Real-world Study of Non-small Cell Lung Cancer Treatment With ALK-tyrosine Kinase Inhibitors (ALK TKI) in Sweden: Drug Sequencing, Treatment Duration and Overall Survival - A Retrospective Study Using Swedish Register Data
Conditions: ALK-positive NSCLC
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title
Real-world study of non-small cell lung cancer treatment with 
ALK-tyrosine kinase inhibitors (ALK TKI) in Sweden: drug 
sequencing, treatment duration and overall survival – A 
retrospective study using Swedish register data
Protocol number
B7461035
Protocol version 
identifier
Version 1.2
Date
3 November 2020
Active substance
L01XE16 Crizotinib
L01XE44 Lorlatinib 
Medicinal product
Xalkori (crizotinib)
Lorviqua (lorlatinib)
Research question 
and objectives
The objectives are to analyse overall survival and duration of 
treatment in Swedish NSCLC patients.
Primary objective:
1. Estimation of overall survival (OS) in ALK-inhibitor users.
Secondary objective: 
2. Estimation of duration of treatment (DOT) in ALK-inhibitor 
users.
Author
, PhD, 
 
, Pfizer Innovations AB, Sweden
, PhD, 
 
, Pfizer Innovations AB, Sweden
, MSc, 
, Quantify Research, Sweden
, MSc, 
, Quantify Research. Sweden
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
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copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................4
3. RESPONSIBLE PARTIES....................................................................................................5
4. AMENDMENTS AND UPDATES.......................................................................................5
5. MILESTONES.......................................................................................................................5
6. RATIONALE AND BACKGROUND..................................................................................6
7. RESEARCH QUESTION AND OBJECTIVES ...................................................................9
8. RESEARCH METHODS ......................................................................................................9
8.1. Study Design .............................................................................................................9
8.2. Setting......................................................................................................................10
8.2.1. Inclusion Criteria ........................................................................................11
8.2.2. Exclusion Criteria.......................................................................................11
8.2.3. Study Definitions........................................................................................11
8.3. Variables..................................................................................................................17
8.4. Data Sources............................................................................................................18
8.4.1. The Swedish National Patient Register ......................................................19
8.4.2. The Swedish Prescribed Drug Register ......................................................19
8.4.3. The Swedish Cause of Death Register........................................................19
8.4.4. The Swedish Cancer Register.....................................................................19
8.5. Study Size................................................................................................................20
8.5.1. Data Management.......................................................................................20
8.6. Data Analysis ..........................................................................................................21
8.6.1. Primary Objective – Overall Survival of ALK-inhibitor Users..................21
8.6.2. Secondary Objective – Duration of Treatment of ALK-inhibitor 
Users ................................................................................................................22
8.7. Quality Control........................................................................................................23
8.8. Limitations of the Research Methods......................................................................23
8.8.1. Internal Validity of Study Design...............................................................23
8.8.2. Missing or Incomplete Information............................................................24
8.8.3. External Validity of Study Results .............................................................25
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8.9. Other Aspects ..........................................................................................................25
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................25
9.1. Patient Information..................................................................................................25
9.2. Patient Consent........................................................................................................25
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............25
9.4. Ethical Conduct of the Study ..................................................................................26
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................26
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........26
11.1. Publication Policy .................................................................................................26
12. REFERENCES ..................................................................................................................28
13. LIST OF TABLES.............................................................................................................32
14. LIST OF FIGURES ...........................................................................................................32
15. ANNEX 1. LIST OF STANDALONE DOCUMENTS ....................................................32
16. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ...................................32
17. ANNEX 3. ADDITIONAL INFORMATION...................................................................33
17.1. Diagnosis and Procedure Codes............................................................................33
17.2. Additional Codes...................................................................................................35
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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
ALK
Anaplastic lymphoma kinase
ATC
The Anatomical Therapeutic Chemical Classification System
CDR
The Swedish Cause of Death Register
Chemo
Chemotherapy
CI
Confidence interval
CNS
Central nervous system 
CUP
Compassionate use programme
CSF
Cerebrospinal fluid
DOT
Duration of treatment
EMA
European Medical Agency
FASS
Pharmaceutical specialities in Sweden
GPP
Guidelines for Good Pharmacoepidemiology Practices
ICD
International Statistical Classification of Diseases and Related 
Health Problems - Tenth Revision
ICMJE
International Committee of Medical Journal Editors
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and Outcomes 
Research
ID
Identification
IEC
Independent ethics committee
IRB
Institutional review board
IV
Intravenous therapy
KM
Kaplan Meier
KVÅ koder
Procedure codes
NBHW
National Board of Health and Welfare
NCSP
NOMESCO Classification of Surgical Procedures
NI
Non-interventional
NOMESCO
The Nordic Medico-Statistical Committee
NPR
The Swedish National Patient Register
NSCLC
Non-small cell lung cancer
MPA
Medical Products Agency
OS
Overall survival
PIN
Personal identifiable number
PDR
The Swedish Prescribed Drug Register
ROS1
C-ros oncogene 1
SCLC
Small-cell lung cancer
CR
The Swedish Cancer Register
SD
Standard deviation
SoC
Standard of care
TKI
Tyrosine kinase inhibitor 
TKR
Tyrosine kinase receptor
TLV
The Dental and Pharmaceutical Benefits Agency, Sweden
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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
 PhD
Study Lead, Senior 
Medical Advisor 
Oncology
Pfizer Innovations AB
 
 PhD 
Health Economics 
Manager Oncology
Health and Value
Pfizer Innovations AB
 
 MSc, 
Project Leader
Quantify Research
 
, MSc
Project Leader
Quantify Research
 
4. AMENDMENTS AND UPDATES
None.
5. MILESTONES
Milestone
Planned date
Start of data collection 
23 November 2020
End of data collection
31 December 2020
Final study report
31 March 2021
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6. RATIONALE AND BACKGROUND
Lung cancer is a malignant tumour characterized by uncontrolled cell growth in tissues of the 
lung. The disease is highly difficult to treat and is the most common cause of cancer-related 
death in Sweden, despite being only the sixth most common tumour type.2 More than 
4000 lung cancer cases are diagnosed in Sweden every year3 with expected 5-year survival of 
16.5%.4 For patients with metastatic disease, the 5-year survival is even poorer amounting to 
only a few percent.5
Median age at lung cancer onset is 71 years, but the disease also affects younger.2 Ninety one 
(91) patients under the age of 50 were diagnosed with lung cancer in 2017 in Sweden.3 Over 
time, the composition of the group of newly diagnosed patients has gradually shifted from an 
overweighing majority of men diagnosed in the 1970’s to a small majority of women in 
recent years,1,3 likely reflecting changes in smoking habits over time. Even if cigarette 
smoking remains the most relevant contributing factor in the development of the disease, a 
distinct group of patients without significant smoking history also develops lung cancer due 
to an acquired genetic predisposition.6
The majority (~85%) of lung cancer cases falls into the category of Non-Small Cell Lung 
Cancer (NSCLC) whereas the Small Cell Lung Cancer (SCLC) represents the second largest 
subtype (~15%).6 NSCLC is further categorized into three major histological subtypes 
according to the site and cell type of origin. Adenocarcinoma, which is most prevailing and 
often observed in non-smokers, represents approximately 40% of all lung cancers, whereas 
squamous cell carcinoma and large cell carcinoma account for 25-30% and 
5-10% respectively.6
Advances in the understanding of molecular tumour biology have led to the deeper 
classification of lung adenocarcinomas through identification of several key genetic 
alterations as primary drivers of tumour growth. Somatic genetic rearrangements including 
genetic fusions can alter the structure and function of different Tyrosine Kinase Receptor 
(TKR) proteins resulting in uncontrolled stimulation of cell growth, proliferation and 
survival. Concurrently, the discovery of these alterations in NSCLC has opened a new realm 
of therapeutic possibilities via direct inhibition of the faulty receptor signalling by targeted 
Tyrosine Kinase Inhibitor (TKI) drugs. 
One of the first oncogenic drivers recognized in lung adenocarcinoma is the genetic 
rearrangement in Anaplastic Lymphoma Kinase (ALK) which defines about 5% of NSCLC 
cases.7 ALK-positive patients, the population pertinent to this study, are typically younger, 
non-smokers, and predominantly women.8
The treatment that cures most lung cancer patients is surgery. The intervention is however 
possible only in a fraction of patients with early disease, likely in combination with 
radiotherapy and/or chemotherapy.2,9 As most lung cancer cases are discovered in a late 
stage, the available therapy options are limited to medical treatments; primarily 
immunotherapy and chemotherapy.2,10 For oncogene-driven disease however, where 
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immunotherapy has shown largely ineffective, TKI drugs represent the principal therapeutic 
strategy followed by chemotherapy.11 For almost a decade now, the ALK inhibitors have 
demonstrated significant benefits in the management of ALK-positive NSCLC and 
substantially exceeded the therapeutic outcomes of conventional approaches.12-14 The
possibility of ALK TKI sequencing, ie, successful management of acquired tumour 
resistance with next, more potent ALK-inhibitor drug, brings a major therapeutic advantage 
by providing long-term disease control alongside high quality of life.
According to the latest available Swedish national lung cancer therapy guidelines (2020),11,15
and in concordance with international recommendations,16,17 patients with ALK-positive 
NSCLC should primarily be offered treatment with an ALK-inhibitor. Nearly all of the 
patients who initially respond to ALK-inhibitors however progress within 1 to 2 years due to 
the molecular evolution of their tumors that renders the targeted agent ineffective. The 
subsequent choice of drug for combating this acquired resistance will depend on which ALK 
TKI has been used at the therapy onset and is dictated by drug approval/reimbursement 
status, therapy guidelines and tumour molecular resistance mechanisms. 
The first ALK TKI which was approved in NSCLC and subsequently received 
reimbursement in Sweden was crizotinib. In addition, three second-generation products 
(ceritinib, alectinib and brigatinib) and one third-generation agent (lorlatinib) are now on the 
market. Regulatory status of individual ALK TKIs for treatment of ALK-positive NSCLC in 
Sweden is described and summarised in Table 1. The reimbursement status corresponds to 
the approved indication for all ALK TKIs with the exception of ceritinib which was 
evaluated by the Swedish reimbursement authority TLV in second-line treatment only. 
Therefore, for ceritinib the second approval date in Table 1. refers to the European Medical 
Agency (EMA) approval date, the timepoint at which ceritinib implicitly gained 
reimbursement. 
Crizotinib, the first ALK TKI developed, has been the standard of care (SoC) for years and it 
still plays a minor role as first-line therapy for selected Swedish patients. Second-generation 
inhibitors however, particularly alectinib, have recently demonstrated superior efficacy over 
crizotinib, especially in the central nervous system (CNS), thereby becoming the new SoC in 
frontline setting. 
With regard to first-line therapy, the Swedish guidelines recommend alectinib as a first-hand 
choice and recognize both crizotinib and ceritinib as alternatives. Regarding the second-line 
treatment, Swedish guidelines deem that patients previously treated with crizotinib should be 
offered second generation agents alectinib, ceritinib or brigatinib. For all patients treated with 
second-generation agents (alectinib, ceritinib or brigatinib) regardless of the line of therapy, 
the Swedish guidelines recommend lorlatinib. Due to their minor efficacy in ALK-positive 
NSCLC, immunotherapies (eg, nivolumab, pembrolizumab and atezolizumab) are not 
preferred by Swedish treatment guidelines and are spared for conclusion of therapy.
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An important aspect which should be mentioned alongside the Swedish lung cancer therapy
guidelines is the national healthcare regulation which allows for use of drugs outside their 
approved indication in the event of high unmet patient need and at the discretion of the 
treating physician.
In addition, a lorlatinib Compassionate Use Program for ALK+/ C-ros oncogene 1 (ROS1) 
+ NSCLC has been active in Sweden from 26 June 2017 until the drug’s EMA-approval. 
According to the agreement with the Swedish MPA, patients who were active in the
Compassionate use programme (CUP) at the time of lorlatinib approval could continue in the 
program until the reimbursement decision was made by the The Dental and Pharmaceutical 
Benefits Agency in Sweden (TLV) in September 2019. At the time of the reimbursement 
decision, the few patients who were still under ongoing lorlatinib therapy were switched to 
commercial product. This switch to commercial lorlatinib may therefore manifest in the 
Prescribed Drug Register in a form of lorlatinib prescription after a period of drug therapy 
gap. In all CUP-patients, lorlatinib was given at the point of failure of all other appropriate
available treatment options.
Table 1. Regulatory Status of ALK Inhibitors in Sweden
Sources: 3,23,29.
ALK
inhibitor
Date of EMA 
approval18-22
Date of
reimbursement
Description of reimbursement
Crizotinib
23 October
2012
March 2014
Treatment of adults with previously treated ALK+ 
advanced NSCLC
June 2016
First-line treatment of adults with ALK+ advanced 
NSCLC
Ceritinib
06 May 2015
December 2015 
Treatment of adult patients with ALK+ advanced 
NSCLC previously treated with crizotinib
June 2017
First-line treatment of adults with ALK+ advanced 
NSCLC
Alectinib
16 February 
2017
November 2017
Treatment of adult patients with ALK+ advanced 
NSCLC previously treated with crizotinib
April 2018
First-line treatment of adult patients with ALK+ 
advanced NSCLC
Brigatinib
22 November 
2018
December 2018
Treatment of adult patients with ALK+ advanced 
NSCLC previously treated with crizotinib
July 2020
First-line treatment of adult patients with ALK+ 
advanced NSCLC
Lorlatinib
06 May 2019
September 2019
Treatment of adult patients with ALK+ advanced 
NSCLC whose disease has progressed after:
-
alectinib or ceritinib as the first ALK TKI 
therapy; or
-
crizotinib and at least one other ALK TKI
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Several real-world evidence studies have reported on treatment patterns and clinical 
outcomes in patients receiving ALK inhibitors. A majority of the studies assessed the TKI 
sequences began with crizotinib followed by second generation ALK TKIs and 
chemotherapy, confirming the benefits of successive ALK TKI treatment.30-32 Davies et al.33
recently studied treatment patterns for crizotinib and ceritinib patients in the US, showing 
predominant use of the two TKIs from first- to third-line therapy. In an Australian study by 
Itchins et al.,34 about half of the patients received at least two lines of ALK inhibitor therapy.
This retrospective observational study aims to inform on sequencing of ALK-inhibitors, the 
settings in which ALK-inhibitors are initiated (eg clinical and demographic characteristics of 
patients), treatment duration and overall survival (OS) for Swedish lung cancer patients.
7. RESEARCH QUESTION AND OBJECTIVES
This study is, to our knowledge, the first real-world study of sequencing of ALK-inhibitors 
and overall survival in Swedish NSCLC patients. The primary objective is to analyse overall 
survival in Swedish NSCLC patients. 
Primary objective:
•
Estimation of overall survival (OS) in ALK-inhibitor users.
Secondary objective:
•
Estimation of duration of treatment (DOT) in ALK-inhibitor users.
8. RESEARCH METHODS 
8.1. Study Design
To address the research objectives, a national retrospective cohort analysis will be conducted 
aiming to study duration of treatment and overall survival in Swedish ALK-positive NSCLC 
patients. The observational study design, which uses and crosslinks several registries, will 
allow the inclusion of a large and broad patient population and analysis of multiple 
real-world outcomes. 
The objectives of the study are:
Primary:
1. Estimation of overall survival (OS) in ALK-inhibitor users.
Secondary:
1. Estimation of duration of treatment (DOT) in ALK-inhibitor users.
Based on the study objectives, the study outcomes are:
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•
Primary: Median survival using Kaplan-Meier estimates, and proportion of patients 
alive after 5 and 6 years.
•
Secondary: DOT (days) for ALK-inhibitor users.
8.2. Setting
The study population will be inclusive of all adults (age ≥18 years) with at least one filled 
prescription of crizotinib, ceritinib, alectinib, brigatinib or lorlatinib (Anatomical Therapeutic 
Chemical Classification System-codes (ATC) listed in Table 2) registered in the Swedish 
Prescribed Drug Register between 01 January 2012 and 31 December 2020 or last available 
data. The first identified prescription date of any of the above-mentioned therapies will 
correspond to the patient’s index date. The study population will be representative of 
Swedish ALK-inhibitor users.
Table 2. ALK-inhibitors
Substance
Product name
ATC-code
Alectinib
Alecensa
L01XE36
Brigatinib
Alunbrig
L01XE43
Ceritinib
Zykadia
L01XE28
Crizotinib
Xalkori
L01XE16
Lorlatinib 
Lorviqua
L01XE44
De-identified individual-level data will be collected from administrative registers in Sweden;
the National Patient Register (NPR), the Prescribed Drug Register (PDR), the Cause of Death 
Register (CDR) and the Swedish Cancer Register (CR). The study will encompass complete 
data on all inpatient and specialist outpatient hospital care, dispensed prescriptions, and 
mortality for the study period, for all patients included in the study population. The study will 
take advantage of the rich content of the Swedish population-based registries with universal 
coverage and detailed patient-level data. 
The study period is defined as 01 January 2007 to 31 December 2020 or last available data 
date. The study period is longer than the inclusion period to allow for a look-back period for 
the included patients.
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8.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. One or more (≥1) filled prescription/s of one or several of the following ALK 
inhibitors (ATC-codes in Table 2):
2. Crizotinib.
3. Ceritinib.
4. Alectinib.
5. Brigatinib.
6. Lorlatinib.
7. Age ≥18 years at index date.
8.2.2. Exclusion Criteria
There are no exclusion criteria for this study.
8.2.3. Study Definitions
8.2.3.1. Overall Study Period
The overall study period is defined as the period during which patients are studied and data 
are used to characterize them. The study period spans from 01 January 2007 to 31 December
2020 or last available data.
8.2.3.2. Identification Period 
Patients will be identified for possible inclusion in the study populations based on recorded 
prescriptions of ALK-inhibitors (Table 2) in the prescription register between 01 January 
2012 to 31 December 2020 or last available data.
8.2.3.3. Index Date
The index date will be defined as the date of the first dispensed prescription (initiation date) of 
an ALK-inhibitor (ATC-codes in Table 2). The index points will be identified from 01 January 
2012 to 31 December 2020 or last available data.
All dispensed prescriptions of ALK-inhibitors before their respective EMA approval dates 
(regardless of indication) will be excluded from the data analyses. EMA approval dates are 
specified in Table 1. 
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8.2.3.4. Baseline Period
The baseline period will be defined as the period five years prior to index date. This period 
will be used for the assessment of baseline demographics and comorbidities. 
8.2.3.5. Follow-up Period
All patients will be followed until the end of the overall study period. Patients who die will 
still be included in the analyses, however, with their status at death carried forward. The 
follow-up period will be used to analyse drug sequencing and to assess the overall survival.
8.2.3.6. Number of Days on ALK-inhibitor Treatment
The number of days on each ALK inhibitor (treatment duration) for each patient will be 
reported. The number of days with available medication during the follow-up period will be 
calculated using the date when a prescription was filled, the number of packs and their size 
and the recommended daily dose according to the Pharmaceutical Specialties in Sweden
(FASS) (see Table 3). In this calculation, we will consider medication stockpiling, which is 
the accumulation of prescription medications for later use. A patient that dispenses a 
prescription while he/she is still expected to have parts of the previous prescription of the 
same drug left, is assumed to start using the new prescription when the previous is expected 
to end. For study definition of persistence and treatment initiation, see Sections 8.2.3.8 and 
8.2.3.9. 
Table 3. FASS Recommended Daily Dose
Substance
FASS recommended daily dose
ATC-code
Alectinib
1200 mg
L01XE36
Brigatinib
First 7 days: 90 mg
After 7 days: 180 mg
L01XE43
Ceritinib
Before June 1st, 2018: 750 mg
From June 1st, 2018: 450 mg
L01XE28
Crizotinib
500 mg
L01XE16
Lorlatinib 
100 mg
L01XE44
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8.2.3.7. Permissible Gap
The “permissible gap” is defined as the maximum time period allowed from the end of the 
previous prescription’s supply until the next prescription. This study will investigate different 
permissible gaps, such as 4 weeks (28 days) and 8 weeks (56 days) as well as “no permissible 
gap enforced”, ie, assuming patients are on treatment until they fill the next prescription or 
begin the next line of treatment. The number of patients identified per sequence using the 
above approaches will be reported. The primary analysis will utilize the alternative “no 
permissible gap enforced”. As sensitivity analyses, one or two alternative permissible gaps 
may be utilized.
8.2.3.8. Persistence
Patients will be defined as persistent as long as they fill prescriptions of the current treatment, 
at least within the defined permissible gap. Time on treatment calculations will assume 
uninterrupted treatment during persistence. Patients will be defined as non-persistent from 
the last day of supply if the permissible gap is exceeded or if a new treatment is initiated. If 
patients switch drugs the stopping date of the old treatment will be defined as the date of the 
first dispensed prescription of the new treatment, even if this date lies within the permissible 
gap for the previous treatment. 
8.2.3.9. Treatment Initiation of Pharmaceuticals
Treatment initiation will be defined as the first filled prescription of that drug (codes 
specified in Table 2). The start of the new treatment will be defined as the date of the first 
dispensed prescription of the new treatment, even if this date lies within the permissible gap
for the previous drug.
All dispensed prescriptions of ALK-inhibitors before their respective EMA approval dates
(regardless of indication) will be excluded from the data analyses. EMA approval dates are 
specified in Table 1.
8.2.3.10. Chemotherapy
In this study, we will stratify patients into those who have received first-line chemotherapy
and those who have not, prior to the first ALK-inhibitor being initiated. This stratification is 
included since chemotherapy may decrease the effect of the ALK-inhibitor treatment. The 
time period of interest is up to two years prior to the index date. 
Since only prescription drugs are found in the Swedish Prescribed Drug Register (and not 
hospital-only drugs), Intravenous therapy (IV) therapies are difficult to identify among the 
study data. We will therefore use procedure codes and recorded healthcare visits to inform 
the assumption that patients received first-line chemotherapy. Chemotherapy administered
later in the drug sequence including amid ALK TKIs and at the conclusion of the therapy will 
not be captured.
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The study definition of chemotherapy is at least one of the following:  
•
Procedure codes listed in Table 9.
•
The patient has at least one outpatient healthcare visit at a oncology department/clinic
recorded in the Swedish National Patient Register every 4 weeks for ≥3 months 
(90 days), but has not received other treatments (Table 2) during this period. 
Chemotherapy is assumed to stop when other treatments start. If several treatment courses 
are found after each other, this will be defined as “one chemotherapy”. 
8.2.3.11. CNS Metastases
A particular feature of metastatic ALK-positive NSCLC is the high tendency of disease 
spread to the brain. CNS-metastases affect from 24 to 42% of patients with the risk 
increasing over time, reaching nearly 60% at 3 years.36 It remains controversial however,
whether this increased risk is an expression of the natural ALK-rearranged disease course 
independent of the therapy received, or if it relates to low Cerebrospinal fluid-penetrance
(CSF-penetrance) of chemotherapy and early generation ALK TKIs.
We will identify CNS-metastases over the whole study period and report the number of 
patients that received a diagnosis before and after initiation of first ALK TKI, respectively.
For analysis of the primary objective, concerned with OS, CNS-metastases identified up to 
two years prior to first ALK TKI will serve as sub-group identifier.
The study definition of CNS-metastases is at least one of the following:
•
Brain metastases diagnosis code in the Swedish National Patient Register 
(International Statistical Classification of Diseases and Related Health Problems code 
- tenth revision [ICD-10] C79.3).
•
Brain metastases diagnosis code in the Swedish Cancer Register (ICD-10 code 
C79.3).
8.2.3.12. Sequencing of ALK Inhibitors
The sequencing of ALK-inhibitor drugs in Sweden between 01 January 2012 and 
31 December 2020 will be described in terms of number of patients per sequence. Patients 
will only be counted once.
Sequences relevant for this study are summarized in Table 4. In total, results will be reported 
for 52 cohorts, where 26 cohorts have received chemotherapy as first-line treatment (cohorts 
2, 4, 6 and 8) and 26 cohorts have not (cohorts 1, 3, 5 and 7). Patients in cohorts 1 and 2 have 
received one line of ALK-inhibitor, patients in cohorts 3 and 4 have received two, patients in 
cohorts 5 and 6 have received three and patients in cohorts 7 and 8 have received at least four 
ALK inhibitors. 
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Table 4. ALK Sequencing Cohorts
1 ALK treatment line: Cohort A (ALK) and Cohort B (Chemo + ALK)
Cohort number
Crizotinib
1.1, 2.1
Alectinib
1.2, 2.2
Ceritinib
1.3, 2.3
2 ALK treatment lines: Cohort C (ALK + ALK) and Cohort D (Chemo + ALK 
+ ALK)
Crizotinib + Alectinib/Brigatinib/Ceritinib
3.1, 3.2, 3.3, 4.1, 4.2, 
4.3
Alectinib + Brigatinib/Ceritinib/Lorlatinib
3.4, 3.5, 3.6,4.4, 4.5, 
4.6
Ceritinib + Alectinib/Brigatinib/Lorlatinib
3.7, 3.8, 3.9, 4.7, 4.8, 
4.9
3 ALK treatment lines: Cohort E (ALK + ALK + ALK) and Cohort F (Chemo 
+ ALK + ALK + ALK)
Crizotinib + Alectinib + Ceritinib/Lorlatinib/Brigatinib
5.1, 5.2, 5.3, 6.1, 6.2, 
6.3
Crizotinib + Ceritinib + Alectinib/Lorlatinib/Brigatinib
5.4, 5.5, 5.6, 6.4, 6.5, 
6.6
Crizotinib + Brigatinib + Alectinib/Lorlatinib
5.7, 5.8, 6.7, 6.8
Alectinib + Brigatinib + Lorlatinib
5.9, 6.9
Alectinib + Lorlatinib+ Brigatinib/Ceritinib
5.10, 5.11, 6.10, 6.11
Ceritinib + Alectinib + Lorlatinib/Brigatinib
5.12, 5.13, 6.12, 6.13
≥4 ALK treatment lines: Cohort 7 (≥ALK*4) and Cohort 8 (Chemo + ≥ALK*4)
At least 4 different ALK inhibitors
7.1, 8.1
Abbreviations: ALK=anaplastic lymphoma kinase, Chemo=chemotherapy.
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Furthermore, results will also be reported for 7 cohort groups, created based on drug 
generation. The first two cohort groups are created based on a sequence of crizotinib 
followed by one second generation drug:
•
Group A1: chemo + crizotinib + any 2nd generation ALK TKI (Cohorts 4.1, 4.2 and 
4.3 in Table 4).
•
Group A2: crizotinib + any 2nd generation ALK TKI (Cohorts 3.1, 3.2, and 3.3 in
Table 4).
The second two groups are created based on a sequence of crizotinib followed by two second 
generation drugs:
•
Group B1: chemo + crizotinib + any 2nd generation ALK TKI + any 2nd generation 
ALK TKI (Cohorts 6.1, 6.3, 6.4, 6.5 and 6.7 in Table 4).
•
Group B2: crizotinib + any 2nd generation ALK TKI + any 2nd generation ALK TKI 
(Cohorts: 5.1, 5.3, 5.4, 5.6 and 5.7 in Table 4).
The third two groups are created based on a sequence of crizotinib followed by one second 
generation drug, followed by lorlatinib:
•
Group C1: chemo + crizotinib + any 2nd generation ALK TKI + lorlatinib (Cohorts: 
6.2, 6.5 and 6.8 in Table 4).
•
Group C2: crizotinib + any 2nd generation ALK TKI + lorlatinib (Cohorts: 5.2, 5.5 
and 5.8 in Table 4).
Finally, one group is created based on a sequence of two consecutive second generation 
drugs:
•
Group D1: Any 2nd generation ALK TKI + any 2nd generation ALK TKI (Cohorts: 
3.4, 3.5, 3.7 and 3.8).
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8.3. Variables
Below is an overview of the variables needed for the outcomes and study variables of the 
proposed analyses. The operational definition describes variables to be processed. 
Variable
Role
Data 
source(s)
Operational definition
Index date
Baseline 
characteristics
PDR
Date of first filled prescription of any of the 
ALK inhibitors in Table 2.
Age
Baseline 
characteristic
PDR
Age will be defined as age at index date 
(continuous; years).
Sex
Baseline 
characteristic
PDR
Male or female gender. (dichotomous 
[0=female, 1=male]).
Place of residence
Baseline 
characteristic
PDR
County council at index date (categorical), 
see Table 11.
Comorbidity profile
Baseline 
characteristic
NPR, CR
Charlson-Quan comorbidity index (ICD-10 
codes: Table 10) primary and secondary 
diagnosis measured in the baseline period 
of five years in specialist outpatient care 
and inpatient care (continuous; score).
CNS metastases prior 
to index date
Baseline 
characteristic, sub-
group identifier
NPR, CR
Defined as patients with CNS metastasis 
diagnosis up to 2 years prior to dispensed 
prescription of first ALK-inhibitor, details 
in Section 8.2.3.11. Dichotomous; yes/no.
Index drug
Exposure
PDR
First filled prescription of ALK inhibitor 
(ATC codes in Table 2).
Received 
chemotherapy before 
index date (ie,
first-line chemo)
Sub-group identifier
NPR, PDR
Patient has received chemotherapy in the 
2-year time period before first ALK TKI, 
ie, index date (dichotomous; yes/no). 
Details in Section 8.2.3.10. 
Number of 
ALK-inhibitor users
Outcome
PDR
All unique patients with at least one 
dispensed prescription of any 
ALK-inhibitor (ATC codes in Table 2).
Number of users per 
sequence
Sub-group identifier
PDR
All unique patients per identified ALK 
treatment sequence. Relevant sequences are 
described in Section 8.2.3.12.
Duration of treatment
Outcome
PDR
Number of days on treatment calculated 
based on FASS recommended dose for 
filled prescriptions of ALK-inhibitors (ATC 
codes in Table 2) taking permissible gap 
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Variable
Role
Data 
source(s)
Operational definition
and stockpiling into account. Details in 
Sections 8.2.3.6, 8.2.3.7 and 8.2.3.9.
Overall survival
Outcome
CDR, PDR
Time from index date to date of death 
(number of days) where death is defined as 
all-cause death; stratification per treatment 
sequence. If no date of death is recorded, 
data is censored at latest available date in 
data.
8.4. Data Sources
The Swedish administrative registries offer high quality data for research with nation-wide 
coverage and close to complete data for most available variables. Patient-level data from 
each register are available for research purposes and individual patients can be linked 
between all datasets via the personal identifier given to all citizens. The administrative 
registers to be used in this study are summarized in Table 5.
Table 5. Overview of Data Sources
Type of 
register
Name 
Data holder
Start of data 
collection
Variables
Patient 
registers
Swedish National 
Patient Register
(NPR)
NBHW
1987/2001
Diagnosis codes (ICD-9/10), 
dates and types of visit
Prescription 
registers
Swedish Prescribed 
Drug Register
(PDR)
NBHW
2005
Dispatch dates, type of 
medication, strengths and dosage 
info (incomplete)
Information 
on mortality
Swedish Causes of 
Death Register
(CDR)
NBHW
1961
Date and cause of death (ICD-10)
Cancer 
register
Swedish Cancer 
Register (CR)
NBHW
1958
Tumour size, tumour spread, 
localisation of tumour, 
morphological diagnosis of the 
tumour (ICD-O/3)
NBHW=National Board of Health and Welfare.
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8.4.1. The Swedish National Patient Register
The Swedish National Patient Register, held by the National Board of Health and Welfare 
(NBHW), contains patient data, geographical data, administrative data and medical data for 
both inpatient and outpatient specialist care. The register contains main and secondary 
diagnosis codes (ICD-10) for each admission and outpatient specialist visit as well as 
procedure codes. The outpatient register includes physician visits only. Surgical procedures 
are recorded based on The Nordic Medico-Statistical Committee (NOMESCO) Classification 
of Surgical Procedures (NCSP). The patient register has nationwide coverage and long 
follow-up with several decades of available data (first data year: 1987). 
Diagnoses from the National Patient Register will be used to assess comorbidities and CNS 
metastases. In addition, recorded visits and hospitalizations will be used to analyse previous 
cancer treatments. 
8.4.2. The Swedish Prescribed Drug Register
The Swedish Prescribed Drug Register, also held by NBHW, contains information on all 
filled prescriptions (ie, dispensed at a pharmacy, excluding prescriptions that are never 
collected by the patient). Data on prescribed drugs can be captured using ATC codes, 
prescription date, dispensing date, dose, pack size, healthcare professional issuing the 
prescription, as well as sex, age and residency of the patients. The Prescribed Drug Register
has nationwide coverage and long follow-up (first data year: 2005). Data from the Prescribed 
Drug Register will be used to identify the study population and to evaluate sequencing of 
ALK-inhibitors.
8.4.3. The Swedish Cause of Death Register
The Swedish Cause of Death Register contains main and contributing causes of death 
presented as diagnosis codes (ICD-10). The register covers all deaths of Swedish residents, 
whether the person in questions was a Swedish citizen or not and irrespective of whether the 
death occurred in Sweden or not. The Cause of Death Register has nationwide coverage and 
long follow-up with several decades of available data (first data year: 1961). Date and cause 
of death will be obtained from the Cause of Death Register. This information will be used to 
study mortality of patients.
8.4.4. The Swedish Cancer Register
The Swedish Cancer Register contains information on site of tumour, clinical and 
morphological diagnosis, and tumour development stage at diagnosis among other. There is 
some underreporting to the Swedish Cancer Register, the extent of which varies with the 
cancer site and the age of the patient. The Cancer Register has nationwide coverage and long 
follow-up with several decades of available data (first data year: 1958). The register is 
updated annually. Only primary tumours are registered in the register. Recurrence as well as 
metastases of previously known and reported primary tumours are not included. Metastases 
are only recorded in cases where the primary tumour is unknown. If the primary tumour is 
clarified at a later stage, the registration shall be updated regarding location code and 
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potentially also morphology. Data from the Cancer Register will be used to identify
metastatic disease.
8.5. Study Size
Sample size calculations are not applicable since there are no a priori hypotheses specified. 
However, using publicly available data for the number of patients receiving crizotinib, 
ceritinib, alectinib, brigatinib or lorlatinib shows that ~300 men and women had filled at least 
one prescription in 2018 (Table 6). Including 2019 and 2020 in the data extraction will likely 
allow for >500 patients to be extracted for analysis.
Table 6. Number of ALK Inhibitor Patients by Year
Year
Crizotinib
Ceritinib
Alectinib
Brigatinib
Lorlatinib
Total
2012
1
0
0
0
0
1
2013
5
0
0
0
0
5
2014
53
0
0
0
0
53
2015
112
9
0
0
0
121
2016
129
58
0
0
2
189
2017
123
56
32
0
2
213
2018
104
41
143
3
1
292
Source: National Board of Health and Welfare.37
Note: Patients can be double counted between years.
8.5.1. Data Management 
In broad terms, the data management for this study will be initiated by the creation of a broad 
study population including patients with at least one filled prescription of ALK-inhibitors 
identified by the national prescription register. A study key including the selected cases 
personal identifiable number (PIN) and a randomly created study identification (ID) will be 
created by the register holder, the NBHW. The NBHW compiles a completely 
pseudonymized analytical dataset comprising all observations and variables required from 
the different registers for the planned analyses. The compiled datasets are shared with
Quantify Research where all PINs will be exchanged with the study ID. No direct identifiable 
personal information will therefore be shared with Quantify Research. The analytic dataset 
will be person-level. 
The central statistical software programs used to evaluate the data will be STATA and/or R.
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All data management will be performed by Quantify Research. A data validity quality check
is always undertaken before data management is started to verify that all variables are 
complete and to create logs for corrupt or ambiguous data entries. 
8.6. Data Analysis 
An overview of the planned analyses by research questions are presented in Sections 8.6.1
and 8.6.2. In general, the study is descriptive and does not involve hypothesis testing. Any 
major modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment.
The study population will be stratified in two main groups with respect to first-line 
chemotherapy: patients who are chemotherapy-naïve prior to first fill of ALK-inhibitor and 
patients who are not. The study definition for chemotherapy is described in Section 8.2.3.10.
Patient characteristics of ALK-inhibitor users will be described per treatment sequence
(number, mean, standard deviation (SD), median, proportions). Patient characteristics include
age, sex, region, comorbidities and CNS metastases. Patients will only be counted once and 
patient characteristics will be measured at, or for 5 years lookback from, index date (date of 
first ALK-inhibitor prescription). Correlative trends may be investigated using a correlation 
matrix and statistical testing. If any correlative trends are identified, these may be further 
investigated through the use of simple regression models.
8.6.1. Primary Objective – Overall Survival of ALK-inhibitor Users
The primary objective is to estimate overall survival (OS) per ALK-inhibitor.
Time-to-event analysis, where the event is all-cause death, will be used to estimate the 
probability of surviving. Results will be presented using Kaplan-Meier curves. All patients 
included in the study are eligible for this analysis. In this survival analysis, patients will also 
be stratified into those with CNS-metastases and those without CNS-metastases in the 
two-year period prior to index date (Table 7). 
Table 7. Primary Objective – Summary of Data Analysis
Objective 
Describe the overall survival of ALK inhibitor users
Design
Cohort
Analysis type
Survival analysis
Outcomes
Overall survival
Measures
Kaplan-Meier estimates (survival function, 95% confidence interval (CI), risk 
table, median survival)
Proportion of patients alive after 5 and 6 years from index
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Objective 
Describe the overall survival of ALK inhibitor users
Strata
Cohort group (see Section 8.2.3.12)
Chemotherapy:
First line chemotherapy
No first-line chemotherapy
CNS-metastases:
CNS-metastases prior to index
No CNS-metastases prior to index
Index date
Date of first prescription (Table 2)
Analysis period
01 January 2012 – 31 December 2020
Reporting interval 
Per month from index date (Kaplan Meier [KM] analysis)
8.6.2. Secondary Objective – Duration of Treatment of ALK-inhibitor Users
The secondary objective is to estimate the duration of treatment (DOT) per ALK-inhibitor. 
Treatment duration will be estimated for the sequences as described in Section 8.2.3.12. In 
each sequence both the total treatment duration for that sequence and treatment duration per 
ALK-inhibitor within the sequence will be reported.
Table 8. Secondary Objective – Summary of Data Analysis
Objective 
Describe the treatment duration of ALK inhibitor users
Design
Cohort
Analysis type
Descriptive
Outcomes
Treatment duration per ALK-inhibitor and sequence
Measures
Number (mean, standard deviation (SD), min, max, median) 
Strata
Cohort group (see Section 8.2.3.12)
Chemotherapy:
First line chemotherapy
No first-line chemotherapy
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Objective 
Describe the treatment duration of ALK inhibitor users
Index date
Date of first prescription (Table 2)
Analysis period
01 January 2012 – 31 December 2020
Reporting interval 
Multi-year periods
8.7. Quality Control
The national and compulsory health registers included in the present study are governed by 
the national authority in charge of public health and welfare. Reporting of information to the 
registers is compulsory by all healthcare providers and pharmacies, thus this guarantees high 
completeness rates and nationwide coverage. Rigorous validation work is constantly ongoing 
in order to ensure that data are complete, comprehensive and of the highest quality possible. 
Data will be examined for completeness and missing data are anticipated to be minimal based 
on previous research and the compulsory nature of the data collection.
A team of researchers at Quantify Research will conduct tasks such as data management, 
analyses, and report writing. The team will be led by a research leader with experience from 
similar projects. 
The steps involved in data management and analysis will be recorded in carefully maintained 
scripts and logs. This will simplify data updates and ensure reproducibility of results, from 
raw data to the end result.
Data analyses are quality controlled according to an in-house protocol that includes a code 
review. The data cleaning and analysis steps performed in the statistical software will be 
reviewed by another programmer. Any errors or omissions found during this review will be 
communicated back to the original analyst and updated accordingly. All quality checks will 
be documented.
8.8. Limitations of the Research Methods
8.8.1. Internal Validity of Study Design
The study on patients treated with ALK-inhibitors is dependent on a successful identification 
strategy and definition of the patients. The current protocol allows a generous study 
population of users, requiring minimum one filled ALK-inhibitor prescription to be included 
in the study. Using another identification strategy when defining patients may lead to a 
different patient population.
In addition, the results from this study are reliant on study definitions which to some extent 
are based on assumptions eg, for persistence and treatment initiation and/or algorithms 
(chemotherapy, CNS-metastases, ALK-positive NSCLC). Using other assumptions and 
algorithms for these study definitions may lead to different study results. 
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Another possible limitation of this study is the potential underrepresentation of cases using 
newer generation drugs due to the relatively short period of time under which some of the
products have been available on the Swedish market. For certain research questions therefore 
the low number of total cases could preclude meaningful analysis due to the risk of 
producing results unrepresentative of the entire patient population treated with 
ALK-inhibitors in Sweden. 
Finally, the switch of lorlatinib CUP patients to commercial product post-reimbursement 
decision in Sweden may create a minor additional uncertainty by introducing a variable 
therapy “gap” imminently before the lorlatinib-prescriptions for these patients appear in the 
Prescribed Drug Register. In general, the plausible compassionate drug use remains a general 
confounding factor with regards to OS-analyses as it is not possible to capture nor evaluate 
compassionate use of any ALK TKIs or other agents among patients included in this study.
8.8.2. Missing or Incomplete Information
This study will to a large extent rely on register-based data which are known to have a high 
degree of completeness. The reporting of many variables in the national health care registers 
used in this study is mandatory and there is therefore almost complete coverage of the 
information related to healthcare visits and prescriptions. 
If information regarding dates, diagnosis codes or treatment information is absent, these 
records would be excluded from analysis since imputation of these types of variables would 
be difficult to implement and justify. In the unlikely event that a patient’s health care visit or 
prescription would not have been captured at all by the registers, this instance of missing data 
would not be possible to identify.
8.8.2.1. Measurement Errors and Misclassifications
Diagnoses of outcomes and comorbidities will be identified using diagnosis and procedure 
codes, which are subject to potential miscoding. Since the study includes already collected 
data, there is no risk of observer bias in this study.  
8.8.2.2. Information Bias
Given that outcomes will be defined using national and population-based health register data, 
there will be an inherent risk of information bias resulting from classification error. 
One limitation of the study is that the presumed treatment date will be based on the date of 
filling the prescription at the pharmacy, which is not necessarily the date of treatment 
administration. There is also a risk that the dispensation of the respective drug does not equal 
actual consumption. This will always be the case in observational studies of 
self-administered treatments since the actual patient behaviour cannot be observed.
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8.8.2.3. Selection Bias
The main analyses in this study will be conducted using the Prescribed Drug Register, the 
Patient Register and the Cause of Death Register. Given that these national registers have 
complete coverage, selection bias does not pose a threat of lung cancer patients treated in 
specialist care, given correct identification of the patients. The severity of the disease and 
clinical practice in Sweden makes it improbable that some patients are managed in primary 
care. 
Inclusion criteria for ALK-positive NSCLC patients will be based on prescription data. Only 
prescriptions filled at pharmacies can be captured in prescription registers, as they do not 
include data on hospital drugs. This is however not likely to introduce a selection bias, given 
that most ALK-inhibitor treatments for patients with NSCLC are given outside the hospital 
setting. 
8.8.3. External Validity of Study Results 
The findings of this study will be based on Swedish data and will as such not necessarily be 
directly transferable to other countries or regions. 
8.9. Other Aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient Information 
This study involves data that exist in anonymized structured format and contain no patient 
personal information.
9.2. Patient Consent
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required.
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
There must be a prospective approval of the study protocol, protocol amendments, and other 
relevant documents (eg, informed consent forms if applicable) from the relevant IRBs/IECs. 
All correspondence with the IRB/IEC must be retained. Copies of IRB/IEC approvals must 
be forwarded to Pfizer. 
Ethical approval will be obtained from the Swedish Ethical Review Authority.
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9.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE) and Good Practices for Outcomes 
Research issued by the International Society for Pharmacoeconomics and Outcomes 
Research (ISPOR).
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves secondary data that exist as structured data by the time of study start or a 
combination of existing structured data and unstructured data, which will be converted to 
structured form during the implementation of the protocol solely by a computer using 
automated/algorithmic methods, such as natural language processing.
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (ie, identify a potential association between) a particular product and medical 
event for any individual. Thus, the minimum criteria for reporting an adverse event (AE) 
(ie, identifiable patient, identifiable reporter, a suspect product, and event) cannot be met.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
The results of this study will be summarized in a study report. It is further planned to submit 
at least one publication based on the results of this study to an international peer-reviewed 
journal. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.  
11.1. Publication Policy
Authorship of any publications resulting from this study will be based on the 
“Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work 
in Medical Journals” by the International Committee of Medical Journal Editors (ICMJE):38
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•
Authorship credit should be based on (1) substantial contributions to conception or 
design, or acquisition analysis or interpretation of data; (2) drafting the article or 
revising it critically for important intellectual content; (3) final approval of the 
version to be published and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved. Authors should meet conditions 1, 
2, and 3 and 4. When a large, multicentre group has conducted the work, the group 
should identify the individuals who accept direct responsibility for the manuscript. 
These individuals should fully meet the criteria for authorship defined above.
•
Examples of activities that alone (without other contributions) do not qualify a 
contributor for authorship are acquisition of funding; general supervision of a 
research group or general administrative support; and writing assistance, technical 
editing, language editing, and proofreading
•
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed.
Each author should have participated sufficiently in the work to take public responsibility for 
appropriate portions of the content.
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12. REFERENCES
1.
Bergman, B. Lungcancer | Läkemedelsboken. 2018 2018-04-24; Available from: 
https://lakemedelsboken.se/kapitel/onkologi/lungcancer.html.
2.
Socialstyrelsen, Cancer i siffror 2018, in Lungcancer. 2018.
3.
Socialstyrelsen, Statistikdatabas för cancer.
4.
Regionala cancercentrum i samverkan. 2. Epidemiologi. Gällande vårdprogram 
lungcancer 2019 2019-04-09; Available from: 
https://www.cancercentrum.se/samverkan/cancerdiagnoser/lunga-och-
lungsack/vardprogram/gallande-vardprogram/2.-epidemiologi/.
5.
Noone, A.M.H., N; Krapcho, M; Miller, D; Brest, A; Yu, M, Ruhl, J; Tatalovich, Z; 
Mariotto, A; Lewis, DR; Chen, HS; Feuer, EJ; Cronin, KA (eds), SEER Cancer 
Statistics Review, 1975-2015, N.C. Institute, Editor. 2018.
6.
Zappa, C. and S.A. Mousa, Non-small cell lung cancer: current treatment and future 
advances. Transl Lung Cancer Res, 2016. 5(3): p. 288-300.
7.
Sasaki, T., et al., The biology and treatment of EML4-ALK non-small cell lung cancer.
Eur J Cancer, 2010. 46(10): p. 1773-80.
8.
Wu, J., J. Savooji, and D. Liu, Second- and third-generation ALK inhibitors for non-
small cell lung cancer. J Hematol Oncol, 2016. 9: p. 19.
9.
Cancerfonden. Lungcancer. 2018  2019-11-06]; Available from: 
https://www.cancerfonden.se/om-cancer/cancersjukdomar/lungcancer.
10.
Regionala cancercentrum i samverkan. 9. Utredning – Diagnostik och tumörutbredning. 
Gällande vårdprogram lungcancer 2019 2019-04-09; Available from: 
https://www.cancercentrum.se/samverkan/cancerdiagnoser/lunga-och-
lungsack/vardprogram/gallande-vardprogram/2.-epidemiologi/.
11.
Regionala cancercentrum i samverkan. 14. Behandling – sammanfattande 
rekommendationer. Gällande vårdprogram lungcancer 2019 2019-04-09; Available 
from: https://www.cancercentrum.se/samverkan/cancerdiagnoser/lunga-och-
lungsack/vardprogram/gallande-vardprogram/2.-epidemiologi/.
12.
Novello, S., et al., Alectinib versus chemotherapy in crizotinib-pretreated anaplastic 
lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III 
ALUR study. Ann Oncol, 2018. 29(6): p. 1409-1416.
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13.
Shaw, A.T., et al., Ceritinib versus chemotherapy in patients with ALK-rearranged non-
small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a 
randomised, controlled, open-label, phase 3 trial. Lancet Oncol, 2017. 18(7): p. 874-
886.
14.
Solomon, B.J., et al., First-line crizotinib versus chemotherapy in ALK-positive lung 
cancer. N Engl J Med, 2014. 371(23): p. 2167-77.
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Regionala cancercentrum i samverkan. Kapitel 13. Läkemedelsbehandling vid 
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https://www.cancercentrum.se/samverkan/cancerdiagnoser/lunga-och-
lungsack/vardprogram/.
16.
Planchard, D., et al., Metastatic non-small cell lung cancer: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2018. 29(Suppl 4): p. 
iv192-iv237.
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ESMO Guidelines Committee. Online publication: METASTATIC NON-SMALL-CELL 
LUNG CANCER: ESMO CLINICAL PRACTICE GUIDELINES FOR DIAGNOSIS, 
TREATMENT AND FOLLOW-UP. 2018  [cited 2020 January]; Available from: 
https://www.esmo.org/guidelines/lung-and-chest-tumours/metastatic-non-small-cell-
lung-cancer.
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Tandvårds- och läkemedelsförmånsverket, Beslut - Xalkori ingår i högkostnadsskyddet 
med begränsning. 2014.
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24.
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med begränsning. 2017.
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med begränsning. 2018.
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38.
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reporting, editing, and publication of scholarly work in medical journals. 2018; 
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13. LIST OF TABLES 
Table 1. Regulatory Status of ALK Inhibitors in Sweden.........................................................8
Table 2. ALK-inhibitors...........................................................................................................10
Table 3. FASS Recommended Daily Dose..............................................................................12
Table 4. ALK Sequencing Cohorts..........................................................................................15
Table 5. Overview of Data Sources.........................................................................................18
Table 6. Number of ALK Inhibitor Patients by Year ..............................................................20
Table 7. Primary Objective – Summary of Data Analysis.......................................................21
Table 8. Secondary Objective – Summary of Data Analysis...................................................22
Table 9. Chemotherapy – Procedure Codes (KVÅ-koder)......................................................33
Table 10. Charlson Comorbidity Score ...................................................................................33
Table 11. County Council Codes.............................................................................................35
14. LIST OF FIGURES
None.
15. ANNEX 1. LIST OF STANDALONE DOCUMENTS
None.
16. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not required.
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17. ANNEX 3. ADDITIONAL INFORMATION
17.1. Diagnosis and Procedure Codes
Table 9. Chemotherapy – Procedure Codes (KVÅ-codes)
Procedure codes
Description (Swedish) 
DT016
Läkemedelstillförsel, intravenös
DT107
Cytostatikatillförsel med annat specificerat administrationssätt
DT108
Cytostatikatillförsel UNS
DT112
Cytostatikatillförsel, intratekal
DT116
Cytostatikatillförsel, intravenös
DT135
Cytostatikatillförsel, intraperitoneal
DV046
Läkemedelsbehandling, utdelning av dosett eller enstaka dos
Z082
Kontrollundersökning efter kemoterapi för malign tumör
Z092
Kontrollundersökning efter kemoterapi för andra tillstånd
Z292
Annan förebyggande kemoterapi
Z511
Kemoterapeutisk behandling för tumör
Z512
Annan kemoterapi
Z542
Konvalescens efter kemoterapi
Z926
Kemoterapi för tumörsjukdom i den egna sjukhistorien
Table 10. Charlson Comorbidity Score
Disease
ICD-10 Code
Score
Myocardial Infarction
I21; I22; I23
1
Congestive Heart Failure
I50; I11.0; I13.0; I13.2
1
Peripheral Vascular Disease
I70; I71; I72; I73; I74; I77
1
Cerebrovascular Disease
I60-I69; G45; G46
1
Dementia
F00-F03; F05.1; G30
1
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Disease
ICD-10 Code
Score
Chronic Pulmonary Disease
J40-J47; J60-J67; J68.4; J70.1; J70.3; J84.1; J92.0; J96.1; J98.2; 
J98.3
1
Connective Tissue Disease
M05; M06; M08; M09; M30; M31; M32; M33; M34; M35; 
M36; D86
1
Ulcer Disease
K22.1; K25-K28
1
Mild Liver Disease 
B18; K70.0; K70.3; K70.9; K71; K73; K74; K76.0
1
Diabetes Mellitus 
1
             Insulin dependent
E10.0; E10.1; E10.9
             Non-Insulin dependent
E11.0; E11.1; E11.9
Hemiplegia or paraplegia
G81; G82
2
Moderate-Severe Renal 
Disease
I12; I13; N00-N05; N07; N11; N14; N17-N19; Q61
2
Diabetes Mellitus with End 
Organ Damage
2
             Insulin dependent
E10.2-E10.8
             Non-Insulin dependent
E11.2-E11.8
Any Tumour
C00-C75
2
Leukaemia
C91-C95
2
Lymphoma
C81-C85; C88; C90; C96
2
Moderate-Severe Liver Disease 
B15.0; B16.0; B16.2; B19.0; K70.4; K72; K76.6; I85
3
Metastatic Solid Tumour
C76-C80
6
AIDS
B21-B24
6
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17.2. Additional Codes
Table 11. County Council Codes
County name
County code
Stockholm County
01
Uppsala County
03
Södermanland County
04
Östergötland County
05
Jönköping County
06
Kronoberg County
07
Kalmar County
08
Gotland County
09
Blekinge County
10
Skåne County
12
Halland County
13
Västra Götaland County
14
Värmland County
17
Örebro County
18
Västmanland County
19
Dalarna County
20
Gävleborg County
21
Västernorrland County
22
Jämtland County
23
Västerbotten County
24
Norrbotten County
25
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