Patient Profiles and Treatment Patterns Among ALK-positive NSCLC Patients Treated With Alectinib
Conditions: Non-Small-Cell Lung Carcinoma
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
 
Study information 
 
Title 
Patient profiles and treatment patterns among 
ALK+ NSCLC patients treated with alectinib. 
Protocol number 
B7461031 
Protocol version identifier 
2.0 
Date 
31 August 2021 
Research question and objectives 
This study aims to understand patient 
profiles, treatment patterns, and clinical 
outcomes among ALK+ NSCLC patients 
treated with alectinib, and post-alectinib 
treatment patterns and outcomes. 
Phase 1 Landscape Objectives (structured 
data): 
These analyses will be performed for all 
study-eligible patients who received 
alectinib during the study identification 
period. Results will be presented overall as 
well as for the subgroups of patients who 
received a subsequent therapy following 
alectinib: 
1. Describe the demographic and clinical 
characteristics of ALK+ NSCLC patients 
who received alectinib overall, and stratified 
by subsequent treatment following alectinib. 
2. Characterize post-alectinib treatment 
patterns and sequencing of other ALK 
inhibitors; categorizing type of treatments 
received after alectinib. 
 
 
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3. Estimate duration of therapy with 
alectinib and duration of therapy for post- 
alectinib treatment. 
4. Examine overall survival of patients post- 
alectinib stratified by subsequent treatment 
following alectinib. 
Phase 2: Chart Review Objectives 
(unstructured data): 
For Phase 2, structured data will be 
supplemented with a targeted chart review to 
confirm alectinib and other ALK inhibitor 
oral drug therapy information and collect 
additional unstructured data for a sample of 
front-line alectinib patients from the eligible 
study population. Results will be presented 
for all patients selected for chart review, as 
well as the subgroups of patients who 
received a subsequent therapy following 
alectinib: 
5. Describe the demographic and clinical 
characteristics of ALK+ NSCLC patients 
who received alectinib overall, and stratified 
by subsequent treatment following alectinib. 
6. Characterize post-alectinib treatment 
patterns and sequencing of other ALK 
inhibitors; categorizing type of treatments 
received after alectinib. 
7. Estimate duration of therapy with 
alectinib and duration of therapy for post- 
alectinib treatment. 
8. Examine reasons for treatment 
discontinuation of alectinib and post- 
alectinib treatment. 
 
 
 
 
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9. Estimate progression-free survival (PFS) 
of patients post-alectinib stratified by 
subsequent treatment. 
 
10. Examine overall survival of patients 
post-alectinib stratified by subsequent 
treatment. 
 
Phase 3: Data Refresh (structured and 
unstructured data) and Exploratory 
Analysis (structured data) 
 
Phases 1 and 2 study objectives will be 
updated with additional follow-up time 
through August 31, 2021. 
 
In addition, patients initiating lorlatinib 
following Food and Drug Administration 
(FDA) approval to end of study period will 
be identified in structured data and the 
following exploratory objectives will be 
examined: 
 
11. Identify patients initiating lorlatinib and 
monitor lorlatinib uptake over time 
 
• 
Evaluate demographic and clinical 
characteristics of patients receiving 
lorlatinib 
 
• 
Characterize lorlatinib treatment 
sequencing utilization and patterns 
Author 
PPD 
PPD 
, PhD 
 
 
Phone: PPD 
Email: PPD 
PPD 
, PhD 
Ontada 
PPD 
 
 
 
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PPD 
Phone: PPD 
Email: PPD 
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS ....................................................................................................... 5 
2. LIST OF ABBREVIATIONS ................................................................................................ 7 
3. RESPONSIBLE PARTIES .................................................................................................. 10 
4. ABSTRACT ......................................................................................................................... 11 
5. AMENDMENTS AND UPDATES ..................................................................................... 15 
6. MILESTONES ..................................................................................................................... 16 
7. RATIONALE AND BACKGROUND ................................................................................ 17 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................. 18 
9. RESEARCH METHODS ..................................................................................................... 20 
9.1. Study design Phases 1 and 2 .................................................................................... 20 
9.2. Study Design Phase 3 (study refresh and exploratory analysis) .............................. 22 
9.3. Setting ...................................................................................................................... 23 
9.3.1. Phase 1 and 2 (original study) and Phase 3 (refresh study) population ...... 25 
9.3.2. Phase 3 exploratory analysis study population ............................................ 26 
9.3.3. Cohort definitions and stratifications .......................................................... 26 
9.3.4. Chart review selection ................................................................................. 27 
9.3.4.1. Chart review for Phase 2 ........................................................... 27 
9.3.4.2. Chart review for Phase 3 study refresh ...................................... 27 
9.4. Variables .................................................................................................................. 28 
9.5. Data sources ............................................................................................................. 37 
9.6. Study size ................................................................................................................. 38 
9.7. Data management .................................................................................................... 39 
9.7.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record ........................................................................................................ 40 
9.7.2. Record retention .......................................................................................... 40 
9.8. Data analysis ............................................................................................................ 41 
9.8.1. Analysis sets ................................................................................................ 41 
9.8.2. Derived and transformed data ..................................................................... 42 
9.8.3. Statistical methods ...................................................................................... 42 
9.8.4. Sequence of analyses ................................................................................... 44 
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9.9. Quality control .........................................................................................................45 
9.10. Limitations of the research methods ......................................................................46 
9.10.1. Internal validity of study design ................................................................46 
9.10.2. External validity of study design ..............................................................47 
9.10.3. Analysis limitations ...................................................................................47 
9.10.4. Limitations due to missing data and/or incomplete data ...........................47 
9.11. Other aspects ..........................................................................................................47 
10. PROTECTION OF HUMAN SUBJECTS .........................................................................47 
10.1. Patient information ................................................................................................47 
10.2. Patient consent .......................................................................................................48 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) .................48 
10.4. Ethical conduct of the study ..................................................................................48 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS .......................................................................................................................49 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ........50 
13. REFERENCES ...................................................................................................................52 
14. LIST OF TABLES .............................................................................................................54 
15. LIST OF FIGURES ............................................................................................................54 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS..........................................................54 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ..........................................54 
ANNEX 3. ADDITIONAL INFORMATION .........................................................................54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AEM 
adverse event monitoring 
ALK 
anaplastic lymphoma kinase 
ANOVA 
analysis of variance 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
CI 
confidence interval 
CNS 
central nervous system 
CRFs 
case report forms 
DCTs 
data collection tools 
DOT 
duration of treatment 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EHR 
electronic health record 
EMA 
European Medicines Agency 
ENCePP 
European Network of Centers for 
Pharmacoepidemiology and Pharmacovigilance 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
GEP 
good epidemiological practice 
GPP 
guidelines for good pharmacoepidemiology 
Practices 
 
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Abbreviation 
Definition 
HIPAA 
health insurance portability and accountability act 
HITECH 
health information technology for economic and 
clinical health 
HR 
hazard ratio 
ICD 
international classification of diseases 
ICMJE 
international committee of medical journal editors 
IHC 
Immunohistochemistry 
iKM 
iKnowMed 
IEA 
International Epidemiological Association 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISPE 
International Society for Pharmacoepidemiology 
K-M 
kaplan meier 
LADMF 
limited access death master file 
MET 
mesenchymal-to-epithelial transition 
MRN 
medical record number 
NI 
non-interventional 
NIS 
non-interventional study 
NOS 
not otherwise specified 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
PD-L1 
programmed death-ligand 1 
 
 
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Abbreviation 
Definition 
PFS 
progression free survival 
QC 
quality control 
RECIST 
response evaluation criteria in solid tumors 
ROS1 
ROS proto-oncogene 1 
RT-PCDR 
reverse transcriptase– polymerase chain reaction 
SSDI 
social security death index 
SSN 
social security number 
US 
United States 
YRR 
your reporting responsibilities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
 
Name, degree(s) 
Job Title 
Affiliation 
Address 
PPD 
, PhD 
PPD 
 
Pfizer NI Study Lead 
Pfizer 
PPD 
 
PPD 
, MA 
PPD 
Pfizer 
PPD 
 
, USA 
PPD  
PPD 
, PhD 
PPD 
 
Pfizer 
PPD 
 
PPD 
, MD 
PPD 
Pfizer 
PPD 
 
 
 
PPD 
 
PPD 
, 
PharmD 
PPD 
Pfizer 
PPD 
 
PPD 
, MD, 
MPH 
Study Principal Clinical 
Investigator 
PPD 
 
PPD 
PPD 
, 
PhD 
Outcomes Researcher 
Ontada 
Office Affiliation: 
PPD 
PPD 
, MPH 
Biostatistician 
Ontada 
Office Affiliation: 
PPD 
 
 
 
 
 
 
 
 
 
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4. ABSTRACT 
Title: Patient profiles and treatment patterns among anaplastic lymphoma kinase (ALK)- 
positive non-small cell lung cancer (NSCLC) patients treated with alectinib. 
 
Version and Date of Protocol: 2.0 31 August 2021 
Main Author: PPD 
, PhD, Pfizer Inc; PPD 
, PhD, Ontada 
Rationale and background: 
Alectinib is a second-generation kinase inhibitor indicated for the treatment of patients with 
ALK+ metastatic NSCLC. Alectinib was first FDA approved in December 2015 for the 
treatment of ALK+ NSCLC in patients following treatment with the first generation ALK 
inhibitor crizotinib. In November of 2017, the FDA approved alectinib for use as first-line 
treatment for ALK+ metastatic NSCLC. 
 
The approval was based on the Phase 3 ALEX trial of 303 first-line ALK+ NSCLC patients. 
Treatment with alectinib demonstrated a significantly reduced risk of progression or death by 
47 percent (HR=0.53, 95 percent CI: 0.38, 0.73, p<0.0001) compared to crizotinib. Median 
PFS was 25.7 months (95 percent CI: 19.9, not estimable) for patients treated with alectinib 
compared with 10.4 months (95 percent CI: 7.7, 14.6) for patients who received crizotinib. 
Treatment with alectinib also reduced the risk of the brain or central nervous system (CNS) 
metastasis compared to crizotinib by 84 percent (HR=0.16, 95 percent CI: 0.10, 0.28, 
p<0.0001).[1] 
 
With the availability of several therapeutic agents, current treatment patterns and outcomes 
with use of multiple ALK-inhibitor treatments in sequence are not well understood. For 
patients with ALK positive NSCLC, first-line therapy with alectinib is the preferred 
treatment option, however, sequence of therapy is not well-defined. This study aims to 
understand patient profiles, treatment patterns, and clinical outcomes among ALK+ NSCLC 
patients treated with alectinib, and post-alectinib treatment patterns and outcomes. 
 
Research question and objectives 
 
Describe patient profiles, treatment patterns, and clinical outcomes among real-world ALK+ 
NSCLC patients treated with alectinib, and post-alectinib treatment patterns and outcomes. 
 
 
 
 
 
 
 
 
 
 
 
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Specifically, we will answer the following objectives: 
 
Phase 1: Landscape Objectives (structured data): 
These analyses will be performed for all study-eligible patients who received alectinib (in 
any line of therapy) during the study identification period. Results will be presented overall 
as well as for the subgroups of patients who received a subsequent therapy following 
alectinib: 
1. Describe the demographic and clinical characteristics of ALK+ NSCLC patients who 
received alectinib overall, and stratified by subsequent treatment following alectinib 
2. Characterize post-alectinib treatment patterns and sequencing of other ALK inhibitors; 
categorizing type of treatments received after alectinib 
3. Estimate duration of therapy with alectinib and duration of therapy for post-alectinib 
treatment 
4. Examine overall survival of patients post-alectinib stratified by subsequent treatment 
following alectinib 
 
Phase 2: Chart Review Objectives (unstructured data): 
 
For Phase 2, structured data will be supplemented with a targeted chart review to confirm 
alectinib and other ALK inhibitor oral drug therapy information and collect additional 
unstructured data for a sample of front-line alectinib (i.e., first treatment administration of 
alectinib not preceded by any other product for NSCLC therapy) patients, from the eligible 
study population. Results will be presented for all patients selected for chart review, as well 
as the subgroups of patients who received a subsequent therapy following alectinib : 
5. Describe the demographic and clinical characteristics of ALK+ NSCLC patients who 
received alectinib overall, and stratified by subsequent treatment following alectinib 
6. Characterize post-alectinib treatment patterns and sequencing of other ALK inhibitors; 
categorizing type of treatments received after alectinib 
7. Estimate duration of therapy with alectinib and duration of therapy for post-alectinib 
treatment 
8. Examine reasons for treatment discontinuation of alectinib and post-alectinib treatment 
9. Estimate progression-free survival (PFS) of patients post-alectinib stratified by subsequent 
treatment (as supported by the final sample size) 
 
10. Examine overall survival of patients post-alectinib stratified by subsequent treatment (as 
supported by the final sample size) 
 
 
 
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Phase 3: Data Refresh (structured and unstructured data) and exploratory analysis 
(structured data) 
 
For Phase 3, the structured and unstructured data study objectives (Phase 1 and Phase 2) will 
be updated with additional follow-up time through 31 August 2021. 
 
In addition, patients initiating lorlatinib following FDA approval to end of study period will 
be identified in structured data and the following exploratory objectives will be examined: 
 
11. Identify patients initiating lorlatinib and monitor lorlatinib uptake over time 
 
• 
Evaluate demographic and clinical characteristics of patients receiving lorlatinib 
 
• 
Characterize lorlatinib treatment sequencing utilization and patterns 
 
Study design: This is a retrospective, observational, descriptive study to examine patient 
characteristics, treatment patterns, and outcomes of patients ALK+ NSCLC treated in The 
United States (US) Oncology Network and Non-Network practices utilizing the iKnowMed 
(iKM) electronic healthcare record (EHR). 
 
Population: The study population will consist of patients with a diagnosis of NSCLC 
receiving alectinib within in The US Oncology Network and Non-Network practices . 
 
Study Population 
The study population for Phases 1 and 2 will be comprised of ALK+ NSCLC patients who 
have evidence of receiving alectinib during 01 June 2017 and 30 June 2019 with The US 
Oncology Network or Non-Network site. Study-eligible patients will be followed 
longitudinally until 31 December 2019, last patient record or date of death, whichever occurs 
first. The index date-1 will be the start date of alectinib treatment during the study 
identification period. Index date-2 will be the start date of the subsequent treatment following 
alectinib, among patients who receive a next treatment. 
 
For Phase 3, the identification period for the study population will be extended to include 
ALK+ NSCLC patients who have evidence of receiving during 01 June 2017 and 31 August 
2020 with The US Oncology Network or Non-Network site. Study-eligible patients will be 
followed longitudinally with additional follow-up until 31 August 2021, last patient record or 
date of death, whichever occurs first. The index date-1 will be the start date of alectinib 
treatment during the study identification period. Index date-2 will be the start date of the 
subsequent treatment following alectinib, among patients who receive a next treatment 
during the study identification period. For the lorlatinib exploratory analysis the 
identification period will be 02 November 2018 to 31 August 2020. Study-eligible patients 
will be followed longitudinally with additional follow-up until 31 August 2021, last patient 
record or date of death, whichever occurs first. 
 
 
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Variables: A complete list of study variables and their associated operational definition are 
presented in Table 1. 
 
Data Sources: Structured data fields within the iKM EHR database will provide information 
needed to address most research questions. These data will be supplemented by additional 
unstructured data collected through chart review for a subset of the study population. 
 
Study size 
A preliminary feasibility assessment for Phases 1 and 2 identified 293 patients who were 
treated with alectinib after 01 November 2017, with approximately half treated in the front- 
line setting. Approximately 20-30% of these patients received a subsequent therapy after 
alectinib. It is estimated that approximately 300 patients will be included in the Phase 1 
structured data analysis. Targeted chart review for Phase 2 is proposed to occur on 150 
patients receiving alectinib to identify at least 100 patients who received alectinib as front- 
line. 
 
For Phase 3 structured analysis, a preliminary feasibility assessment identified 521 patients 
who were treated with alectinib from 01 June 2017 through 31 December 2020. Chart review 
for Phase 3 will include patients who had ongoing treatment at the end of Phase 2 study 
period, and an additional 125 patients will be targeted to identify 100 new patient who 
received alectinib as front-line therapy. For Phase 3 exploratory analysis, a preliminary 
feasibility assessment identified 134 patients who were treated with lorlatinib from 01 
November 2018 through 31 December 2020. 
 
The final study population for analysis will be defined after identification and review of the 
patient population meeting the eligibility criteria in the iKM database. A specific power 
calculation will not be performed as this is a descriptive analysis. 
 
Data analysis 
Descriptive analyses will be conducted to evaluate demographic, clinical and treatment 
characteristics overall, as well as for each of the study cohorts. Time-to-event outcomes (OS, 
DOT, PFS) will be assessed using the Kaplan-Meier method with 95% CIs and summary 
tables. All analyses will be presented for each of the study cohorts and, as supported by the 
final sample size, stratified by front-line alectinib and non front-line alectinib treatment 
groups. 
 
Milestones 
Interim reports for Phase 1 are expected to be delivered May 2020, with the final study report 
expected October 2020. 
 
The final report for Phase 3 is expected to be delivered in March 2022. 
 
 
 
 
 
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5. AMENDMENTS AND UPDATES 
 
Amendmen 
t number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 
1 
31 August 
2021 
Sections 3, 4, 
6, 7, 8, and 9 
An amendment for Phase 3 includes a 
data refresh and updated analysis of 
Phases 1 and 2 with increased sample 
size and data through 31 August 2021. 
Responsible parties were updated. 
Increased sample 
size and longer 
study period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. MILESTONES 
 
Milestone 
Planned date 
Finalization of study protocol 
February 2020 
Submission to the Institutional Review Board (IRB) 
February 2020 
Start of structured data collection 
December 2019 
End of structured data collection 
January 2020 
Interim Report (analyses to meet the Phase 1 
objectives) 
May 2020 
Start of chart review 
May 2020 
End of chart review 
July 2020 
Final Report (analyses to meet the Phase 2 
objectives) 
October 2020 
Finalization of Phase 3 study protocol 
September 2021 
Phase 3 Submission to the Institutional Review 
Board (IRB) 
September 2021 
Structured data extraction for Phase 3 
October 2021 
Start of chart review for Phase 3 
November 2021 
End of chart review for Phase 3 
January 2022 
Analysis for Phase 3 
February 2022 
Final Report including updated analysis for Phase 3 
March 2022 
 
 
 
 
 
 
 
 
 
 
 
 
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7. RATIONALE AND BACKGROUND 
Lung cancer is the second most common cancer in the United States (US) with 
approximately 235,760 new lung cancer diagnoses estimated to occur in 2021 with 131,880 
deaths during this time.[2] Worldwide, lung cancer is a predominant cause of cancer related 
mortality as the disease is usually diagnosed late. At the initial diagnosis, almost 70% of 
patients with lung cancer either have a locally advanced disease or have distant metastases. 
The median overall survival (OS) from diagnosis for patients with stage IV anaplastic 
lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is 6.8 years. [3] 
 
Lung cancer is of mainly 2 types, small cell lung cancer and non-small cell lung cancer 
(NSCLC). These 2 subtypes are treated differently through different chemotherapy and 
radiotherapy regimens. NSCLC comprises around 85-90% of all lung cancers with 40% of 
these having adenocarcinoma histology. This type of lung cancer occurs mainly in current or 
former smokers, but it is also the most common type of lung cancer seen in non-smokers. It 
is more common in women than in men, and it is more likely to occur in younger people than 
other types of lung cancer. [4] 
 
A genetic alteration of the anaplastic lymphoma kinase (ALK) gene is present in 3-5% of 
NSCLCs. Over the last decade, there has been an increase in the number of oral anticancer 
agents available for use as treatment. The availability of orally available cancer treatments 
has made it possible for patients to receive their treatments without having to travel long 
distances. [5] 
 
Biomarker driven therapies have revolutionized the treatment of non-small cell lung cancer 
(NSCLC). The first FDA-approved ALK inhibitor for ALK+ (ALK+) metastatic NSCLC 
treatment in 2011, crizotinib, has shown significant improvement in progression-free survival 
(PFS) and tumor responses in patients with metastatic NSCLC who carry the ALK gene 
rearrangement. While crizotinib has demonstrated significant improvement in PFS in Phase 3 
studies, a subset of patients may develop acquired resistance to the drug after approximately 
12 months, most likely due to secondary mutations to the ALK gene. [6-15] 
 
For patients who progress on crizotinib, second generation ALK-inhibitors have been 
developed. Additional ALK-inhibitors that have subsequently been approved include 
ceritinib (April 2014), alectinib (December 2015), and brigatinib (April 2017). 
 
Alectinib is a second-generation kinase inhibitor indicated for the treatment of patients with 
ALK+ metastatic NSCLC. Alectinib was first FDA approved in December 2015 for the 
treatment of ALK+ NSCLC in patients following treatment with the first generation ALK 
inhibitor crizotinib. In November of 2017, the FDA approved alectinib for use as first-line 
treatment for ALK+ metastatic NSCLC. 
 
The approval was based on the Phase 3 ALEX trial of 303 first-line ALK+ NSCLC patients. 
Treatment with alectinib demonstrated a significantly reduced risk of progression or death by 
47 percent (HR=0.53, 95 percent CI: 0.38, 0.73, p<0.0001) compared to crizotinib. Median 
 
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PFS was 25.7 months (95 percent CI: 19.9, not estimable) for patients treated with alectinib 
compared with 10.4 months (95 percent CI: 7.7, 14.6) for patients who received crizotinib. 
Treatment with alectinib also reduced the risk of the brain or central nervous system (CNS) 
metastasis compared to crizotinib by 84 percent (HR=0.16, 95 percent CI: 0.10, 0.28, 
p<0.0001).[1] 
 
Likewise, ceritinib (Zykadia®), has been tested in the frontline setting. In the ASCEND-4 
Phase 3 trial, ceritinib was compared to a platinum/pemetrexed demonstrating a median 
progression free survival of 16.6 months as compared to only 8.1 months in the 
platinum/pemetrexed chemotherapy arm. Other comparisons of second and third generation 
ALK inhibitors to ceritinib are ongoing.[16] 
 
More recently, in November 2018, the FDA granted accelerated approval to lorlatinib for 
patients with ALK+ metastatic NSCLC whose disease has progressed on crizotinib and at 
least one other ALK inhibitor or whose disease has progressed on alectinib or ceritinib as the 
first ALK inhibitor therapy.[17] The accelerated FDA approval was converted to a full 
approval and the indication was expanded to include first-line treatment for patients with 
ALK+ metastatic NSCLC in March 2021. [18] 
 
With the availability of several therapeutic agents, current treatment patterns and outcomes 
with use of multiple ALK-inhibitor treatments in sequence are not well understood. For 
patients with ALK positive NSCLC, first-line therapy with alectinib is the preferred 
treatment option, however, sequence of therapy is not well-defined. This study aims to 
understand patient profiles, treatment patterns, and clinical outcomes among ALK+ NSCLC 
patients treated with alectinib, and post-alectinib treatment patterns and outcomes. 
 
8. RESEARCH QUESTION AND OBJECTIVES 
The overall goal of this study is to understand the patient characteristics, treatment patterns, 
and clinical outcomes of ALK+ NSCLC patients treated with alectinib in US community 
oncology practices. To efficiently and effectively address research questions, we will 
leverage both the structured and unstructured data of the EHR and execute the study in 2 
phases. Phase 1 will consider a population of ALK+ NSCLC patients who received alectinib 
during the study intake period. For Phase 2, a sample of patients who received alectinib as 
front-line therapy will be selected for chart review. 
 
The study plan utilizes structured data and unstructured (chart review data). For the 
landscape objectives in Phase 1, study data will originate from structured fields of the EHR, 
which are controlled and mapped data elements, and will be available ahead of chart review 
data. For the second phase, specific study objectives will be assessed among a subset of 
patients selected for chart review using both structured and unstructured data. In this phase, 
data will also be derived from unstructured fields in the EHR, such as providers’ free-text 
notes, which can only be captured through a chart review. 
 
 
 
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Phase 1: Landscape Objectives (structured data): 
These analyses will be performed for all study-eligible patients who received alectinib (in 
any line of therapy) during the study identification period. Results will be presented overall 
as well as for the subgroups of patients who received a subsequent therapy following 
alectinib: 
 
1. Describe the demographic and clinical characteristics of ALK+ NSCLC patients who 
received alectinib overall, and stratified by subsequent treatment following alectinib 
 
2. Characterize post-alectinib treatment patterns and sequencing of other ALK inhibitors; 
categorizing type of treatments received after alectinib 
 
3. Estimate duration of therapy with alectinib and duration of therapy for post-alectinib 
treatment 
 
4. Examine overall survival of patients post-alectinib stratified by subsequent treatment 
following alectinib 
 
Phase 2: Chart Review Objectives (unstructured data): 
For Phase 2, structured data will be supplemented with a targeted chart review to confirm 
alectinib and other ALK inhibitor oral drug therapy information and collect additional 
unstructured data for a sample of front-line alectinib (i.e., first treatment administration of 
alectinib not preceded by any other product for NSCLC therapy) patients from the eligible 
study population. Results will be presented for all patients selected for chart review, as well 
as the subgroups of patients who received a subsequent therapy following alectinib: 
 
5. Describe the demographic and clinical characteristics of ALK+ NSCLC patients who 
received alectinib overall, and stratified by subsequent treatment following alectinib 
 
6. Characterize post-alectinib treatment patterns and sequencing of other ALK inhibitors; 
categorizing type of treatments received after alectinib 
 
7. Estimate duration of therapy with alectinib and duration of therapy for post-alectinib 
treatment 
 
8. Examine reasons for treatment discontinuation of alectinib and post-alectinib treatment 
 
9. Estimate progression-free survival (PFS) of patients post-alectinib stratified by subsequent 
treatment (as supported by the final sample size) 
 
10. Examine overall survival of patients post-alectinib stratified by subsequent treatment (as 
supported by the final sample size) 
 
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Phase 3: Data Refresh (structured and unstructured data) and Exploratory Analysis 
(structured data) 
 
For Phase 3, the structured and unstructured data study objectives (Phase 1 and Phase 2) will 
be updated with additional follow-up time through 31 August 2021.. 
 
In addition, patients initiating lorlatinib following FDA approval to end of study period will 
be identified in structured data and the following exploratory objectives will be examined: 
 
11. Identify patients initiating lorlatinib and monitor lorlatinib uptake over time 
 
• 
Evaluate demographic and clinical characteristics of patients receiving lorlatinib 
 
• 
Characterize lorlatinib treatment sequencing utilization and patterns 
 
9. RESEARCH METHODS 
9.1. Study design Phases 1 and 2 
This is a retrospective, observational, descriptive study to examine patient characteristics, 
treatment patterns, and outcomes of patients ALK+ NSCLC treated in The US Oncology 
Network and Non-Network practices utilizing the iKM EHR. During phases 1 and 2, patients 
who have evidence of receiving alectinib during 01 June 2017 and 30 June 2019 will be 
eligible for inclusion in the study. 
 
Complete study eligibility criteria and cohort definitions are presented in Section 9.3. Study- 
eligible patients will be followed longitudinally until 31 December 2019, last patient record 
or date of death, whichever occurs first. 
 
An overview of the study design for Phases 1 and 2 is presented below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1. 
Phases 1 and 2 study design 
 
 
Phase 1 objectives will be assessed among patients who meet study eligibility criteria as 
specified in Section 9.3.1 and stratified by subsequent treatment following alectinib. 
Phase 2 objectives will be assessed in a sample of patients who received alectinib as front- 
line therapy and stratified by subsequent treatment following alectinib. 
The number of cohort stratifications may depend on sample size of patients receiving 
subsequent therapy following alectinib1 including chemotherapy (further stratified into 
platinum doublet and single agent), immunotherapy, and ALK inhibitors. Up to 5 cohorts 
will be considered: 
Cohort A: Patients who received alectinib during the study period (overall population) 
Cohort B (alectinib only cohort): Patients with ongoing alectinib treatment, or patients who 
discontinued alectinib, and patients who did not have a subsequent treatment2 
Cohort C: patients who received alectinib followed by treatment X (top 3 most frequent) 
Cohort D: patients who received alectinib followed by treatment Y (top 3 most frequent) 
Cohort E: patients who received alectinib followed by treatment Z (top 3 most frequent) 
 
1 Final cohorts will be decided upon sample size. Patients receiving chemotherapy and immunotherapy 
after initiating alectinib will be included in the patient sample. Chemotherapy cohort may be further stratified 
into platinum doublet chemotherapy and single agent chemotherapy depending on sample size. 
2 Patients with ongoing alectinib treatment, patients who discontinued alectinib and patients who did not 
have a subsequent treatment may be analyzed as separate cohorts depending on sample size of patients 
 
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9.2. Study Design Phase 3 (study refresh and exploratory analysis) 
During the Phase 3 data refresh, patients who have evidence of receiving alectinib during 01 
June 2017 and 31 August 2020 will be eligible for inclusion in the study. Patients will be 
followed longitudinally until 31 August 2021, last patient record or date of death, whichever 
occurs first. 
An overview of the study design for Phase 3 is presented in Figure 2. 
Figure 2. Phase 3 data refresh study design 
 
 
Phase 3 structured data objectives will be assessed among patients who meet study eligibility 
criteria as specified in 9.3.1 and stratified by subsequent treatment following alectinib. 
 
Cohort A: All alectinib treated patients (overall population) 
Cohort B (Alectinib only cohort): Alectinib treatment ongoing, or discontinued and no 
subsequent treatment3 
Cohort C: Alectinib followed by treatment X (top 3 most frequent) 
Cohort D: Alectinib followed by treatment Y (top 3 most frequent) 
Cohort E: Alectinib followed by treatment Z (top 3 most frequent) 
 
 
3 Patients with ongoing alectibin treatment, patients who discontinued alectinib and patients who did not 
have a subsequent treatment may be analyzed as separate cohorts depending on sample size of patients 
 
 
 
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Two groups of patients are planned for chart review during Phase 3. The first group includes 
patients from Phase 2 chart review who had ongoing treatment at the end of the observation 
period (31 December 2019). These patients will undergo additional follow-up through 31 
August 2021. 
An additional sample of approximately 100 patients who meet the Phase 3 eligibility criteria 
and received alectinib as front-line therapy and received subsequent treatment among the 
following groups will also undergo chart review: 
 
• Alectinib  lorlatinib 
• Alectinib  crizotinib 
• Alectinib  brigatinib 
• Alectinib only 
• Alectinib  chemotherapy (optional) 
 
Figure 3. 
Phase 3 exploratory analysis study design 
 
 
9.3. Setting 
The study population will consist of patients with a diagnosis of NSCLC receiving alectinib 
within The US Oncology Network and Non-Network sites. The US Oncology Network 
includes approximately 1,400 affiliated physicians operating in over 480 sites of care across 
states and treats approximately 1.2 million US cancer patients annually. There are more than 
2,650 active Non-Network supported oncology and non-oncology sites of care. [19] 
 
 
 
 
 
 
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Figure 1 and Figure 2 presents graphical depictions of the study time periods, which are as 
follows: 
 
• 
Phase 1 and 2 study observation period: 01 June 2017 – 31 December 2019. 
 
• 
Phase 1 and 2 study identification period: 01 June 2017 – 30 June 2019. 
 
• 
Phase 3 study refresh observation period: 01 June 2017 – 31 August 2021. 
 
• 
Phase 3 study refresh identification period: 01 June 2017 – 31 August 2020. 
 
• 
Phase 3 exploratory analysis study observation period: 02 November 2018 – 31 
August 2021. 
 
• 
Phase 3 exploratory analysis study identification period: 02 November 2018 – 31 
August 2020. 
 
• 
Phase 1 and 2 index date-1: start date of alectinib treatment during the study 
identification period 
 
• 
Phase 1 and 2 index date-2: start date of the subsequent treatment following alectinib, 
among patients who receive the next treatment during the study observation period 
 
• 
Phase 3 study refresh index date-1: start date of alectinib treatment during the study 
identification period 
 
• 
Phase 3 study refresh index date-2: start date of the subsequent treatment following 
alectinib, among patients who receive the next treatment during the study observation 
period 
 
• 
Phase 3 exploratory analysis index date-1: start date of lorlatinib treatment during the 
study identification period 
 
• 
Phase 3 exploratory analysis index date-2: start date of lorlatinib treatment among 
patients who receive next treatment during the study observation period 
 
• 
Baseline: The baseline period or “at index” includes up to 30 days prior to and up to 
30 days after index. If a patient has multiple baseline values for a particular 
demographic or clinical characteristic during this ± 30-day time frame, the one closest 
(in absolute value) prior to the index date will be used. If no values prior to index are 
available, then the one closest to the index date up to 30 days after will be used. 
 
• 
Prior medical history: Patients’ available history in the iKnowMed (iKM) EHR will 
vary based on the length of disease and the time within The US Oncology Network. 
Disease characteristics such as time of NSCLC diagnosis and date of metastatic 
 
 
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disease will take into account patients’ available medical history. The prior medical 
history period will end the day prior to the index date-1. 
 
• 
Follow-up: Patients will be followed through the end of the study observation period, 
date of last visit or date of death, whichever occurs first. For analysis, patients will 
have a potential of at least 6 months of follow-up duration; however, patients will 
have variable follow-up time periods, depending on their index dates and last contact 
dates. 
 
9.3.1. Phase 1 and 2 (original study) and Phase 3 (refresh study) population 
Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
 
1. Patients with a documented diagnosis of NSCLC. 
 
2. Patients ≥ 18 years of age at initial recorded diagnosis of NSCLC. 
 
3. Patients who received treatment with alectinib within The US Oncology Network or Non- 
Network sites during the study identification period. 
 
4. During the study observation period, patients observed with at least 2 visits4 after the 
index date-1. 
 
Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
 
1. Receipt of treatment indicated for another primary cancer or diagnosis of another primary 
cancer (with the exception of non-melanotic skin cancer), within 5 years of index date-1 
will be excluded. 
 
2. Patients enrolled in clinical trials prior to receiving alectinib during the study ID period 
(index date-1), will be excluded. 
 
 
 
 
 
 
 
 
 
4 Visits are defined as physical encounters with the practice, detected by vital sign records. The second 
and third visits must be observed after the index date-1 to demonstrate continuity of care. There is no required 
time span between the additional visits and the index date-1. 
 
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9.3.2. Phase 3 exploratory analysis study population 
Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
 
1. Patients with a documented diagnosis of NSCLC. 
 
2. Patients ≥ 18 years of age at initial recorded diagnosis of NSCLC. 
 
3. Patients who received treatment with lorlatinib within The US Oncology Network or 
Non-Network practices during the study identification period. 
 
4. During the study observation period, patients observed with at least 2 visits4 after the 
index date-1. 
 
Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
 
1. Receipt of treatment indicated for another primary cancer or diagnosis of another primary 
cancer (with the exception of non-melanotic skin cancer), within 5 years of index date-1 
will be excluded. 
 
2. Patients enrolled in clinical trials prior to receiving lorlatinib during the study ID period 
(index date-1) will be excluded. 
 
9.3.3. Cohort definitions and stratifications 
Separate study cohorts will be considered in all phases of the project. 
 
For Phase 1, results will be presented for all patients who meet study eligibility criteria listed 
in Section 9.3.1 and stratified by subsequent treatment following alectinib (as described in 
Section 9.1 ). 
 
For Phase 2, a sample of patients who received alectinib as front-line therapy (i.e., first 
treatment administration of alectinib not preceded by any other product for NSCLC therapy) 
will be selected for chart review and results will be presented for all patients selected for 
chart review and stratified by subsequent treatment following alectinib. 
 
For Phase 3, the stratifications for Phases 1 and 2 will be replicated for all patients who meet 
study eligibility criteria with the extended identification and observation period as outlined in 
9.3. An additional sample of patients identified for chart review for Phase 3 will be stratified 
by the specified subsequent treatment groups specified in 9.3.1. 
 
 
 
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9.3.4. Chart review selection 
9.3.4.1. Chart review for Phase 2 
Among patients who meet the eligibility criteria defined by the inclusion/exclusion criteria 
listed in Section 9.3.1, a sample size of approximately 100 qualified front-line alectinib 
patient charts will be selected to undergo a targeted chart review. In the event the total 
number of eligible patients following structured data screening exceeds the planned number 
of charts for review, a random sample will be selected. 
 
During the course of abstraction, patients’ eligibility for the study will be verified and some 
of these patients may be found to be ineligible. A total of up to 150 charts are assumed to be 
reviewed to identify at least 100 patients who received alectinib as front-line. 
 
9.3.4.2. Chart review for Phase 3 study refresh 
Two groups of patients are planned for chart review during Phase 3. The first group includes 
patients from Phase 2 chart review who had ongoing treatment at the end of the observation 
period (31 December 2019). These patients will undergo additional follow-up through 31 
August 2021. 
 
An additional sample of approximately 100 patients who meet the Phase 3 eligibility criteria 
and received alectinib as front-line therapy and received subsequent treatment among the 
following groups will undergo chart review: 
 
• Alectinib  lorlatinib 
• Alectinib  crizotinib 
• Alectinib  brigatinib 
• Alectinib only 
• Alectinib  chemotherapy (optional) 
 
In the event the total number of eligible patients following structured data screening exceeds 
the planned number of charts for review, a random sample will be selected. 
 
During the course of abstraction, patients’ eligibility for the study will be verified and some 
of these patients may be found to be ineligible. A total of up to 125 charts are assumed to be 
reviewed to identify at least 100 patients who received post-alectinib treatment from the above 
listed priority groups. 
 
 
 
 
 
 
 
 
 
 
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9.4. Variables 
Table 1. Study variables and operational definitions 
 
Main Study 
 
Index date-1= start date of alectinib treatment during the study identification period 
 
Index date-2= start date of the subsequent treatment following alectinib, among patients who 
receive a next treatment during the study identification period 
 
Exploratory Analysis 
 
Index date-1= start date of lorlatinib treatment during the study identification period 
 
Index date-2= start date of the subsequent treatment following lorlatinib, among patients who 
receive a next treatment during the study observation period 
 
Table 1. 
Study variables and operational definitions 
 
Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
Demographic and patient characteristics 
PatID 
iKM 
structured 
data 
Data linkage 
Study 
observation 
period 
Unique patient identifier that will be used to link 
clinical records. This information will not be 
disclosed to the study sponsor. 
Medical record 
number (MRN) 
iKM 
structured 
data 
Data linkage 
Study 
observation 
period 
Unique patient identifier that will be used to link 
clinical records. This information will not be 
disclosed to the study sponsor. 
Clinical trial 
participation 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria 
Follow-up 
Patients enrolled in interventional clinical trials 
(patients in only observational studies will be 
retained, if applicable) in The US Oncology 
Network or Non-Network during the study 
observation period will be flagged. 
Other cancer 
diagnosis 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria 
Prior medical 
history + 
study 
observation 
period 
Patients will be confirmed as having no 
additional primary or secondary malignancies 
(with the exception of non-melanotic skin cancer) 
within the 5 years prior to and after the index 
date-1. Patients with a secondary diagnosis or 
receipt of treatment indicated for another primary 
cancer within 5 years prior to index date-1 will 
be excluded. 
Additional 
visits 
iKM 
structured 
data 
Eligibility 
criteria 
Follow-up 
To capture a sample of patients with longitudinal 
records, patients will be required to have 2 
records of either additional visits following the 
index date-1 visit and/or a record of death prior 
to the end of the study follow-up period. Visits 
are defined as physical encounters with the 
practice, detected by vital sign records. There 
will be no distinction made, for purposes of 
inclusion, between patients that have an 
 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
additional US Oncology Network or Non- 
Network visit and those with a record of death. 
There is no minimum or maximum requirement 
on time from index date-1 to these qualifying 
events. 
Gender 
iKM 
structured 
data + 
chart 
review 
Baseline 
characteristic 
Prior medical 
history 
Patients will be categorized as: 
Male 
Female 
Date of birth 
iKM 
structured 
data 
Eligibility; 
Data linkage; 
Baseline 
characteristic 
Prior medical 
history 
Patient’s date of birth as recorded in iKM. This 
information will not be disclosed to the study 
sponsor. 
Age 
iKM 
structured 
data 
(derived) 
Eligibility; 
Baseline 
characteristic 
Baseline 
Patient’s age (in years) at the date of diagnosis, 
which will be calculated as the integer of 
[(diagnosis date – date of birth + 1) / 365.25]. 
Patients aged less than 18 years at the initial 
recorded diagnosis of NSCLC will be excluded 
from the study. 
Age groups 
iKM 
structured 
data 
(derived) 
Baseline 
characteristic 
Baseline 
Multiple age categories will be created based on 
the continuous age data: 
<65 years 
≥65 years 
No information 
Race 
iKM 
structured 
data 
Baseline 
characteristic 
Prior medical 
history 
Categorized as: 
Caucasian 
African American 
Asian 
Native American 
Other 
No information 
The specific categories outside of Caucasian and 
African American will be confirmed after 
reviewing sample sizes and the added value to 
the study with Ontada’s Privacy and Compliance 
team. 
Smoking 
history 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
Never smoked 
Current smoker 
Former smoker 
No information 
Healthcare setting and provider characteristics 
Practice 
location 
iKM 
structured 
data 
(derived) 
Baseline 
characteristic 
Baseline 
The US census region of The US Oncology 
Network clinic where the patient received care at 
the index visit: 
Midwest: Illinois, Indiana, Michigan, Ohio, 
Wisconsin, Iowa, Kansas, Minnesota, 
 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
Missouri, Nebraska, North Dakota and South 
Dakota 
Northeast: Connecticut, Maine, 
Massachusetts, New Hampshire, Rhode 
Island, Vermont, Pennsylvania, New Jersey 
and New York 
South: Delaware, Florida, Georgia, Maryland, 
North Carolina, South Carolina, Virginia, 
Washington D.C., West Virginia, Alabama, 
Kentucky, Mississippi, Tennessee, Arkansas, 
Louisiana, Oklahoma and Texas 
West: Arizona, Colorado, Idaho, Montana, 
Nevada, New Mexico, Utah, Wyoming, 
California, Oregon and Washington State 
Missing clinic values will be captured in a “no 
information” category. 
Some of the regions may need to be collapsed if 
there are small sample sizes (e.g., South vs. non- 
South). This determination will be confirmed 
after reviewing sample sizes and the added value 
to the study with Ontada’s Privacy and 
Compliance team. 
Disease characteristics 
Initial NSCLC 
diagnosis 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria, 
Baseline 
characteristic 
Medical 
history prior 
to index 
To assess NSCLC diagnoses that occurred prior 
to index date-1, patients’ available medical 
history in iKM will be searched. The 
completeness of this history will vary based on 
the length of disease and the time within The US 
Oncology Network or Non-Network. Records 
may also be incomplete for patients with an 
initial NSCLC diagnosis that occurred outside of 
The US Oncology Network or Non-Network. 
Diagnosis of NSCLC will be determined through 
a review of iKM’s discrete diagnosis and 
histology fields, which are populated during the 
routine course of care (International 
Classification of Diseases [ICD] codes will not 
be used). 
If no initial diagnosis date is documented, the 
first recorded diagnosis date in iKM will be used. 
This date will be used in calculations, not 
reported separately. 
Patients without a recorded diagnosis of NSCLC 
will be excluded from the study. 
Stage at initial 
NSCLC 
diagnosis 
iKM 
structured 
data 
Baseline 
characteristic 
Medical 
history prior 
to index 
Categorized as: 
Early stage (IA, IB, IIA, IIIB) 
Limited/Regional (IIIA) 
Locally advanced (IIIB) 
 
 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
Metastatic (IV) 
Unknown 
Date of 
metastatic 
disease 
diagnosis 
iKM 
structured 
data + 
chart 
review 
Baseline 
characteristic 
Medical 
history prior 
to index 
Date of first recorded diagnosis of metastatic 
disease within the EHR. Patients will be qualified 
initially based on the date identified in the 
structured data; this will be confirmed during 
chart review among patients selected for chart 
review. Ultimately, the primary source will be 
the chart if available. 
All patients receiving ALK inhibitors are 
assumed to be metastatic at time of ALK 
inhibitor treatment. 
Structured data will confirm the patient as 
metastatic and as available, indicate the earliest 
associated date of any of these criteria: 
1) Stage IV disease 
2) TNM with M value of 1 
3) Record of location of metastatic disease 
4) Current or prior disease status containing 
reference to metastatic disease 
Metastatic 
disease at 
diagnosis 
iKM 
structured 
data + 
chart 
review 
Categorized 
as: 
Baseline 
characteristic 
At diagnosis 
Categorized as: 
Yes 
No 
No information 
Note, “no information” can indicate that 
metastases were not documented in the chart, not 
necessarily that patients did not have metastases. 
Distant 
metastatic 
site(s) at index 
date-1 
(alectinib or 
lorlatinib start 
date) 
iKM 
structured 
data + 
chart 
review 
Baseline 
characteristic 
Baseline 
Baseline metastatic location(s) will be identified 
and categorized as: 
Bone (single) 
Bone (multiple) 
Brain 
CNS 
Liver (single) 
Liver (multiple) 
Lung (single) 
Lung (bilateral) 
Lung (pleural effusion) 
Lymph nodes (regional) 
Lymph nodes (distant) 
Ovary 
Other 
No information 
Note, “no information” can indicate that 
metastases were not documented in the chart, not 
necessarily that patients did not have metastases. 
 
 
 
 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
Tumor 
histology 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
Adenocarcinoma 
Squamous 
Large 
Not otherwise specified (NOS) 
Missing/unknown 
ALK testing 
order source 
and date 
iKM 
Chart 
Review 
Baseline 
characteristic 
Baseline 
Categorized as: 
Lab report 
Order requisition 
Pathology report 
Progress note 
ALK mutation 
status 
iKM 
structured 
data + 
Chart 
Review 
Baseline 
characteristic 
Baseline 
Categorized as: 
Not performed 
Positive fusion/rearrangement 
Negative 
Equivocal 
Indeterminate 
QNS 
Other 
Inconclusive 
Not documented 
If multiple test results are available, used last 
documented value 
Biopsy type for 
ALK testing 
Chart 
Review 
Baseline 
characteristic 
Baseline 
Categorized as: 
Pleural 
Tissue 
Blood 
Other 
Not documented 
Assay type for 
ALK testing 
Chart 
Review 
Baseline 
characteristic 
Baseline 
Categorized as: 
Fluorescence in situ hybridization (FISH) 
Immunohistochemistry (IHC) 
Next-generation sequencing (NGS) 
Reverse transcriptase– polymerase chain reaction 
(RT-PCDR) 
Other 
Not documented 
Date of ALK 
mutation result 
Chart 
Review 
Baseline 
characteristic 
Baseline 
Date as captured in chart review 
BRAF (v-raf 
murine 
sarcoma viral 
oncogene 
homolog B1) 
mutation status 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
BRAF V600E (Mutated) 
Mutations 
Wild-type 
Unknown 
 
 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
EGFR 
(epidermal 
growth factor 
receptor) 
mutation status 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
EGFR sensitizing mutation (+) 
EGFR non-sensitizing mutation (+) 
T790M (+) 
EGFR mutation (-) 
Equivocal 
Not performed 
Unknown 
PD-L1 
expression 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
>= 50% Expression 
1-49% Expression 
Negative 
Unknown 
ROS1 
iKM 
structured 
data 
Baseline 
characteristic 
Baseline 
Categorized as: 
Positive, 
Negative, 
Unknown 
MET 
iKM 
Baseline 
Baseline 
Categorized as: 
(Mesenchymal- 
structured 
characteristic 
Positive, 
to-epithelial 
data 
Negative, 
transition) 
Unknown 
exon 14 
mutations 
Eastern 
iKM 
Baseline 
Baseline 
The ECOG performance status score is a rating 
of a patient’s disease status, daily living activities 
and quality of life, with low scores indicating 
greater functioning than high scores: 
0 
1 
2 
≥3 
No information 
Karnofsky performance status is a similar 
measure and will be converted to ECOG using 
the methodology outlined below.[20] 
Cooperative 
structured 
characteristic 
Oncology 
data 
Group (ECOG) 
performance 
status 
Karnofsky 
Performance 
Status 
ECOG 
Performance 
Status 
ECOG 
Performance 
Status 
Description 
100 
0 
Fully active 
80, 90 
1 
Restricted in 
physically 
strenuous 
activity 
60, 70 
2 
Ambulatory 
and capable 
of self-care 
 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
but unable to 
work 
40, 50 
3 
Capable only 
of limited 
self-care 
10, 20, 30 
4 
Completely 
disabled 
0 
5 
Dead 
Treatment characteristics 
Date of 
alectinib or 
lorlatinib 
receipt during 
the patient 
identification 
period (i.e., 
index date-1) 
iKM 
structured 
data + 
chart 
review 
Eligibility 
criteria, 
Treatment 
characteristics 
Study 
observation 
period 
The date of alectinib or lorlatinib receipt during 
the study identification period. 
Patients who did not receive alectinib during the 
patient identification period for the main study 
and patient who did not receive lorlatinib for the 
exporatory analysis will be excluded from the 
study. 
Prior 
iKM 
Treatment 
Study 
Chemotherapy or immunotherapy received by 
chemotherapy 
structured 
pattern 
observation 
patients for NSCLC treatment prior to the index 
or 
data + 
period 
treatment (adjuvant treatment will be excluded). 
immunotherapy 
chart 
treatment 
review 
ALK inhibitor 
iKM 
Treatment 
Study 
Any ALK inhibitor treatment received by 
treatments 
structured 
pattern 
observation 
patients during the study identification period. 
data + 
period 
chart 
review 
ALK inhibitor 
iKM 
Treatment 
Study 
Date of initiation with ALK inhibitor during the 
start date 
structured 
pattern 
observation 
study identification period. 
data + 
period 
chart 
review 
ALK inhibitor 
iKM 
Treatment 
Study 
Date of final treatment for each ALK inhibitor. It 
stop date(s) 
structured 
pattern 
observation 
is possible that the patient’s treatment stop date is 
data + 
period 
not documented if the patient dies, is lost-to 
chart 
follow-up or is still on-therapy. The final 
review 
treatment date, death date or end of study date 
will be used, whichever is earliest. If patient does 
not have a stop date and initiates a subsequent 
therapy, the start date of the subsequent therapy 
will be considered as stop date of initial therapy. 
Subsequent 
treatments 
received post- 
alectinib or 
post-lorlatinib 
iKM 
structured 
data + 
chart 
review 
Treatment 
pattern 
Study 
observation 
period 
Immediate next treatment post-alectinib (or post- 
lorlatinib) and subsequent treatments received 
post-alectinib (or post-lorlatinib) treatment 
during the study period. 
*Lorlatinib treatment for the exploratory analysis 
will be sourced from structured data only 
 
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Table 1. 
Study variables and operational definitions 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
Subsequent 
treatments 
(post alectinib 
or post- 
lorlatinib) start 
and end date(s) 
iKM 
structured 
data + 
chart 
review 
Treatment 
pattern 
Study 
observation 
period 
Date of initiation and end date of immediate next 
treatment post-alectinib (or post-lorlatinib) and 
subsequent treatments received post-alectinib (or 
post-lorlatinib) treatment during the study period. 
*Lorlatinib treatment for the exploratory analysis 
will be sourced from structured data only 
Reason for 
ALK inhibitor 
(alectinib, and 
subsequent 
treatment ) 
treatment 
discontinuation 
Chart 
review 
Treatment 
characteristics 
Study 
observation 
period 
Data for alectinib and subsequent treatment 
discontinuation reason will exclusively come 
from chart review. Reviewers will be asked to 
select reason(s) as explicitly documented in 
patients’ charts. 
If available, reason patients discontinued 
treatment will be abstracted: 
Completion of therapy 
Provider-documented disease progression 
Death 
Insurance/cost-related 
Loss to follow-up 
Patient preference 
Toxicity 
Other 
No information 
Reviewers will specify other reasons; these will 
be reported if any represent >5% of patients. 
ALK inhibitor 
treatment 
sequencing 
iKM 
structured 
data + 
chart 
review 
Treatment 
pattern 
Study 
observation 
period 
ALK inhibitor treatment paths (e.g. initiate 
crizotinib followed by ceritinib, initiate crizotinib 
followed by alectinib, etc.) 
Front-line 
alectinib 
iKM 
structured 
data + 
chart 
review 
Treatment 
pattern 
Study 
observation 
period 
First treatment administration of alectinib not 
preceded by any other product for NSCLC 
therapy except up to 3 months of chemotherapy 
and immunotherapy preceding alectinib therapy 
initiation to classify patient as receiving 1L 
alectinib 
Clinical outcomes 
Last US 
Oncology 
Network visit 
date 
iKM 
structured 
data + 
chart 
review 
Clinical 
outcomes 
Study 
observation 
period 
Each patient’s most recent visit date, prior to or 
on close of study observation period, in the 
structured data will be recorded. A visit is 
defined as a physician encounter with the 
practice where either treatment is given, or vital 
signs are recorded. For patients with a death date, 
this last visit date should occur prior to the death 
date. 
 
 
 
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Table 1. 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
This will not be reported separately; it will be 
used in calculating the patient’s available follow- 
up time as a descriptive measure. 
Available follow-up time = Integer (latest of last 
visit date or death date – index date +1).7 
Death date 
iKM 
structured 
data + 
limited 
access 
death 
master 
file 
(LADMF) 
+ chart 
review 
Clinical 
outcomes 
Study 
observation 
period 
Date of death will be captured from the LADMF 
as well as iKM. If dates conflict between the 2 
sources, the LADMF date will be prioritized. If 
severe data discordance is observed (i.e., death is 
reported to occur prior to the index date), then the 
iKM death date will be used. 
Vital status 
iKM 
structured 
data + 
LADMF 
+ chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
Patients without a date of death in either the 
LADMF or iKM will be assumed to be alive at 
the end of the study. Those with a date of death 
in either LADMF or iKM will be flagged as 
deceased. 
ALK inhibitor 
(alectinib and 
stratified by 
subsequent 
treatment) 
duration of 
therapy (DOT) 
iKM 
structured 
data + 
chart 
review 
(derived) 
Treatment 
characteristics 
Study 
observation 
period 
An intent to treat approach will be used. DOT 
will be defined as duration of time (in months) 
between alectinib initiation and discontinuation, 
or the last administration date of alectinib, or 
start date of a subsequent ALK inhibitor, or 
evidence of new non-ALK inhibitor treatment (as 
a proxy for evidence of discontinuation) will be 
used as a stop date. 
There may be some patients who do not have 
evidence of discontinuation or who do not move 
on to a subsequent therapy. 
Descriptive statistics (mean, median) and K-M 
methodology will be calculated from initiation of 
alectinib, until evidence of discontinuation for 
any reason, including but not limited to a 
treatment stop date, a last alectinib administration 
date, evidence of new ALK inhibitor treatment or 
non-ALK inhibitor treatment, death or check-in 
in a hospice. Patients who do not have evidence 
of discontinuing, starting new therapy, or whose 
last prescription date is <30 days from the end of 
 
 
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Variable 
Source(s) 
Role(s) in 
study 
Period of 
measurement 
Operational definition 
the study period, will be censored at last visit 
date or end of study period. 
Overall 
survival (OS) 
(alectinib and 
stratified by 
subsequent 
treatment) 
iKM 
structured 
data + 
LADMF 
+ chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
OS will be defined as the interval (in months) 
between alectinib start date and the date of death 
(any cause) as documented in the LADMF and 
the iKM EHR database. OS will be reported for 
overall alectinib and stratified by subsequent 
treatment. Patients who did not die within the 
study observation period will be censored on the 
study end date or the last visit date available in 
the dataset, whichever occurred first. OS will be 
analyzed using the Kaplan-Meier method with 
95% CIs, and summary tables of the number of 
events and censored patients 3, 6, 12, 18, and 24 
months. 
Progression 
date after index 
date 
(physician- 
assessed) 
Chart 
review 
Clinical 
outcomes 
Study 
observation 
period 
Physician-assessed disease progression (and 
corresponding date of note) recorded from 
physician’s progress notes in Chart Review. 
Progression- 
free survival 
(alectinib, and 
subsequent 
treatment) 
iKM 
structured 
data + 
LADMF 
+ chart 
review 
(derived) 
Clinical 
outcomes 
Study 
observation 
period 
The PFS will be measured from the initiation of 
alectinib to the date of progression or date of 
death due to any cause, censoring patients who 
are still alive at the end of the study observation 
period and did not progress at the last visit date. 
PFS will be reported for overall alectinib and 
stratified by subsequent treatment. The PFS will 
be estimated in weeks using the Kaplan-Meier 
method with 95% CIs, and summary tables of the 
number of events and censored patients at 3, 6, 
12, 18, and 24 months. 
 
 
9.5. Data sources 
Table 1 presents the data elements that will be evaluated through this study and their 
associated source. Most study data will originate from the EHR system of The US Oncology 
Network and Non-Network, iKM. Independent community-based oncology practices that 
participate in the Non-Network Select Program have implemented the iKM EHR, although 
the clinics are distinct from The US Oncology Network. iKM captures outpatient practice 
encounter histories for patients under community-based care, including, but not limited to 
patient demographics such as age and gender; clinical information such as disease diagnosis, 
diagnosis stages, performance status information and laboratory testing results; and treatment 
information, such as dosages and treatment administration within The US Oncology 
Network. 
 
 
 
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Structured data fields within the iKM EHR database will provide information needed to 
address most research questions. These data will be supplemented by additional unstructured 
data collected through chart review for a subset of the study population (selection 
methodology described in Section 9.3.4). Electronic chart review data will be collected by 
means of a secure, web-based electronic case report form (eCRF) by healthcare professionals 
with oncology experience. 
 
The study will only use data from US Oncology Network practices utilizing full EHR 
capacities of iKM. Data management and administrative processing is supported by Ontada’s 
quality assurance procedures. Additionally, iKM has previously been used to evaluate patient 
profiles, treatment patterns and outcomes among metastatic NSCLC patients and the results 
have been consistent with other published studies.[21-23] Thus the study team does not plan 
to conduct any additional studies to validate the accuracy of demographic, clinical, treatment 
and outcome information in the iKM EHR database. 
 
The Limited Access Death Master File (LADMF) of the Social Security Administration will 
be an additional source of vital status (death), in addition to death dates recorded in the EHR. 
Common patient identifiers (patient identification, name, and birth date) will be used to link 
patients from the iKM data warehouse and iKM chart review. The social security number 
(SSN) will be used to link patients from iKM and LADMF data sources. All patients within 
iKM are assigned a unique patient identifier by iKM version (e.g., some large practices have 
separate installations by location). When linking to the LADMF, patient SSN is used. Some 
practices do not collect SSN and some patients may not report it. In all cases, reported deaths 
captured in iKM will supplement the Social Security Administration data. 
 
Data from all sources and any derived variables will be merged into one master dataset for 
analysis. Data will be handled in compliance with the Health Insurance Portability and 
Accountability Act (HIPAA) and Health Information Technology for Economic and Clinical 
Health (HITECH). 
 
9.6. Study size 
A preliminary feasibility assessment for Phases 1 and 2 identified 293 patients who were 
treated with alectinib after 01 November 2017, with approximately half treated in the front- 
line setting. Of the 293 patients receiving alectinib, 74% (n=217) patients had an ALK result. 
Approximately 20-30% of the 293 patients received a subsequent therapy after alectinib. It is 
estimated that approximately 300 patients will be included in the Phase 2 structured data 
analysis. Targeted chart review for Phase 2 is proposed to occur on 150 patients receiving 
alectinib to identify at least 100 patients who received alectinib as front-line. In the event the 
total number of eligible patients following structured data screening exceeds the planned 
number of charts for review, a random sample will be selected. 
 
For Phase 3 structured analysis, a preliminary feasibility assessment identified 521 patients 
who were treated with alectinib from 01 June 1 2017 through 31 December 2020. Chart 
review for Phase 3 will include patients who had ongoing treatment at the end of Phase 2 
 
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study period, and an additional 125 patients will be targeted to identify 100 new patient who 
received alectinib as front-line therapy. For Phase 3 exploratory analysis, a preliminary 
feasibility assessment identified 134 patients who were treated with lorlatinib from 01 
November 2018 through 31 December 31 2020. 
 
The final study population for analysis will be defined after identification and review of the 
patient population meeting the eligibility criteria in the iKM database. A specific power 
calculation will not be performed as this is a descriptive analysis. 
 
9.7. Data management 
For Phases 1 and 2, the Ontada study team will collaborate with Ontada’s Commercial 
Intelligence group to collect the structured iKM data that will be used for analysis. The 
Commercial Intelligence team will be provided with a Data Collections Variable List, which 
will detail the specific data elements that will need to be included in the study dataset. A Data 
Analyst will begin by generating high-level study sample counts that demonstrate attrition 
rates of the inclusion/exclusion criteria. 
 
The study team will review the attrition count and the Data Analyst will proceed with 
collecting the remaining data elements on the Data Collections Variable List. The Data 
Analyst will perform an initial quality control check of the study dataset before providing the 
file to the study team’s Biostatistician on a secure server. Once received by the 
Biostatistician, data validation will continue and will consist of, but is not limited to, quality 
control checks for appropriate values, logical sequences and quantity of missing values. 
 
During Phase 3, the Ontada Biostatistician will collect the structured iKM data that will be 
used for analysis. The biostatistician will begin by generating high-level study sample counts 
that demonstrate attrition rates of the inclusion/exclusion criteria. The study team will review 
the attrition count and the Biostatistician will proceed with collecting the remaining data 
elements detailed in the study protocol. The Biostatistician will perform data validation 
activities that will consist of, but are not limited to, quality control checks for appropriate 
values, logical sequences, and quantity of missing values. 
 
For Phases 2 and 3, the Biostatistician will generate a list of patients eligible for chart review 
and will apply a sampling technique to identify the specific patients that will undergo chart 
review. This list of patients will then be securely transmitted to the Chart Review Team 
Manager. The chart review team consists of experienced oncology healthcare providers. 
 
The Ontada study team will lead a training session with chart abstractors to discuss study 
specific considerations. Reference materials will also be provided to abstractors at this time. 
If chart abstractors have questions during the abstraction process, these will first be raised to 
the Chart Review Team Manager. If needed, questions can be escalated to the Outcomes 
Researcher and Principal Investigator. 
 
 
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Chart review will be accomplished by use of a secure, web-based eCRF. The main purpose 
of the eCRF is to obtain data required by this non-interventional study protocol in a 
complete, accurate, legible and in a timely manner. 
 
The unstructured data will be linked to structured data, which will be converted to structured 
form by a computer using automated/algorithmic methods, such as natural language 
processing. Analyses will be conducted using SAS® (SAS Institute Inc., Cary, NC, US) 
and/or R: A Language and Environment for Statistical Computing (R Foundation for 
Statistical Computing, Vienna, Austria) as appropriate. 
 
9.7.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
 
A completed CRF is required for each included patient. The completed original CRFs are the 
sole property of Pfizer and should not be made available in any form to third parties, except 
for authorized representatives of Pfizer or appropriate regulatory authorities, without written 
permission from Pfizer. The Ontada study team shall ensure that the CRFs are securely 
stored and will be password protected to prevent access by unauthorized third parties. 
 
The Ontada study team has ultimate responsibility for the collection and reporting of all data 
entered on the CRFs as required and ensuring that they are accurate, authentic/original, 
attributable, complete, consistent, legible, timely (contemporaneous), enduring, and available 
when required. The CRF serves as the source document. Any corrections to entries made in 
the CRFs must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
 
9.7.2. Record retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, Ontada 
agrees to keep all study-related records, including the identity of all participating patients 
(sufficient information to link records, e.g., CRFs[/DCTs] and hospital records), copies of all 
CRFs[/DCTs], safety reporting forms, source documents, detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, and telephone call reports). The records should be retained by Ontada according to 
local regulations or as specified in the Ontada contract whichever is longer. Ontada must 
ensure that the records continue to be stored securely for so long as they are retained. 
 
If Ontada becomes unable for any reason to continue to retain study records for the required 
period, Pfizer should be prospectively notified. The study records must be transferred to a 
designee acceptable to Pfizer. 
 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless Ontada and Pfizer have expressly agreed to a different period of retention 
 
 
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via a separate written agreement. Record must be retained for longer than 15 years if 
required by applicable local regulations. 
 
Ontada must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met. 
 
9.8. Data analysis 
As the foreseen analyses are defined in enough detail in this protocol, no further statistical 
analysis plan will be developed. 
9.8.1. Analysis sets 
Phases 1 and 2 
 
For analyses performed to meet the Phase 1 objectives, all patients who the meet the 
eligibility criteria defined in Section 9.3.1 will be considered. The study cohorts will be 
identified based on subsequent therapy following alectinib. For these analyses, datasets 
consisting of the structured data elements, plus the LADMF to confirm vitality status, 
required for the landscape analyses will be constructed. 
 
The Phase 2 (chart review) analyses will be limited to a sample of 100 qualified front-line 
alectinib patient charts identified from Phase 1. The chart review analysis sets will be 
constructed from both structured and unstructured data, with the LADMF used to confirm 
vitality status. 
 
Phase 3 
 
For analyses performed to meet the Phase 3 unstructured objectives, all patients who the 
meet the eligibility criteria defined in Section 9.3.1 will be considered. The study cohorts will 
be identified based on subsequent therapy following alectinib. For these analyses, datasets 
consisting of the structured data elements, plus the LADMF to confirm vitality status, 
required for the landscape analyses will be constructed. 
 
Phase 3 chart review analyses will include a subset of patients from Phase 2 chart review 
who had ongoing treatment at the end of the observation period and an additional sample of 
100 qualified front-line alectinib patients from Phase 3. The chart review analysis sets will be 
constructed from both structured and unstructured data, with the LADMF used to confirm 
vitality status. 
 
Some data elements will be captured with both structured and unstructured data. Since the 
chart review data are expected to provide a richer source of information, if data are available 
from both sources for a single patient, then chart review data will supersede what is available 
in the structured iKM data for the final analysis. To account for this, a final analysis data set 
will be constructed and used to update the landscape analyses once chart review data are 
available. 
 
 
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For Phase 3 exploratory analysis, all patients who meet the eligibility criteria defined in 
Section 9.3.2 will be considered. The study cohorts will be identified based on subsequent 
therapy following lorlatinib. For these analyses, datasets consisting of the structured data 
elements will be constructed. 
 
9.8.2. Derived and transformed data 
Some of the data elements needed for the study objectives will be derived from available data 
during the analysis phase of the study. Details about these calculations are provided along 
with the operational definition in Table 1. Prior to constructing these variables, the Ontada 
biostatistician will perform data validation activities. Data validation will continue and will 
consist of, but is not limited to, quality control checks for appropriate values, logical 
sequences, and quantity of missing values. 
 
Missing data will be identified and reported in the results tables as percentages for all 
variables. If there is a large amount of missing or illogical data, a decision to include, exclude 
or impute that variable will be subsequently made based on the study sponsor’s decision. 
 
9.8.3. Statistical methods 
Description of study enrollment 
To be included in the study patients must meet each of the inclusion criteria and none of the 
exclusion criteria listed in Section 9.3.1. Counts of patients excluded for each criterion will 
be summarized. 
 
Additionally, the counts of patients to be classified into the following subgroups will be 
presented5: 
• Cohort A: All alectinib treated patients (overall population) 
• Cohort B (Alectinib only cohort): Alectinib treatment ongoing, or discontinued and 
no subsequent treatment6 
• Cohort C: Alectinib followed by treatment X (top 3 most frequent) 
• Cohort D: Alectinib followed by treatment Y (top 3 most frequent) 
• Cohort E: Alectinib followed by treatment Z (top 3 most frequent) 
 
Description of patient demographic, clinical and treatment characteristics 
 
Descriptive analyses will be conducted to evaluate the demographic, clinical and treatment 
characteristics overall, as well as for each of the study cohorts. Results will be reported in 
 
5 Final cohorts will be decided upon sample size. Patients receiving chemotherapy after initiating alectinib 
will be included in the patient sample 
6 Patients with ongoing alectibin treatment, patients who discontinued alectinib and patients who did not 
have a subsequent treatment may be analyzed as separate cohorts depending on sample size of patients 
 
 
 
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aggregate. Categorical variables (e.g., ECOG performance status) will be reported as 
frequency and percentage. Continuous variables such as age will be reported as mean, 
standard deviation, median and range (minimum-maximum). In the case of missing 
observations, the number and percentage of missing values will be reported. 
 
For comparative analysis, i.e. comparing 2 or more treatment groups (e.g., ALK inhibitor 
sequences) or strata (front-line alectinib and non front-line alectinib), statistical significance 
will be reported with level of statistical significance based on p = 0.05 level as well as 95% 
confidence intervals. 
 
Chi-square testing will be used to assess associations between categorical variables when 
patient counts for single cells within the results tables are greater or equal to 5. When 
distribution cannot be assumed to be Chi-square, then Fisher’s exact test will be used. 
Depending on normality, Analysis of variance (ANOVA)/t-tests or Kruskall-Wallis tests will 
be used for continuous variables. An alpha level of 0.05 will be the primary criterion for 
statistical significance of this study. 
 
All descriptive tables will be presented for each of the study cohorts defined above and, as 
supported by the final sample size, stratified by front-line alectinib and non front-line 
alectinib treatment groups. 
 
For Phase 3 exploratory objectives, descriptive analyses will be conducted to evaluate the 
demographic, clinical and treatment characteristics among patients treated with lorlatinib. 
Results will be reported in aggregate. Categorical variables (e.g., ECOG performance status) 
will be reported as frequency and percentage. Continuous variables such as age will be 
reported as mean, standard deviation, median and range (minimum-maximum). In the case of 
missing observations, the number and percentage of missing values will be reported. 
 
Clinical outcomes 
ALK inhibitor DOT, OS, PFS will be assessed using the Kaplan-Meier method with 95% 
CIs, and summary tables of the number of events and censored patients at 3, 6, 12, 18, and 24 
months. Further details about these calculations are presented below and in Table 1. 
 
Clinical outcome results will be presented by study cohort and stratified by front-line 
alectinib and non-front line alectinib (pending sample size). 
 
Overall survival (OS) will be defined as the interval between start date of alectinib to the 
date of death as documented in the LADMF and/or iKM EHR database. Patients who did not 
die will be censored on the study end date or the last visit date available in the database, 
whichever occurred first. In order to handle censoring, the Kaplan-Meier method will be used 
to calculate median overall survival with 95% confidence intervals (in number of months). 
Additionally, 3, 6, 12, 18, and 24-month survival probabilities will be reported. OS will be 
estimated for the full study population and stratified by study cohort. Log-rank tests will be 
used to assess statistical differences. 
 
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Duration of Therapy (DOT) for ALK inhibitors: An intent to treat approach will be used. 
DOT will be defined as duration of time (in months) between alectinib treatment initiation 
and discontinuation, or the last administration date of alectinib, or start date of a subsequent 
ALK inhibitor, initiation of any subsequent non-ALK inhibitor treatment (as a proxy for 
evidence of discontinuation), death or check-in in a hospice will be used as a stop date. 
 
There may be some patients who do not have evidence of discontinuation or who do not 
move on to a subsequent therapy. 
 
Descriptive statistics (mean, median) and K-M methodology will be calculated from 
initiation of alectinib, until evidence of discontinuation for any reason, including but not 
limited to a treatment stop date, a last alectinib administration date, or evidence of new ALK 
inhibitor treatment or non-ALK inhibitor treatment. Patients who do not have evidence of 
discontinuing, starting new therapy, or whose last prescription date is <30 days from the end 
of the study period, will be censored at last visit date or end of study period. 
DOT = ( date of ALK treatment discontinuation – index date + 1 ) 
30.4375 
Progression-free survival: The PFS will be measured from the initiation of alectinib to the 
date of progression or date of death due to any cause, censoring patients who are still alive at 
the end of the study observation period and did not progress at the last visit date. Progression 
will be clinician-noted progression as noted per physician notes only, not by traditional 
Response Evaluation Criteria in Solid Tumors (RECIST) imaging, as this is impacted by 
frequency of imaging and may not be assessed the same across groups in daily clinical 
practice. Patients who did not progress or die will be censored on the study end date or the 
last visit date available in the database, whichever occurred first. The PFS will be estimated 
in months using the Kaplan-Meier method with 95% CIs, and summary tables of the number 
of events and censored patients at 3, 6, 12, 18, and 24 months. PFS will be estimated for the 
full study population and separately by study cohort. Log-rank tests will be used to explore 
statistical differences. 
 
9.8.4. Sequence of analyses 
Five separate data collection activities are planned for this study. First, structured data will be 
collected for all eligible patients and will be used to classify patients into the cohorts defined 
in Section 9.3. Chart review will then be undertaken in a sample of 100 front-line alectinib 
patients. As chart review data become available, analyses will be undertaken to meet the 
study objectives in Phase 2. 
 
During Phase 3, all eligible patients for structured data and a sample of additional patients for 
chart review as defined by the cohorts specified in Section 9.3.1 will be identified. Structured 
data collection and chart review will occur simultaneously. Analyses to meet study objectives 
will occur after chart review is complete. No interim analysis is planned. 
 
 
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All eligible patients for the Phase 3 exploratory analysis as defined by the criteria in 
Section 9.3.2 will be identified and analyses to meet the exploratory objectives will occur 
after the main objectives are complete. 
9.9. Quality control 
For structured data, Ontada’s Real World Research team conduct quality assurance checks on 
all analytics projects. The process includes both technical and clinical quality checks. 
Technical review of the dataset consists of identifying inappropriate values (e.g., out of 
range, illogical), logical sequences and quantity of missing values. Illogical and missing data 
will be reported to the study team, which may opt to exclude or impute these values. Clinical 
review of the data subsequently occurs to ensure aggregate data are aligned with expectations 
and prior publications. 
 
The quality assurance process includes the following areas: 
 
• 
Project scope and study rules 
 
• 
Protocol development 
 
• 
Data extraction and integrity 
 
• 
Populated tables and study report development 
 
As results of quality assurance and quality control, we confirm: 
 
• 
The source of the data and/or results will be documented, and that results/data will be 
verified against the source 
 
• 
The internal consistency of the medical research data presented 
 
• 
The conclusions are objective, balanced and consistent with the study results 
 
• 
The format and content of the document are aligned with the agreed upon template 
and standards 
 
Quality control and validation of chart review (unstructured) data will occur in multiple 
phases. Prior to full chart review, a pilot will be conducted with at least 5% of the patient 
population, up to 25 patients. Charts will be reviewed by each reviewer on the team to ensure 
inter-rater reliability. Data Collection Manager/Team Lead will review pilot data for 
accuracy and consistency, including implausible dates (i.e., date of death prior to last date of 
treatment), non-standard treatments, results which are inconsistent with known clinical 
parameters or other clinical data which is inconsistent with known standards and outcomes. 
Chart review team will meet following pilot and before launch of full chart review to clarify 
ambiguous or conflicting data and address potential problems and questions. Pilot data will 
be presented to the research team for review and approval. If necessary, revisions to the tool 
and/or additional training will be implemented. 
 
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Once the pilot chart review is complete, the remaining chart reviews will proceed. During 
this phase of chart review, Data Collection Manager/Team Lead will perform random and 
detailed checks of the data by verifying original source data. The Data Collection Manager 
will also initiate queries, Quality Control (QC) of randomly selected charts and review of 
final data set before submission to researcher. Finally, the researcher and study’s statistical 
lead will provide a final examination of the final dataset by looking for missing or illogical 
data before preparing it for analyses. This analysis will include a descriptive analysis of the 
provider characteristics, demographics, baseline clinical and disease characteristics, and 
characteristics of treatment patterns. Data points flagged as outliers will be reviewed by the 
Chart Review Team Lead. 
 
Based on extensive experience with chart abstraction of real-world oncology data, the Ontada 
Life Sciences team has created chart abstraction guidelines to reflect best practices in data 
collection across a number of disease areas.[24] The intent of this document is to ensure 
accurate, objective and consistent data capture. 
 
9.10. Limitations of the research methods 
9.10.1. Internal validity of study design 
Measurement error(s)/misclassification(s) 
This observational and retrospective study uses iKM EHR data. The iKM database is not 
collected for research purposes but for clinical practice reasons. This may impede the 
standardization of the data collection methods and instruments and the reporting practices of 
the physician. As with all administrative databases, iKM data are subject to coding errors of 
omission and commission. Problems with inadequate or inaccurate codes in the databases 
may introduce some level of misclassification bias of certain diagnoses, events, or procedures 
of interest.in the study. Likewise, some variables of interest may not be as complete across 
the entire population. The iKM EHR contains information on patients only when they are 
seen by US Oncology Network physicians. Services and procedures provided outside of The 
US Oncology Network are not captured by the database, as well as drugs received by 
patients from pharmacies not affiliated with US Oncology Network practices. 
 
A patient’s treatment history prior to his/her first encounter at a US Oncology Network 
practice may be only available in physician progress notes and is not well captured in the 
iKM EHR. We cannot rule out the possibility that some patients coded as receiving being 
treatment naïve for advanced disease in iKM EHR actually had previous chemotherapy or 
other treatment for advanced disease in healthcare facilities outside The US Oncology 
Network. 
 
Information bias 
Due to the nature of the study design, there is potential for bias to be introduced into the 
calculations of clinical outcomes. Specifically, patients who received treatment during the 
patient identification period may be meaningfully different from other patients who received 
therapy prior or after the study identification period. 
 
 
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Confounding 
The iKM system is used for clinical practice reasons, not solely for research purposes. As 
such, associations but not causality can be detected, thus bias may be introduced by 
confounding factors. For example, data may be collected with an intent-to-treat approach, 
meaning based on when treatment is assigned rather than received. In particular, it will not be 
possible to determine if oral therapies were dispensed or taken; therefore, we’ll use an intent- 
to-treat approach for analysis, with the assumption that all prescribed oral therapies were 
taken. Likewise, patients who do and do not receive the treatment at one point in time may be 
fundamentally different than those who received treatment during the observation period. 
These confounding factors are most likely to affect the outcomes being considered for this 
estimation study. 
9.10.2. External validity of study design 
Not all community oncology practices are included in the iKM dataset. Furthermore, not all 
of The US Oncology Network utilize the full capabilities of the iKM EHR. The US Oncology 
Network encourages use of evidence-based treatment guidelines. Therefore, practices that 
participate in The US Oncology Network may be different from other community oncology 
practices in the patient population that is seen or the prescribing practices of the physicians. 
9.10.3. Analysis limitations 
As a retrospective observational study, data entry errors at the point of care cannot be 
detected or corrected during analysis. 
9.10.4. Limitations due to missing data and/or incomplete data 
Although data quality checks are conducted, it is possible that some variables of interest may 
not be as complete across the entire population. 
 
9.11. Other aspects 
Not applicable. 
 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
Patient personal data will be stored at Ontada in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access. Ontada will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster. In the event of a potential personal data breach, 
Ontada shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law. 
 
 
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To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, any patient names will be removed and will be replaced by a single, specific, 
numerical code. All other identifiable data transferred to Pfizer or other authorized parties 
will be identified by this single, patient-specific code. Ontada will maintain a confidential 
list of patients who participated in the study, linking each patient’s numerical code to his or 
her actual identity. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patients’ personal data consistent with the clinical study 
agreement and applicable privacy laws. 
 
10.2. Patient consent 
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required. 
 
The Ontada study team will submit a request for exemption, waiver of informed consent and 
authorization to the IRB. This project involves the study of existing data and records; study 
information will be analyzed by the Ontada study team in such a manner that research 
participants will not be directly identified. Once exemption status and a waiver of informed 
consent are met, a waiver of authorization can be approved, allowing the retrospective study 
to occur. 
 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) 
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (e.g., informed consent forms if applicable) from the relevant IRBs/IECs. 
All correspondence with the IRB/IEC must be retained. Copies of IRB/IEC approvals must 
be forwarded to Pfizer. 
 
10.4. 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), Good Epidemiological Practice 
(GEP) guidelines issued by the International Epidemiological Association (IEA), Good 
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR), European Medicines Agency (EMA) European Network 
of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on 
Methodological Standards in Pharmacoepidemiology. 
 
 
 
 
 
 
 
 
 
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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
Structured Data Analysis 
 
This study involves EHR 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 (i.e., identify a potential association between) a particular product and 
medical event for any individual. Thus, the minimum criteria for reporting an adverse event 
(AE) (i.e., identifiable patient, identifiable reporter, a suspect product, and event) cannot be 
met. 
 
Human Review of Unstructured Data 
 
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol). Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE. 
 
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows: 
• All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the eCRF and reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
 
• Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form. 
 
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted. 
 
 
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All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources. While not all demographic fields will be completed, at the 
very least, at least one patient identifier (e.g., gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation. All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...” Other identifiers will have been removed. 
 
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month /year of occurrence in the day/month/year 
(DD/MMM/YYYY ) format. 
All research staff members must complete the following Pfizer training requirements: 
• “Your Reporting Responsibilities (YRR) Training for Vendors”. 
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format. Copies of all signed training certificates must be provided to Pfizer. 
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials. 
 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the party responsible 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. 
 
A phased approach to project execution will be undertaken, with interim results and reports 
provided at completion of the cohort analyses (see Section 9.8.4 for further description of the 
sequence of analyses). The completed study will be summarized in final reports that 
accurately and completely presents the study objectives, methods, results, limitations of the 
study and interpretation of the findings. 
 
Publication 
 
It is anticipated that the results of this analysis will be disseminated in the following 
publications: 
 
• 
At least 1 conference abstract 
 
• 
At least 1 manuscript 
 
 
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The Ontada study team will collaborate with the Sponsor to determine the appropriate 
conference(s) and journal(s) for submission, following assessment of the study findings. 
 
Authorship will follow the guidelines proposed by the International Committee of Medical 
Journal Editors. All authors should meet the criteria for authorship, and all people who meet 
the criteria should be authors. Any potential conflicts of interest will be disclosed. Authors 
will adhere to the ICMJE guidelines, specifically, all authors will have (1) made substantial 
contributions to conception and design, acquisition of data, or analysis and interpretation of 
data; (2) participated in drafting the article or revising it critically for important intellectual 
content; (3) approved the version to be published, and (4) agreed 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. Acquisition of funding, collection of 
data, or general supervision of the research group does not justify authorship. Each author 
should have participated sufficiently in the work to take public responsibility for appropriate 
portions of the content. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13. REFERENCES 
1. 
Peters S, Ross CD, Shaw A, et al. Alectinib versus Crizotinib in Untreated ALK- 
Positive Non–Small-Cell Lung Cancer. N Engl J Med 2017; 377:829-838. 
2. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA CANCER J CLIN 
2019;69:7–34. . 
3. 
Pacheco JM, Gao D, Smith D, et al. Natural History and Factors Associated with 
Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer. J 
Thorac Oncol. 2019 Apr;14(4):691-700. 
4. 
Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of 
patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 
2009;27:4247-53. 
5. 
Camidge DR, Doebele RC. Treating ALK-positive lung cancer — early successes and 
future challenges. Nat Rev Clin Oncol 2012;9:268-77. . 
6. 
Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, et al. Novel 
ALK inhibitors in clinical use and development. J Hematol Oncol. 2015;8(1):17. doi: 
10.1186/s13045-015-0122-8. 
7. 
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK 
fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566. . 
8. 
Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl 
Cancer Inst. 2010;102:672-675. . 
9. 
Takeuchi K, Choi YL, Soda M, et al. Multiplex Reverse Transcription-PCR Screening 
for EML4-ALK Fusion Transcripts. Clin Cancer Res: 2008;14: 6618-24. 
10. 
Palmer RH, Vernersson E, Grabbe C, et al. Anaplastic lymphoma kinase: signaling in 
development and disease. Biochem J. 2009;420:345-361. . 
11. 
Mosse YP, Wood A, Maris JM. Inhibition of ALK signaling for cancer therapy. Clin 
Cancer Res. 2009;15:5609-14. . 
12. 
Sasaki T, Rodig SJ, Chirieac LR, et al. The biology and treatment of EML4-ALK non- 
small cell lung cancer. Eur J Cancer. 2010;46:1773-80. . 
13. 
Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of 
an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008; 14:4275-83. . 
14. 
Wong DW, Leung EL, So KK, et al. The EML4-ALK Fusion Gene Is involved in 
Various Histologic Types of Lung Cancers from Nonsmokers with Wild-type EGFR 
and KRAS. Cancer. 2009;115:1723–33. 
15. 
Schein PS, Scheffler B. Barriers to efficient development of cancer therapies. Clin 
Cancer Res. 2006;12:3243-3248. 
16. 
Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based 
chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND- 
4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917- 
929. 
17. 
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 19:1654- 
1667, 2018. 
 
 
 
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18. 
FDA approves lorlatinib for metastatic ALK-positive NSCLC. 
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves- 
lorlatinib-metastatic-alk-positive-nsclc. Accessed 30 June 2021. 
19. 
The US Oncology Network, 2018. 
20. 
Ma C, Bandukwala S, Burman D, et al: Interconversion of three measures of 
performance status: an empirical analysis. Eur J Cancer 46:3175-83, 2010. 
21. 
Reynolds C, Masters ET, Black-Shinn J, Boyd M, Mardekian J, Espirito JL, Chioda 
M. Real-World Use and Outcomes of ALK-Positive Crizotinib-Treated Metastatic 
NSCLC in US Community Oncology Practices: A Retrospective Observational Study. 
J. Clin. Med. 2018, 7, 129. . 
22. 
Nadler E, Espirito JL, Pavilack M, Boyd M, Vergara-Silva A, Fernandes A. 
Treatment Patterns and Clinical Outcomes Among Metastatic Non-Small-Cell Lung 
Cancer Patients Treated in the Community Practice Setting.Clin Lung Cancer. 2018 
Jul;19(4):360-370. 
23. 
McKay C, Burke T, Cao X, Abernethy AP, Carbone DP. Treatment Patterns for 
Advanced Non-Small-cell Lung Cancer After Platinum-containing Therapy in U.S. 
Community Oncology Clinical Practice. Clin Lung Cancer. 2016 Sep;17(5):449- 
460.e7. 
24. 
Robert N, Espirito J, Haydon W, et al: Development of Playbook for Chart Review in 
Real-World Data. Presented at the ISPOR, New Orleans, LA, May 21, 2019. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14. LIST OF TABLES 
Table 1. 
Study variables and operational definitions .............................................. 28 
15. LIST OF FIGURES 
Figure 1. 
Phases 1 and 2 study design ...................................................................... 21 
Figure 2. 
Phase 3 data refresh study design .............................................................. 22 
Figure 3. 
Phase 3 exploratory analysis study design ................................................ 23 
 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
 
None 
 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
 
Not applicable. 
 
ANNEX 3. ADDITIONAL INFORMATION 
 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PPD 
 
 
Annexes 
 
Approval Signatures 
Pfizer Signatures 
[Pfizer Study Lead: 
, PhD] 
Date (Day Month Year) 
 
 
 
 
Ontada/US Oncology Network Signature(s) 
 
 
 
 
[PI: PPD 
, MD, MPH] 
Date (Day Month Year) 
 
 
 
 
[Ontada Outcomes Researcher: PPD 
, PhD] 
Date (Day Month Year) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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