, subjects with documented PR or 
CR should still be followed with regular assessments for the duration of the study to 
see if there is a change in status with time.  
The same method and technique should be used to characterize each lesion identified 
and reported at Baseline, during the study treatment period, and during follow up.  
7.2.2 Blood Specimens for Circulating Nucleic Acid (CNA) Profiling 
Collection of peripheral plasma samples optimized for nucleic acid analysis (e.g., 
circulating free DNA [ctDNA] or RNA [ctRNA]) will be mandatory for all patients 
at baseline, week 8. Markers that may be analyzed include, but may not be limited 
to ALK rearrangement, and ALK kinase domain mutations. 
7.3 Safety Assessments 
The following parameters will be assessed at time points detailed in Table 1 Schedule 
of Activities: 
⚫ ECG; 
⚫ Safety laboratory data;  
⚫ ECOG PS (ref to Appendix 1 is needed);  
⚫ Vital signs; 
⚫ AEs. 
7.3.1 12 Lead ECG 
A 12-Lead ECG will be performed at screening and baseline with a 10 second rhythm 
strip. If the subject experiences signs or symptoms of a cardiac or neurologic disorder 
(specifically syncope, dizziness, seizures, or stroke), ECG should be obtained at the 
time of the event. 

ENGLISH 
 
35 
 
To ensure safety, if there is finding of QTc >500 msec, the ECG must be repeated.  
If there is finding of QTc >500 msec again (i.e., ≥CTCAE Grade 3), the ECG must be 
reviewed by qualified personnel at the site as soon as the finding is made, including 
verifying that the machine reading is accurate and that the Fridericia’s or Bazett’s 
correction formula is applied.  
An electronic reading of prolonged QTc must be confirmed by a manual reading.  
Before concluding that an episode of QTc prolongation is due to study drug, thorough 
consideration should be given to potential precipitating factors (e.g., a change in the 
subject’s clinical condition, the effect of concurrent medication, electrolyte 
disturbance) and a possible evaluation by a specialist.  If the QTc reverts to 
500 msec, and it is the opinion of the investigator that the prolongation was not due 
to the study drug, treatment may be continued with regular ECG monitoring.  
7.3.2 Safety Laboratory Data 
Safety laboratory studies may be done up to 72 hours prior to the point indicated on 
the Schedule of Activities (Table 1) on any cycle, to facilitate availability of results to 
the investigator at the time of the clinic visit.   
Table 5: Laboratory Evaluations  

ENGLISH 
 
36 
 
 
7.3.3 Vital Signs 
Vital signs include pulse rate, sitting or supine blood pressure, respiratory rate and 
body temperature.   
The information will be recorded in the subject’s medical records and if clinically significant, data will be recorded 
as an AE in the CRF.  
8. ADVERS`E EVENT REPORTING 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the 
following sections.  
Screening for Eligibility 
Hematology 
Blood Chemistry  
Other 
Hemoglobin 
Platelet count 
WBC count  
Absolute neutrophil count 
Absolute lymphocyte 
count 
Absolute monocyte count 
AST (SGOT) 
ALT (SGPT) 
Creatinine 
Total bilirubin 
Urinalysis 
(blood, 
protein, 
glucose, 
by 
dipstick; microscopic examination of sediment 
if abnormalities on urine dipstick) 
 
Calculation 
of 
the creatinine 
clearance 
determined by the Cockcroft-Gault formula or 
site’s standard formula. 
Pregnancy Test (urine or serum) 
 
Baseline and during the Treatment Period  
Hematology 
Blood Chemistry 
Other 
Hemoglobin 
Platelet count 
WBC count  
Absolute neutrophil count 
Absolute lymphocyte 
count 
Absolute monocyte count 
Alkaline phosphatase 
AST, ALT 
Total bilirubin 
Calcium (total or ionized) 
Magnesium 
Potassium 
Sodium 
BUN or urea  
Albumin  
Pregnancy test (urine or serum) at baseline.  
In case of serum sample, pregnancy test needs 
to be conducted within 72 hours prior to Day 
1 of the first 8 weeks. In case of urine 
sample, pregnancy test needs to be conducted 
on Day 1 of the first 8 weeks before 
study treatment is started.  Pregnancy test 
(urine or serum) at end of treatment if 
mandated by institutional policy or at the 
discretion of the investigator.  

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37 
 
For all AEs, the investigator must pursue and obtain adequate information both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as a SAE requiring immediate notification to the Sponsor or its 
designated representative. For all AEs, sufficient information should be obtained by 
the investigator to determine the causality of the AE. The investigator is required to 
assess causality. Follow-up by the investigator may be required until the event or its 
sequelae resolve or stabilize at a level acceptable to the investigator, and the Sponsor 
concurs with that assessment. 
As part of ongoing safety reviews conducted by the Sponsor any non-serious AE that 
is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be 
requested from the investigator to provide clarity and understanding of the event in 
the context of the clinical study.   
8.1 Reporting Period 
For SAEs, the active reporting period to the Sponsor or its designated representative 
begins from the time that the subject provides informed consent, which is obtained 
prior to the subject’s participation in the study, i.e., prior to undergoing any 
study-related procedures and/or receiving investigational product, through and 
including 28 calendar days after the last administration of the investigational product 
regardless of the start of any subsequent cancer therapy.  SAE should be reported via 
the CRF in the active reporting period.  Following the active safety reporting period, 
other SAEs of which the investigator becomes aware should be reported to Pfizer, 
unless the SAE is attributed by the investigator to complications of either the 
underlying malignancy or any subsequent anti-cancer therapy or to the patient’s 
participation in a subsequent clinical study.  
Non-serious adverse events should be recorded on the CRF from the time the subject 
has taken at least one dose of study treatment through last subject visit. 

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38 
 
If a subject begins a new anticancer therapy, the AE reporting period for non-serious 
AEs ends at the time the new treatment is started.   
8.2 Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation during which a 
subject is administered a product or medical device; the event need not necessarily 
have a causal relationship with the treatment or usage.  Examples of AEs include but 
are not limited to:   
⚫ Abnormal test findings; 
⚫ Clinically significant symptoms and signs; 
⚫ Changes in physical examination findings; 
⚫ Hypersensitivity; 
⚫ Drug abuse; 
⚫ Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
⚫ Drug overdose; 
⚫ Drug withdrawal; 
⚫ Drug misuse;  
⚫ Drug interactions; 
⚫ Exposure during pregnancy; 
⚫ Exposure via breast-feeding; 
⚫ Medication error. 
Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF. Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as an AE. 

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39 
 
8.3 Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows:  
⚫ Test result is associated with accompanying symptoms, and/or 
⚫ Test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
⚫ Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
⚫ Test result is considered an AE by the investigator. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not constitute an AE. Any abnormal test result that is determined to be an error does 
not require reporting as an AE. 
8.4 Serious Adverse Events 
A SAE is any untoward medical occurrence at any dose that: 
⚫ Results in death; 
⚫ Is life-threatening (immediate risk of death); 
⚫ Requires inpatient hospitalization or prolongation of existing hospitalization; 
⚫ Results in persistent or significant disability/incapacity (substantial disruption 
of the ability to conduct normal life functions); 
⚫ Results in congenital anomaly/birth defect. 
Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as a SAE unless the outcome is fatal within the 
safety-reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as a SAE.  If the malignancy has a fatal outcome 
during the study or within the safety-reporting period, then the event leading to death 
must be recorded as an AE and as a SAE with CTCAE Grade 5 (see Section 8.6). 

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40 
 
Medical and scientific judgment is exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization. However, if it is determined 
that the event may jeopardize the subject or may require intervention to prevent one of 
the other AE outcomes, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
9. DATA ANALYSIS/STATISTICAL METHODS  
9.1 Sample Size Determination 
The primary objective of this real-world study is to demonstrate that locally therapy 
during 1L lorlatinib is instrumental in prolonging TTD by investigator assessment per 
RECIST v1.1. 
Approximately 100 patients who receive lorlatinib in first line are expected to be 
included in this study. Since this study is descriptive without specified hypothesis, the 
sample size is not determined based on statistical assumptions, but according to the 
following information: epidemiology, China marketing competition environment, 
marketing research report, drug availability, patient affordability, health insurance 
coverage, and at least 20% dropout rate. Comprehensively, the final sample size of this 
study is expected to reach for about 100 cases. 
9.2 Effectiveness Analysis 
9.2.1 Analysis Populations 
The following subject populations will be assessed: 

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41 
 
Safety-Analysis-Set (SAT) Population  
The SAT Population will include all subjects who receive at least 1 dose of study 
medication. The SAT Population will be the primary population for evaluating 
treatment administration/compliance and safety.   
Censoring for time-to-event efficacy endpoints (i.e., PFS and OS) will be elaborated 
in the SAT. 
9.2.2 Definition of Primary Endpoint 
Time-to treatment discontinuation (TTD) is defined as the time from start of treatment 
to the date of discontinuation of lorlatinib. 
9.2.3 Analysis of Primary Endpoint 
TTD will be summarized using Kaplan-Meier methods and displayed graphically. 
Potential influences of other demographic baseline characteristics including 
biomarker profile use parametrical text, χ2 or Fisher exact test .  
9.2.4 Definitions of Secondary Efficacy Endpoints 
Real world Intracranial Objective Response Rate is defined as the proportion of 
subjects with a BOR of either CR or PR of intracranial disease, where BOR is the best 
response recorded from the start of treatment until disease progression or start of other 
anticancer therapy in real world setting. As per RECIST v1.1 guidelines, PR and CR 
do not need to be confirmed following initial response documentation. 
Real world Objective Response Rate is defined as the proportion of subjects with a 
BOR of either CR or PR, where BOR is the best response recorded from the start of 
treatment until disease progression or start of other anticancer therapy in real world 
setting. As per RECIST v1.1 guidelines, PR and CR do not need to be confirmed 
following initial response documentation. 

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42 
 
Real world Disease control rate is defined as the proportion of patients with complete 
response (CR) or partial response (PR) or subjects with stable disease (SD) as per 
investigator assessment according to RECIST 1.1 criteria in real world setting. 
Overall Survival is defined as the time from start of treatment to the date of death for 
any cause.  In the absence of confirmation of death, survival time will be censored at 
the last date the subject is known to be alive. 
Real world Intracranial Time To Progression is defined as the time from 
randomization to the date of the first documentation of objective progression of 
intracranial disease, based on either new brain metastases or progression of existing 
brain metastases in real world setting.  
9.2.5 Analysis of Secondary Endpoints 
rwPFS, IC-TTP and Overall Survival will be summarized using Kaplan-Meier 
methods and displayed graphically. The 1/2/3/4/5-year rwPFS, IC-TTP and survival 
probability will be estimated using Kaplan-Meier methods and the 2-sided 95% CI 
will be provided.  Potential influences of other demographic, baseline characteristics 
including biomarker profile use parametrical text, χ2 or Fisher exact test. Objective 
Response Rate will be summarized for the SAT Population based on the investigator’s 
assessment.  The number and percent of subjects achieving objective response (CR 
or PR) will be summarized along with corresponding 2-sided 95% CI using the 
binomial distribution.  
Intracranial Objective Response Rate will be summarized for the SAT Population 
based on the investigator’s assessment. The assessment of intracranial response will 
be conducted on subjects with measurable and unmeasurable CNS metastases. The 
number and percent of subjects achieving objective response (CR or PR) will be 
summarized along with corresponding 2-sided 95% CI using the binomial 
distribution. 

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43 
 
Subgroup analysis is considered to be conducted by baseline characteristics such as 
CNS (Yes/No), TP53 status (Yes/No), ALK-EML4 fusion variant (V1, V2, V3) in 
patients with baseline who receive lorlatinib in first line. Depending on the actual 
sample size at the time of analysis, adjustment by either combining or re-classifying 
the subgroups will be applied as needed. 
Subgroup comparisons, where is applicable, will be performed using the Kaplan-
Meier method and the log-rank test. Statistically significant level of α=0.05 (two 
sides) is used for tests. 
The qualitative exploratory endpoints will be categorized and summarized 
descriptively by count and percentage of patients. Missing data will be categorized by 
missing, unknown, or can’t be determined. 
The interim analysis will be performed when the completion of 2.5 year follow-up in 
late patient. The final full analysis will take place at the time of data cut-off (i.e. the 
completion of 60-month follow-up for all the participants). 
Descriptive statistics will be used to summarize subject characteristics, study conduct, 
subject disposition, treatment administration/compliance, and safety parameters.  
Data will also be displayed graphically, where appropriate. 
9.3 Safety Analysis 
The SAT Population will be the primary population for evaluating safety. 
All subjects who receive at least one dose of study medication will be included in the 
summaries and listings of safety data. The overall safety profile and toleration of 
lorlatinib will be characterized by type, frequency, severity (as graded by CTCAE 
v5.0), timing and relationship of study treatment of AEs and laboratory abnormalities. 

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44 
 
10. STUDY ORGANISATION AND COMMITTEES 
10.1 Study Coordination 
The study is an investigator-initiated, cooperative trial group trial. 
10.2 Trial Management Committee 
The Trial Management Committee will oversee study planning, monitoring, progress, 
review of information from related research, and implementation of recommendations 
from other study committees and external bodies (e.g. ethics committees). 
Selection Bias: Real-world study population is relatively unselected compared with 
randomized clinical trials in terms of stringent inclusion and exclusion criteria. 
However, selection bias still exists because the participants are not randomly drawn 
from the target population. First, patients will be recruited from particular sites that 
are characterized by the site’s prevalent demographics, specific routine clinical 
practice procedures, and the different levels of experience in the investigators. 
Second, there is also selection bias due to loss to follow up (also known as 
informative censoring), which often happen when a patient can no longer be tracked 
due to various reasons such as hospital referral or migration. 
Information Bias: Information bias due to missing data exists in almost all kinds of 
studies. In contrast to the prospective clinical trials, where study variables are 
intentionally prespecified and collected, the availability, completeness of the data in 
this study requires special attention since the data is originally recorded without any 
intervention to prevent missingness. 
Generalizability: While the real-world study can include a wider population than 
randomized control studies, the generalizability of this study may still be affected by 
the geographic location of the sample study population and hospital specific 
characteristics and may lead to differences in variations in outcomes. The analysis 

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45 
 
will be done for each site to validate generalizability of outcomes respective of 
geographic location of the participants. Furthermore, disease assessment will be based 
on evaluations performed by the attending physicians in real-world clinical practice. 
Although a significant proportion of physicians use RECIST in their clinical practice, 
it may still result in an inconsistent definition of tumor response and disease 
progression. Such information bias can be minimized to some extent by following a 
well-designed data management process and through appropriated definition of 
variables to sufficiently use available information. Lastly, no hypotheses will be 
tested in this study and only descriptive analysis will be performed. Thus, results 
cannot serve as a general conclusion on the effectiveness and safety of lorlatinib. 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, the Sponsor or its agent will conduct periodic monitoring visits 
to ensure that the protocol and Good Clinical Practice (GCP) are being followed.  
The monitors will review source documents to confirm that the data recorded on 
CRFs are accurate.  The investigator and institution will allow Sponsor monitors or 
its agents and appropriate regulatory authorities direct access to source documents to 
perform this verification. 
The study site may be subject to review by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), and/or to quality assurance audits 
performed by Sponsor or companies working with or on behalf of Sponsor, and/or to 
inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during 
the monitoring visits and possible audits or inspections, and that sufficient time is 
devoted to the process. 

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46 
 
12. DATA HANDLING AND RECORD KEEPING 
12.1 Case Report Forms/Electronic Data Record 
As used in this study, the LinkDoc data management platform should be understood 
to refer to an electronic data record. Some of the sourced documents may be in paper 
format but whenever possible these should be transferred to an electron format. 
The investigator has ultimate responsibility for the collection and reporting of all 
clinical, safety and laboratory data entered on the LinkDoc data management platform 
and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  
In most cases, the source documents are the hospital's or the physician's subject chart.  
In these cases, data collected on the LinkDoc data management platform must match 
the data in those charts.  
12.2 Record Retention 
The records should be retained by the investigator according to International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH), local regulations, or as specified in the 
Clinical Study Agreement, whichever dictates a longer period. If the investigator 
becomes unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), the Sponsor should be prospectively notified.  
The study records must be transferred to a designee acceptable to the Sponsor, such as 
another investigator, another institution, or to an independent third party arranged by 
the Sponsor.  The investigator must obtain the Sponsor’s written permission before 
disposing of any records, even if retention requirements have been met. 

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47 
 
13. ETHICS 
13.1 Institutional Review Board /Independent Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study 
protocol, study amendments, informed consent forms, and other relevant documents 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC. All 
correspondence with the IRB/IEC should be retained in the Investigator File. Copies 
of IRB/IEC approvals should be forwarded to the Sponsor.    
The only circumstance in which an amendment may be initiated prior to IRB/IEC 
approval is where the change is necessary to eliminate apparent immediate hazards to 
the subjects. In that event, the investigator must notify the IRB/IEC and Sponsor in 
writing immediately after the implementation. 
13.2 Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as 
well as the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International 
Organizations of Medical Sciences 2002), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008).  
In addition, the study will be conducted in accordance with the protocol, the ICH 
guideline on GCP, and applicable local regulatory requirements and laws. 
13.3 Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject 
names on any Sponsor forms, reports, publications, or in any other disclosures, except 
where required by law.  

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Subject names, address, birth date and other identifiable data will be replaced by an 
alphanumerical code consisting of a numbering system provided by the Sponsor.  In 
case of data transfer, the Sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The informed consent form must be in compliance with ICH GCP, 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/IEC and the 
Sponsor before use. 
The investigator must ensure that each study subject, 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 subject or the 
subject's legally acceptable representative before any study-specific activity is 
performed. The investigator will retain the original of each subject's signed consent 
form. 
13.4 Subject Recruitment 
Advertisements approved by IRB/IEC and investigator databases may be used as 
recruitment procedures.   
13.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an 
applicable Competent Authority in any area of the world, or if the investigator is 
aware of any new information which might influence the evaluation of the benefits 
and risks of the investigational product, the Sponsor should be informed immediately.   

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In addition, the investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the investigator to protect the study subjects against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCP of which the 
investigator becomes aware. 
 
14. PUBLICATION OF STUDY RESULTS 
Publication of study results is discussed in the Clinical Study Agreement. 
14.1 Communication of Results by the Sponsor 
The Sponsor shall fulfill its commitment to publicly disclose clinical study results 
through posting the results of this study on www.clinicaltrials.gov 
(ClinicalTrials.gov).   
14.2 Publications by Investigators 
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the study results themselves) before disclosure. 
The investigator agrees that the first publication is to be a joint publication covering 
all centers.  However, if a joint manuscript has not been submitted for publication 
within 12 months of completion or termination of the study at all participating sites, 
the investigator is free to publish separately, subject to the other requirements of this 
section. 
For all publications relating to the study, the institution will comply with recognized 
ethical standards concerning publications and authorship, including Section 
II - “Ethical Considerations in the Conduct and Reporting of Research” of the 
Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 

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http://www.icmje.org/index.html#authorship, established by the International 
Committee of Medical Journal Editors. 
Publication of study results is defined in the Clinical Study Agreement between the 
Sponsor and the institution.  In this section, entitled Publications by Investigators, 
the defined terms shall have the meanings given to them in the Clinical Study 
Agreement. 
15. REFERENCES 
1. 
Rongshou Zheng, Siwei Zhang, Hongmei Zeng, Shaoming Wang, Kexin Sun, Ru Chen, Li 
Li, Wenqiang Wei, Jie He, Cancer incidence and mortality in China, 2016, Journal of the 
National Cancer Center, Volume 2, Issue 1, 2022, Pages 1-9, 
2. 
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global 
Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 
Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. 
3. 
Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-
positive lung cancer. N Engl J Med 2014; 371: 2167-77. 
4. 
Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-
positive non–small-cell lung cancer. N Engl J Med 2017; 377: 829-38. 5. Camidge DR, Kim 
HR, Ahn M-J, et al.  
5. 
Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer. N Engl J Med 
2018; 379: 2027-39. 6. Selvaggi G, Wakelee HA, Mok T, et al.  
6. 
Phase III randomized study of ensartinib vs crizotinib in anaplastic lymphoma kinase 
(ALK) positive NSCLC patients: EXALT3. Presented at the International Association for the 
Study of Lung Cancer World Conference on Lung Cancer, Singapore, August 8, 2020. abstract. 
7. 
Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and safety data and impact 
of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive 
advanced non-small cell lung cancer in the global Phase III ALEX Study. J Thorac Oncol 2019; 
14: 1233-43.  
8. 
Camidge DR, Kim HR, Ahn M-J, et al. Brigatinib versus crizotinib in advanced ALK 
inhibitor-naive ALK-positive non-small cell lung cancer: second interim analysis of the Phase 
III ALTA-1L trial. 
9. 
Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and 
second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov 2016; 6: 
1118-33. 
10. Katayama R, Friboulet L, Koike S, et al. Two novel ALK mutations mediate acquired 
resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res 2014; 20: 5686-96. 
11. Dagogo-Jack I, Oxnard GR, Fink J, et al. A phase II study of lorlatinib in patients (pts) 
with ALK-positive (ALK+) lung cancer with brain-only progression. J Clin Oncol 2020; 38: 

ENGLISH 
 
51 
 
Suppl 15: 9595. abstract. 
12. Bauer TM, Shaw AT, Johnson ML, et al. Brain penetration of lorlatinib: cumulative 
incidences of CNS and non-CNS pro- gression with lorlatinib in patients with previously treated 
ALK-positive non-small cell lung cancer. Target Oncol 2020; 15: 55-65.  
13. Gainor JF, Chi AS, Logan J, et al. Alectinib dose escalation reinduces central nervous 
system responses in patients with anaplastic lymphoma kinase-positive non-small cell lung 
cancer relapsing on standard dose alectinib. J Thorac Oncol 2016; 11: 256-60.  
14. Ali A, Goffin JR, Arnold A, Ellis PM. Survival of patients with non-small cell lung cancer 
after a diagnosis of brain metastases. Curr Oncol 2013; 20(4): e300-e306.  
15. Venur VA, Ahluwalia MS. Targeted therapy in brain metastases: ready for primetime? Am 
Soc Clin Oncol Educ Book 2016; 35: e123-e130. 
16. Zou HY, Friboulet L, Kodack DP, et al. PF-06463922, an ALK/ROS1 inhibitor, overcomes 
resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell 2015; 
28: 70-81. 
17. Horn L, Whisenant JG, Wakelee H, et al. Monitoring therapeutic response and resistance: 
analysis of circulating tumor DNA in patients with ALK+ lung cancer. J Thorac Oncol 2019; 
14: 1901-11. 
18. Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)-7-amino-12-fluoro- 
2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)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: 
4720-44. 
19. Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or 
ROS1 rearrangement: an international, multi-center, open-label, single-arm first-in-man phase 
1 trial. Lancet Oncol 2017; 18: 1590-9. 
20. 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: 1654-67. 
21. Lu S, Zhou Q, Liu X, et al. Lorlatinib for Previously Treated ALK-Positive Advanced 
NSCLC: Primary Efficacy and Safety From a Phase 2 Study in People's Republic of China. J 
Thorac Oncol. 2022 Jun;17(6):816-826. 
22. Shaw AT, Bauer TM, de Marinis F, et al. CROWN Trial Investigators. First-Line Lorlatinib 
or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020 Nov 
19;383(21):2018-2029. 
23. Benjamin J, et al.present at AACR2022. Abstract #CT223 
24. Chaft JE, Oxnard GR, Sima CS, et al. Disease flare after tyrosine kinase inhibitor 
discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib 
or gefitinib: implications for clinical trial design. Clin Cancer Res 17: 6298-303, 2011. 
25. Camidge DR, Pao W and Sequist LV:.Acquired resistance to TKIs in solid tumours: learning 
from lung cancer. Nat Rev Clin Oncol 11(8): 473-448, 2014. 
26.Stephens SJ, Moravan MJ and Salama JK: Managing patients with oligometastatic non-
small-cell lung cancer. J Oncol Pract 14(1): 23-31, 2018.  
 

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

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APPENDIX 2   Medications with Potential PR Interval Prolongation 
Effect 
Note that the drugs listed below are examples and this is not intended to be an all-
inclusive listing 
 
Electrophysiologic Effects of Select Drugs on PR Interval Based on Product Labeling 
Drug 
Action 
Indications 
Affecting AV nodal conduction (PR interval 
Adenosine 
Adenosine receptor 
PSVT 
Amiodarone 
Cardiac ion channels 
Antiarrhythmics 
Disopyarmide 
Encainide 
Flecainide 
Moricizine 
Propafenone 
Verapamil 
Arsenic trioxide 
Multiple actions 
Acute promyelocytic Leukemia 
Atazanavir 
HIV-protease inhibitors 
Antiretroviral inhibitor 
Lopinavir/Ritonavir 
Saquinavir 
Digoxin 
Multiple actions 
Congestive heart failure 
Dolasetron 
5HT3 receptor antagonist 
Antiemetic 
Fingolimod 
S1P receptor modulator 
Multiple sclerosis 
Lacosamide 
Not fully characterized 
Partial-onset seizures 
Pregabalin 
Not fully characterized 
Neuropathic pain 
Mefloquine 
Plasmodicidal effects 
Antimalarial 
Drugs were initially screened using the PDR3D database for PR interval prolongation using terms “PR 
interval prolongation”, “AV block”, “AV conduction delay”, or “heart block”. Drugs were subsequently 
selected for inclusion on the basis on descriptions of PR interval prolongation/AVB contained with Warning 
or Precautions sections of drug labels. 
PSVT, Paroxysmal supraventricular tachycardia. 
 
 
 
 
 
 

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APPENDIX 3   RECIST Version 1.1 
 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.  
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions   
Lesions that can be accurately measured in at least one dimension. 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when 
assessed by CT or MRI (slice thickness 5-8 mm) 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray   
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper   
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other measurable lesions.  
Non-measurable disease  
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
Bone disease: Bone disease is non-measurable with the exception of soft tissue components that 
can be evaluated by CT or MRI and meet the definition of measurability at baseline.   
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be 
recorded either as target or non-target disease.  Cystic lesions thought to represent cystic 
metastases can be measurable lesions, if they meet the specific definition above. If non-cystic 
lesions are also present, these are preferred as target lesions. 

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Normal nodes: Nodes with short axis <10 mm are considered normal and should not be recorded 
or followed either as measurable or non-measurable disease. 
RECORDING TUMOR ASSESSMENTS  
All sites of disease must be assessed at baseline.  Baseline assessments should be done as close as 
possible prior to study start. For an adequate baseline assessment, all required scans must be done 
within 28 days prior to treatment and all disease must be documented appropriately.  If baseline 
assessment is inadequate, subsequent statuses generally should be indeterminate.   
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of 
all involved organs, should be identified as target lesions at baseline. Target lesions should be 
selected on the basis of size (longest lesions) and suitability for accurate repeated measurements.  
Record the longest diameter for each lesion, except in the case of pathological lymph nodes for 
which the short axis should be recorded.  The sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to 
assessments performed on study.  
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large target 
lesion splits, the sum of the parts is used. 
Measurements for target lesions that become small should continue to be recorded.  If a target 
lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to have 
disappeared; otherwise a default value of 5 mm should be recorded. 
Non-target disease  
All non-measurable disease is non-target. All measurable lesions not identified as target lesions are 
also included as non-target disease.  Measurements are not required but rather assessments will be 
expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, INCREASED.  
Multiple non-target lesions in one organ may be recorded as a single item on the case report form 
(e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case must be 
discussed with the radiologist to determine if substitution is possible.  If not, subsequent objective 
statuses are indeterminate.   

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56 
 
Target disease 
Complete Response (CR): Complete disappearance of all target lesions with the exception of 
nodal disease.  All target nodes must decrease to normal size (short axis < 10 mm).  All target 
lesions must be assessed. 
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions.  The short diameter is used in the sum for target 
nodes, while the longest diameter is used in the sum for all other target lesions.  All target 
lesions must be assessed.   
Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less than 20% 
from the nadir, but enough that a previously documented 30% decrease no longer holds.   
Progression Disease (PD):  20% increase in the sum of diameters of target measurable lesions 
above the smallest sum observed (over baseline if no decrease in the sum is observed during 
therapy), with a minimum absolute increase of 5 mm.   
Indeterminate: Progression has not been documented, and  
one or more target measurable lesions have not been assessed  
or assessment methods used were inconsistent with those used at baseline 
or one or more target lesions cannot be measured accurately (e.g., poorly visible unless due 
to being too small to measure) 
or one or more target lesions were excised or irradiated and have not reappeared or 
increased.   
Non-target disease 
CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All 
lymph nodes must be ‘normal’ in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the 
normal limits.  
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden must 
increase sufficiently to merit discontinuation of therapy.  In the presence of SD or PR in target 
disease, progression due to unequivocal increase in non-target disease should be rare.   
Indeterminate: Progression has not been determined and one or more non-target sites were not 
assessed or assessment methods were inconsistent with those used at baseline. 

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57 
 
New Lesions  
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the initial 
assessment.  A lesion identified in an area not previously scanned will be considered a new lesion. 
Subjective Progression 
Subjects requiring discontinuation of treatment without objective evidence of disease progression 
should not be reported as PD on tumor assessment CRFs.  This should be indicated on the end of 
treatment CRF as discontinuation due to Global Deterioration of Health Status.  Every effort 
should be made to document objective progression even after discontinuation of treatment.   
Table 1. Objective Response Status at Each Evaluation 
Target Lesions 
Non-target Disease 
New 
Lesions 
Objective status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Indeterminate 
or 
Missing  
No 
PR 
PR 
Non-CR/Non-PD, 
Indeterminate, 
or 
Missing 
No 
PR 
SD 
Non-CR/Non-PD, 
Indeterminate, 
or 
Missing 
No 
Stable 
Indeterminate 
or 
Missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
If the protocol allows enrollment of patients with only non-target disease, the following table will 
be used: 
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease 
Only 
Non-target Disease 
New Lesions 
Objective status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Indeterminate 
No 
Indeterminate 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 

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58 
 
 
Best Overall Response 
The best overall response (BOR) is the best response recorded from the start of treatment until 
disease progression.  This is derived from the sequence of objective statuses.  Objective statuses 
are not considered after objective progression is documented or after start of the first anticancer 
treatment post discontinuation of protocol treatment. BOR for each patient will be derived as one 
of the following categories.   
Complete Response (CR): At least one objective status of CR documented before progression. 
Partial Response (PR): At least one objective status of PR documented before progression. 
Stable Disease (SD): At least one objective status of stable documented at least 8 weeks after 
start of treatment date and before progression but not qualifying as CR, PR. 
Progressive Disease (PD): Objective status of progression within 12 weeks of start of treatment 
date, not qualifying as CR, PR or SD.   
Indeterminate (IND): Progression not documented within 12 weeks after start of treatment date 
and no other response category applies. 
 
 
 
 
 
 
 
 
 
 
APPENDIX 4   PRO Instrument 
• EORTC QLQ-C30 (version 3) 
 
 
 
EORTC QLQ-C30 (version 3) 

ENGLISH 
 
59 
 
We are interested in some things about you and your health. Please answer all of the 
questions yourself by circling the number that best applies to you. There are no 
"right" or "wrong" answers. The information that you provide will remain strictly 
confidential. 
 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year):  
 
Today's date (Day, Month, Year): 
 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very Much 
1. 
Do you have any trouble doing strenuous 
like carrying a heavy shopping bag or a 
suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk 
id
f h h
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during 
h d
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very Much 
6. 
Were you limited in doing either your work or 
h
d il
i i i
1 
2 
3 
4 
7. 
Were you limited in 
pursuing your hobbies or 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 

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60 
 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
17.Have you had diarrhea? 
1 
2 
3 
4 
18.Were you tired? 
1 
2 
3 
4 
19.Did pain interfere with your daily activities? 
1 
2 
3 
4 
20.Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21.Did you feel tense? 
1 
2 
3 
4 
22.Did you worry? 
1 
2 
3 
4 
23.Did you feel irritable? 
1 
2 
3 
4 
24.Did you feel depressed? 
1 
2 
3 
4 
25.Have you had difficulty remembering things? 
1 
2 
3 
4 
26.Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27.Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28.Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
For  the  following  questions  please  circle  the  number  between  1  
and  7  that best applies to you 
 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 

ENGLISH 
 
61 
 
 
Very poor 
Excellent 
©  Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0