A Retrospective Non Interventional Study on First Line Treatment for Patients With BRAFV600E Mutant Metastatic Colorectal Cancer (mCRC)
Conditions: BRAF V600E Mutation Positive, Metastatic Colorectal Cancer
Sponsor: Pierre Fabre Medicament

 
 
 
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Pierre Fabre – Strictly confidential – NIS-PF0-2020-3141 – Final Version 2.0 –12 Mar 2020 
 
 
 
A Retrospective Non-Interventional Study 
on First Line Treatment for Patients with 
BRAFV600E Mutant Metastatic Colorectal 
Cancer (mCRC)  
Final Version 2.0 
12 March 2020 
 
Sponsor  
 
 
 
 
Scientific responsible 
Medical responsible 
PIERRE FABRE MEDICAMENT 
45, PLACE ABEL GANCE 
92100 BOULOGNE BILLANCOURT - FRANCE 
Phone: + 33 (0)1 49 10 80 00 
 
Abir Tadmouri Sellier 
Sadya Khan  
Vendor 
CLINACT 
VELIZY ESPACE - IMMEUBLE SANTOS DUMONT 
13 AVENUE MORANE SAULNIER 
78457 VELIZY VILLACOUBLAY CEDEX - FRANCE  
Phone: + 33 (0)1 80 13 14 70 
Scientific Committee 
Dr Bernard Asselain, France 
Pr. Dirk Arnold, Germany 
Pr. Erika Martinelli, Italy 
 
 
 

 
 
 
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SIGNATURE PAGE 
 
The undersigned have read this protocol and agreed to conduct this study in accordance with all 
stipulations of the protocol and in accordance with the Declaration of Helsinki. 
 
Sponsor Pierre Fabre 
 
François Denjean 
(Medical Director) 
 
 
 
 
Sadya Khan 
(Medical Advisor) 
 
 
 
 
Abir Tadmouri 
(Director Real World Data) 
 
 
 
Date: ……………/………/……….. 
 
Signature: 
 
 
 
Date: ……………/………/……….. 
 
Signature: 
 
 
 
Date: ……………/………/……….. 
 
Signature: 
 
 
CRO CLINACT 
 
Ann-Kathrin Ghattas 
(Project Manager Scientific 
Affairs) 
 
Date: ……………/………/……….. 
 
Signature: 
 
 
 
 

 
 
 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ......................................................................................................................... 5 
PROTOCOL SYNOPSIS ................................................................................................................................ 7 
1 
BACKGROUND AND RATIONALE ................................................................................................ 13 
2 
STUDY OBJECTIVES ......................................................................................................................... 17 
2.1 
PRIMARY OBJECTIVE ................................................................................................... 17 
2.2 
SECONDARY OBJECTIVES ........................................................................................... 17 
2.3 
EXPLORATORY OBJECTIVES ...................................................................................... 17 
3 
RESEARCH METHODS ..................................................................................................................... 17 
3.1 
STUDY DESIGN ............................................................................................................... 17 
3.2 
POPULATIONS ................................................................................................................ 18 
3.2.1 Source population (if applicable) .................................................................................. 18 
3.2.2 Study population ............................................................................................................ 18 
3.2.3 Participants recruitment and follow-up ......................................................................... 19 
3.3 
STUDY OUTCOMES........................................................................................................ 20 
3.3.1 Primary endpoint ........................................................................................................... 20 
3.3.2 Secondary endpoints ...................................................................................................... 20 
3.3.3 Exploratory endpoints .................................................................................................... 21 
3.3.4 Exposure definition and measurement ........................................................................... 21 
3.3.5 Outcome variables and measurements .......................................................................... 22 
3.3.6 Confounding variables ................................................................................................... 23 
3.4 
DATA SOURCES AND COLLECTION .......................................................................... 25 
3.5 
STUDY SIZE ..................................................................................................................... 27 
3.6 
PERSONAL DATA MAPPING .................................................................................................. 28 
3.7 
DATA MANAGEMENT ................................................................................................... 28 
3.8 
DATA ANALYSIS ............................................................................................................ 29 
3.8.1 General considerations .................................................................................................. 29 
3.8.2 Primary analyses............................................................................................................ 29 
3.8.3 Secondary analyses ........................................................................................................ 29 
3.8.4 Exploratory analyses...................................................................................................... 30 
3.8.5 Missing data ................................................................................................................... 31 
3.9 
QUALITY CONTROL ...................................................................................................... 31 
3.10 
STUDY MANAGEMENT ................................................................................................. 32 
3.10.1 
Sponsor....................................................................................................................... 32 
3.10.2 
CRO responsible for the management of the study .................................................... 32 
3.10.3 
Scientific Committee (SC) .......................................................................................... 32 
3.11 
LIMITATIONS OF THE RESEARCH METHODS .......................................................... 32 
3.11.1 
Selection bias ............................................................................................................. 32 
3.11.2 
Information bias ......................................................................................................... 33 
3.11.3 
Follow-up bias ........................................................................................................... 33 
4 
PROTECTION OF HUMAN SUBJECTS AND LOCAL REGULATORY ASPECTS ................ 33 
4.1 
ETHICS .............................................................................................................................. 33 
4.2 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD 
(IEC/IRB) ....................................................................................................................................... 33 
4.3 
PATIENT INFORMATION .............................................................................................. 34 
4.4 
PRIVACY OF PERSONAL DATA ................................................................................... 34 
4.4.1 Personal data protection ................................................................................................ 34 
5 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ....... 34 

 
 
 
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5.1 
TRAINING ........................................................................................................................ 34 
5.2 
REPORTING OF ADVERSE EVENTS/ADVERSE DRUG REACTIONS ..................... 35 
5.2.1 Definitions ...................................................................................................................... 35 
5.2.2 Reporting ........................................................................................................................ 36 
5.2.3 Reconciliation ................................................................................................................ 36 
6 
TIMELINES .......................................................................................................................................... 37 
7 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS (IF 
APPLICABLE) .............................................................................................................................................. 37 
8 
REGULATORY CONSIDERATIONS .............................................................................................. 37 
8.1 
CONFIDENTIALITY ........................................................................................................ 37 
9 
REFERENCES...................................................................................................................................... 38 
10 
APPENDICES ....................................................................................................................................... 41 
 
 
LIST OF TABLES 
 
Table 1 Study Exposure .................................................................................................................. 22 
Table 2 Study Outcomes ................................................................................................................. 22 
Table 3 Study Covariates ................................................................................................................ 23 
Table 4 Data Collection Schedule ................................................................................................... 26 
Table 5 Precision estimates for a range of proportions and cohort sizes ........................................ 27 
Table 6 Study timelines ................................................................................................................... 37 
 
 
 

 
 
 
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LIST OF ABBREVIATIONS 
 
5-FU 
5-fluorouracil  
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BMI 
Body Mass Index 
BRAF 
B- Raf proto-oncogene 
BRAFV600E 
BRAF residue 600 
CI 
Confidence Interval 
CR 
Complete Response  
CRC 
Colorectal Cancer 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein  
eCRF 
Electronic Case Report Form 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EMR 
Electronic Medical Records 
EQ-5D 
European Quality of Life-5 Dimensions Questionnaire  
ERK 
Extracellular Signal-regulated Kinase 
EU GDPR 
European Union General Data Protection Regulation 
FAS 
Full Analysis Set 
FOLFOX 
5-fluorouracil, leucovorin, oxaliplatin 
FOLFIRI 
5-fluorouracil, leucovorin, irinotecan  
FOLFOXIRI 
5-fluorouracil, leucovorin, oxaliplatin, irinotecan 
GDPR 
General Data Protection Regulation 
GPP 
Good Pharmacoepidemiological Practices 
GVP 
Good Pharmacovigilance Practices 
HR 
Hazard Ratio 
HR-QoL 
Health-related Quality of Life  
ICD-10 
International Classification of Diseases 10th Revision 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 

 
 
 
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IRB 
Institutional Review Board 
ISPE 
International Society for Pharmacoepidemiology 
KM 
Kaplan-Meier 
KRAS 
Kirsten Rat Sarcoma Viral Oncogene  
LOT 
Line of Treatment 
mCRC 
Metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen Activated Protein Kinase 
MSI 
Microsatellite Instability 
MMR 
Mismatch Repair 
NCCN 
National Comprehensive Cancer Network Panel  
NIS 
Non-interventional Study 
NLM 
Neutrophil-to-lymphocyte ratio 
NRAS 
Neuroblastoma RAS viral oncogene homolog 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFM 
Pierre Fabre Medicament 
PFS 
Progression Free Survival  
PIK3CA 
Phosphatidylinositol 3-Kinase Catalytic Subunit 
PR 
Partial Response 
PROs 
Patient-reported Outcomes  
PT  
Preferred Term 
PV 
Pharmacovigilance 
QC 
Quality Control 
SACT 
Systemic Anti-Cancer Therapy 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
STROBE 
STrengthening 
the 
Reporting 
of 
OBservational 
studies 
in 
Epidemiology 
TNM 
Tumor, Node, Metastasis 
VEGF 
Vascular Endothelial Growth Factor  
WT 
Wild Type 
 
 

 
 
 
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PROTOCOL SYNOPSIS 
 
Background 
Colorectal cancer (CRC) is the third most common cancer in men and women worldwide with an estimated 1.4 million 
cases and 694,000 deaths in 2012; the majority of cases occur in the developed countries.1 About one-quarter of the 
patients with CRC have metastatic disease at the time of initial diagnosis and half of the patients develop metastatic 
disease following their initial diagnosis.2  
First line treatment in patients with metastatic CRC (mCRC) includes a combination of chemotherapy regimens and 
biological agents.3 4 Systemic anticancer therapy (SACT) is the main treatment option where combination chemotherapy 
remains the consensus standard of care. First line chemotherapy options include: 5-fluorouracil (5-FU), leucovorin, and 
oxaliplatin (FOLFOX); 5-FU, leucovorin, and irinotecan (FOLFIRI); and capecitabine plus oxaliplatin.2 Bevacizumab, 
an anti-vascular endothelial growth factor (anti-VEGF) agent, when given in combination with chemotherapy has shown 
to significantly improve overall survival (OS) compared to chemotherapy alone.5 6 The survival benefit was retained in 
patients who continued using bevacizumab as a combination therapy, beyond first line progression.7 Other biological 
agents such as cetuximab and panitumumab, both of which are epidermal growth factor receptor (EGFR) monoclonal 
antibodies, have demonstrated benefits in survival, progression free survival (PFS) and response rate when used as first-
line treatment of patients with wild-type Kirsten Rat Sarcoma Viral Oncogene (KRASwt) tumors in combination with 
FOLFIRI and FOLFOX when compared to chemotherapy alone, but not with other oxaliplatin-based regimens such as 
FLOX (combination of fluorouracil, leucovorin and oxaliplatin) and CAPOX (combination of capecitabine and 
oxaliplatin).8 
Approximately 10% of CRC patients have B-Raf proto-oncogene (BRAF) mutation,9 which is a marker of poor 
prognosis.10 Metastatic colorectal cancer patients with BRAFV6000E mutation have median OS of 10 to 15 months 
compared to 21 to 35 months for patients with BRAF wild-type (BRAFwt) tumors.11-13 Considering the prognostic 
importance of BRAFV6000E mutation, the European Society of Medical Oncology has recommended assessment of BRAF 
mutation status alongside RAS gene mutation status in mCRC patients.2 
To date, there is no agent specifically indicated for patients with BRAFV600E mutant mCRC. Limited data from unplanned 
retrospective analyses of patients receiving first-line treatment have produced inconclusive results.3 Because RAS and 
BRAFV600E mutations are almost always mutually exclusive, BRAFV600E mutant mCRC patients are typically treated with 
standard-of-care regimens for KRASwt tumors, i.e., either oxaliplatin- or irinotecan-based SACT, with or without 
bevacizumab (anti-VEGF antibody) or cetuximab (anti-EGFR antibody) but with substantially poorer outcomes than 
patients without BRAFwt tumors. A retrospective study reported no differences in PFS irrespective of whether 
oxaliplatin- or irinotecan-based chemotherapy was administered in the first-line setting in patients with BRAF mutant 
CRC (6.4 versus 5.4 months; P=0.99).14 There is insufficient evidence to conclude that BRAF is a predictive biomarker 
for irinotecan or oxaliplatin, as patients benefit regardless of their mutational status. 
In the Phase III study TRIBE, BRAF-mutated mCRC patients treated with the combination of 5-FU, leucovorin, 
oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab showed a trend towards improved OS with 19.0 months 
compared with 10.7 months (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.24–1.20) and PFS (HR 0.57, 95% 
CI 0.27–1.23) compared with FOLFIRI plus bevacizumab among the 28 patients with BRAF mutation.15 16 FOLFOXIRI 
plus bevacizumab, however, significantly increases the incidence of grade 3 or grade 4 adverse events (AEs) in mCRC 
patients compared to FOLFIRI plus bevacizumab.17   
 
Rationale  
The presence of a BRAFV600E mutation is considered a marker of poor prognosis in patients with mCRC, and findings 
from clinical trials have largely remained inconclusive regarding the efficacy of first line treatments for BRAF-mutant 
mCRC patients. In the absence of targeted/specific treatment for BRAF-mutant mCRC, treatment practices can vary based 
on local practices and guidelines. There is, therefore, an unmet need to document the current practices for first-line 
treatment of BRAF-mutant mCRC, and their effectiveness and safety in a real-world setting. 
This real-world, multicenter non-interventional study (NIS) will describe the treatment patterns, effectiveness and safety 
of current treatment regimens in BRAFV600E mutant mCRC patients in Europe, with the aim to put the clinical study 
findings of the ongoing Phase 2, single-arm, open label trial (ANCHOR) into context of the current treatment landscape 
excluding investigational therapies. Additionally, the NIS output may be used to support future health technology 
assessment submissions and publications. 
 

 
 
 
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Objectives 
Primary objective 
To describe first line treatment patterns in BRAFV600E mutant mCRC patients. 
Secondary objectives 
1. To describe baseline demographic and clinical profile of BRAFV600E mutant mCRC patients receiving first-line 
treatment, overall and by treatment regimen  
2. To describe PFS in BRAFV600E mutant mCRC patients receiving first-line treatment, overall and by treatment 
regimen 
3. To describe OS in BRAFV600E mutant mCRC patients receiving first-line treatment, overall and by treatment 
regimen 
4. To describe treatment response in BRAFV600E mutant mCRC patients receiving first-line treatment, overall and 
by treatment regimen 
5. To describe treatment duration (i.e., time to treatment cessation) in BRAFV600E mutant mCRC patients receiving 
first-line treatment, overall and by treatment regimen 
6. To describe BRAF mutation testing procedure and timing in regards with the first-line treatment in BRAFV600E 
mutant mCRC patients 
7. To describe the frequency of relevant AEs in BRAFV600E mutant mCRC patients receiving first-line treatment, 
overall and by treatment regimen 
Exploratory objectives 
1. To describe the reason(s) for treatment discontinuation or switch in BRAFV600E mutant mCRC patients starting 
first-line treatment 
2. To describe the treatment(s) received, by line of treatment (LOT), after first progression in BRAFV600E mutant 
mCRC patients 
 
Study design 
This retrospective, multi-center longitudinal study on BRAFV600E mutant mCRC patients will be conducted in Europe to 
characterize the first-line treatment patterns. All BRAFV600E mutant patients having initiated a first-line treatment for 
mCRC between January 1st, 2016 and December 31st, 2018 (both days inclusive) with drugs registred for mCRC in 
respective country will be eligible to participate. Thus the observation period is earlier than the date of inclusion of the 
patient in the study. The study will not provide or recommend any treatment or procedure; all decisions regarding 
treatment are made at the sole discretion of the treating physician in accordance with their usual practices and all eligible 
patients will be considered for enrollment.  
The target countries for patient enrollment will include Germany, France, Italy, UK, Spain, Belgium, Austria and the 
Netherlands. Approximately 300 adult patients (≥18 years) from a mix of academic and non-academic sites (up to 65 
sites) will be enrolled. 
In order to obtain a representative sample of real-world patients undergoing treatment for BRAFV600E mutant mCRC, an 
evidence-based approach will be adapted to (1) find and select sites within a country that meet the right criteria for success 
and representability (taking into account various site-level factors such as center type [public/private, academic/non-
academic], center size, center practice, etc.), and (2) identify and mitigate risks that could impact patient enrollment. A 
strategy plan for site selection will be created before site enrolement to ensure site representativeness, and will describe 
all processes related to the representativity survey. The site survey will be conducted prior site selection.  
Patient data will be collected from the date of the start of first-line treatment for mCRC until the end of the observation 
period (date of death or last day of study observation period for patients alive at the time of data abstraction). Patients lost 
to follow-up will be censored at the date of their last available medical record. 
For eligible patients, relevant data will be abstracted from their medical records and entered into a centrally-designed 
electronic case report form (eCRF). The data will be anonymized during the entry into the eCRF by using an algorithm 
which generates a random patient number without any indication of the patient, centre or country. This anonymization 
will be maintained in the database used for statistical analysis.  
 
 

 
 
 
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Study population 
Patients diagnosed with BRAFV600E mutant mCRC (determined by local laboratory result) in the target countries and 
initiating first line treatment between January 1st, 2016 and December 31st, 2018 (both days inclusive) will be eligible for 
enrollment into the study.  
The following inclusion and exclusion criteria will be applied: 
Inclusion criteria 
Patients will be eligible for inclusion if they fulfil all the following criteria: 
• 
Male or female aged ≥18 years at diagnosis for mCRC  
• 
Diagnosis of histologically or cytologically confirmed CRC that is metastatic and unresectable  
• 
Presence of BRAFV600E mutation in tumor tissue, as determined by a local assay  
• 
Initiated first-line treatment with drugs registered for mCRC in the respective country at the time of treatment 
between January 1st, 2016 and December 31st, 2018 (both days inclusive) 
• 
Provision of informed consent or non-opposition to the patient (or next-of-kin, if applicable) for the use of data, 
according to local regulations 
Exclusion criteria 
Patients will be excluded from the study if they fulfil any of the following criteria: 
• 
Patients with another concomitant tumor (or neoplasm) at the time of diagnosis* 
• 
Patients participating in interventional trials on investigational drugs at the time of initiation of first-line 
treatment 
* Except for non-metastatic non-melanoma skin cancers, or in situ or benign neoplasms; a cancer will be considered 
concomitant if it occurs within 5 years of mCRC diagnosis. 
For patients who fulfil the eligibility criteria, but do not participate in the study (non-consent or opposition, non-inclusion 
because of patient selection process), a screening log will be maintained (subject to local regulations) to record the reason 
for non-participation, gender, age at diagnosis, first line treatments received (if available) and survival status. 
 
Patient selection process 
In each participating center, all eligible patients will be identified and assigned a random number. Data will be abstracted 
consecutively. If necessary applicable by local regulations, written informed consent from patient or next of kin (for 
patients alive at the time of data abstraction and for dead patients, if required by local regulations) will be obtained prior 
to data abstraction. If consent is needed and not provided, the reason will be noted in a screening log.  
 
Data collection/data sources  
The source of collected data will be all elements that can constitute a reliable source of patient-level information and that 
are available at the site. This includes data available in the patient medical charts (e.g., consultation notes, discharge 
summaries, laboratory test results, recorded prescription data and any other documentation of communication with other 
health care providers). The site investigator will be responsible for ensuring that all the required data is collected and 
entered into the eCRF. 
The exposure of interest will be the first line SACT (monotherapy, doublet chemotherapy, or triplet chemotherapy with 
or without a targeted therapy [either VEGF inhibitor or EGFR inhibitor]) for the treatment of BRAFV600E mutant mCRC. 
The following key data items will be collected, where available: 
• 
Patient demographic and clinical characteristics 
o 
Age, gender, weight, height, body mass index at mCRC diagnosis  
o 
Date of diagnosis of CRC and mCRC 
o 
Performance status using Eastern Cooperative Oncology Group score at at mCRC diagnosis 
o 
Comorbidities at mCRC diagnosis 
o 
Tumor/node/metastasis stage (I, II, III, IV) at the time of initial diagnosis of CRC 
o 
Histology at the time of initial diagnosis of CRC: adenocarcinoma, other carcinoma 

 
 
 
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o 
Location of the primary tumor at the time of initial diagnosis of CRC: colon left-sided, colon right-sided, 
colon transverse, rectum, unknown 
o 
Tests and diagnosis collected at mCRC diagnosis or during follow-up 
▪ 
Tumor Biomarker Assessments: BRAF on tumor sample or ctDNA (including date of ordering 
test and date of test result); RAS; MSI (microsatellite instability); MMR (mismatch repair) 
▪ 
Blood biomarker assessments: C-reactive protein; CEA; CA 19-9 
o 
Biological parameters 
▪ 
Other selected routine laboratory tests at at mCRC diagnosis 
o 
Metastasis 
▪ 
Location: Liver, lung, lymph nodes, bone, peritoneum, central nervous system, other locations, 
unknown 
▪ 
Number of metastatic sites 
 
• 
Treatment history at mCRC diagnosis and during follow-up 
o 
Prior medications/therapies/procedures for treatment of CRC 
o 
Treatment for mCRC  
▪ 
LOT (to be derived using a data-driven approach if disease progression is poorly documented 
in the patient medical record) 
▪ 
SACT medications (chemotherapies and targeted therapies): monotherapy, doublet therapy or 
triplet therapy; name of the agent(s); start date and end date 
▪ 
Treatment alteration (e.g., switch, discontinuation, dose reduction): dates and reasons for 
treatment alteration 
▪ 
Maintenance therapy (if any) of first-line treatment: name of agent(s); start date and stop date 
o 
Treatment response (as recorded in patient medical record by the treating physician) of first-line 
treatment of mCRC: type of response: complete response (CR), partial response (PR), progressive 
disease (PD); date recorded 
o 
Date of documented progression 
o 
Date of death or last patient visit date; cause of death (if patient died) 
 
• 
Safety data 
o 
Relevant AEs reported during the follow-up period. Relevant AEs are defined as AEs leading to first-
line treatment switch, dose adaptation or discontinuation, or leading to death. 
 
The data collection schedule is presented in Table 4. 
All relevant AE data will be extracted from medical records and mapped into the Medical Dictionary for Regulatory 
Activities (MedDRA) and grouped by system organ class (SOC) and preferred term (PT).  
 
Data management and quality assurance   
A data management plan will be created before the start of data collection and will describe all functions, processes, and 
specifications for data collection, cleaning and validation to ensure that the data are as clean and accurate as possible 
when presented for analysis. Data collection and validation procedures will be detailed in appropriate operational 
documents. 
A study monitoring plan, including for-cause monitoring, that is appropriate for the study design will be developed and 
implemented. Data quality control (QC) will be performed remotely and at the site level, where permissible according to 
local regulations, by qualified designated personnel under professional secrecy. 
All medical data will be confidential. Pierre Fabre Medicament (PFM), as the Sponsor of the study and data controller, is 
responsible for the processing of personal data in accordance with the provisions of Regulation 2016/679/EU of the 
European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing 
of personal data and the free movement of such data (GDPR), the data collected being for research purposes in the field 
of health, the legal basis of the processing being the legitimate interest of the data controller. 
 
Safety   

 
 
 
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Within the timeframe of study documentation/data collection, Pierre Fabre has not registered any drug used for the 
treatment of mCRC, therefore no Pierre Fabre-owned drug was authorized for use within clinical routine treatment for 
mCRC or BRAFV600E-mutant mCRC. Moreover, patients treated in the frame of interventional clinical studies for mCRC 
and patients treated with concomitant systemic therapies for cancers other than mCRC, will be excluded. Therefore, this 
NIS is not expected to generate any safety reports with regard to Pierre Fabre-owned drugs within the frame of the 
eligibility criteria. 
 
Irrespective of this retrospective anonymized data retrieval, the participating physicians will be reminded of their general 
reporting obligations with regard to adverse drug reactions concerning any Pierre Fabre product or drugs of other manu-
facturers in accordance with the respective national law and regulations. 
 
Study endpoints 
Primary endpoint 
First-line SACT treatment patterns in BRAFV600E mutant mCRC patients, described by: 
o 
Agent or combination of agents received 
o 
Duration of treatment 
o 
Maintenance therapy (if any) 
 
The first-line SACT regimen(s) will be described from the time of treatment initiation (for mCRC) until the time of first 
documented disease progression or treatment discontinuation, whichever is earlier.  
LOT definition will be connected to treatment progression. The LOT will be defined using a data-driven algorithm; in the 
Statistical Analysis Plan (SAP) an algorithm for LOT definition will be specified, which will consider the specific 
treatment(s) received (stop and start dates), progression, tumor response (as recorded in the patient medical record, 
including date), documented reasons for discontinuation of treatments and gap(s) between subsequent treatment regimens, 
and will be further elaborated in the protocol and the SAP.  
Secondary endpoints 
1. Description of demographic and clinical profile of patients at the time of treatment initiation (for mCRC) 
2. PFS, defined as the length of time between initiation of first-line treatment for mCRC and the first documented 
disease progression (if disease progression is not well documented in patient’s medical record, then start of 
subsequent LOT may be considered as proxy for disease progression) or death (whichever is earlier)  
3. OS, defined as the time between first-line treatment initiation (for mCRC) and death (due to any cause) 
4. ORR, defined as CR or PR, described at the end of firstline treatment for mCRC 
5. Time to treatment cessation, defined as the length of time between initiation of first-line treatment for mCRC 
and documented disease progression (or start of subsequent LOT, if disease progression is not well documented 
in patient medical record), treatment discontinuation or switch to another treatment (defined as change from one 
treatment regimen to another treatment regimen, e.g., change from FOLFOX-based regimen to FOLFIRI or 
irinotecan-based regimen) 
6. Time to BRAF mutation testing since mCRC diagnosis and since first-line treatment for mCRC, and description 
of testing procedures 
7. Frequency of relevant AEsduring first-line treatment for mCRC. Relevant AEs are defined as AEs leading to 
first-line treatment switch, dose adaptation or discontinuation, or leading to death. 
Exploratory endpoint(s) 
1. Description of reasons for treatment discontinuation or switch at the end of first-line treatment for mCRC 
2. Second (and subsequent) line treatment patterns in BRAFV600E mutant mCRC patients, defined as treatments 
received after disease progression following first line treatment, and described by: 
o 
Agent or combination of agents received 
o 
Duration of treatment 
 
 
Statistical considerations   

 
 
 
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Sample size 
The primary objective of this NIS is to assess the treatment patterns of BRAFV600E mutant mCRC patients. The sample 
size was determined based on the precision with which the primary objective could be achieved. Precision estimates (95% 
[CIs) were calculated around percentages ranging from 1% to 20% for sample sizes ranging from 200 to 1000. The range 
of proportions was determined based on projected estimates of patient share as per different regimens in first-line of 
therapy in UK, Germany, France, Spain, and Italy using Oncology Dynamics data which projected proportions of different 
lines of therapy between 1% to 21%. A sample size of 300 patients will be able to measure treatment regimens prescribed 
to 5%, 10%, and 20% patients with a precision of ±2.5% (95% CI: 2.5% to 7.5%), ±3.4% (95% CI: 6.6% to 13.4%) and 
±4.5% (95% CI: 15.5% to 24.5%), respectively. This was considered adequate to meet the descriptive objectives of this 
study. Further details are provided in section 3.5. 
Statistical analyses 
Statistical analyses will be fully described in a written SAP. The study endpoints will be analyzed overall, by country 
and by predefined subgroup(s) of interest (e.g., age, gender, primary tumor location, number of metastatic organs). 
Analyses will be descriptive in nature, as no hypothesis will be tested. In general, missing data will not be imputed (except 
for dates) and the data will be analyzed according to the complete case approach. 
The treatment patterns of patients, baseline demographic and clinical characteristics, time to BRAF mutation testing and 
description of testing procedures, and reasons for treatment discontinuation will be described using summary statistics. 
Categorical variables will be summarized by frequencies and percentages. Continuous variables will be summarized by 
descriptive statistics (mean, and standard deviation, median, 25th and 75th percentiles, minimum and maximum). The 
number of missing observations for each variable will also be reported. Relevant AEs will be coded by MedDRA and 
summarized as SOC and PT.  
Time-to-event data (PFS, OS, time to treatment cessation) will be evaluated using Kaplan-Meier survival curves. Median 
survival estimates will be reported along with the 25th and 75th percentiles, and corresponding 95% CIs. Cox regression 
analysis may be performed to adjust for predefined (baseline) covariates.   
Objective response rate (best overall response of CR or PR) will be summarized using frequency tables with their 
associated 95% CIs. Logistic regression may be used to adjust for predefined (baseline) covariates. 
 
Ethical and regulatory considerations   
This study will be conducted under the guidelines of good pharmacoepidemiology practices (GPPs) issued by the 
International Society for Pharmacoepidemiology (ISPE), the Declaration of Helsinki and its amendments, the European 
Union General Data Protection Regulation (EU GDPR) and any applicable national guidelines. 
Consistent with local regulations and prior to enrollment of patients at a given site, the study protocol will be submitted 
together with its associated documents (e.g., informed consent form [ICF]) to the responsible IRB/IEC for its review. 
Before implementation of any substantial changes to the protocol, protocol amendments will also be submitted to the 
relevant IRB/IEC in a manner consistent with local regulations.  
 The data will be anonymized during the entry into the eCRF by using an algorithm which generates a random patient 
number without any indication of the patient, centre or country. This anonymization will be maintained in the database 
used for statistical analysis. The patient will be informed of this data collection according to applicable regulations. 
 
 

 
 
 
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1 
BACKGROUND AND RATIONALE 
 
Globally, colorectal cancer (CRC) is the third most common cancer in men and women, with an 
estimated 1.4 million new cases and 694,000 deaths in 2012; the majority of which occur in developed 
countries. In Europe, CRC is the second most common cancer, with an estimated 447,136 new cases 
and 214,855 deaths in 2012.1 Approximately one-quarter of patients with CRC have metastatic 
disease at the time of initial diagnosis and half of the patients develop metastatic disease following 
their initial diagnosis.2 
 
Metastases in CRC can be synchronous (detected prior/during surgery of the primary tumor or within 
3 to 12 months following initial intervention) or metachronous (discovered more than 1 year after 
surgical resection of the primary tumor). Synchronous metastases are usually associated with a locally 
advanced CRC following a greater metastatic burden and a poor outcome.18 The most frequently 
involved organs in metastatic CRC (mCRC) are the liver, peritoneum, lungs, bone and brain. The 
liver is often the single site of metastasis in CRC at the time of initial diagnosis (20% to 25% of cases) 
or after resection of the primary tumor (40% of cases).19 Peritoneal metastases are detected in 4% to 
19% of patients after surgical resection of the primary tumor, and have survival rates of 5-24 
months.20 Lung metastases occur in 10% to 30% of patients at 5-60 months after resection of the 
primary tumor.21 The incidence of bone metastases in CRC varies from 6% to 10%, with a median 
time of detection of 11-21 months after resection of the primary tumor.22 Brain metastases occur in 
2% to 12% of CRC patients during the course of the disease, with a median survival rate ranging from 
2.8 to 6 months without surgery and from 6 to 10 months after metastatic resection.23 Recent research 
suggests that certain gene mutations, such as Kirsten Rat Sarcoma Viral Oncogene (KRAS), B-Raf 
proto-oncogene (BRAF), phosphatidylinositol 3-kinase catalytic subunit (PIK3CA), and 
Neuroblastoma RAS viral oncogene homolog (NRAS) oncogenes, may affect the metastatic behavior 
of tumors and the patterns of metastatic spread.  
 
Treatment options for mCRC patients 
 
First-line treatment in patients with mCRC includes a combination of chemotherapy regimens and 
biological agents.3 4 Systemic anti-cancer therapy (SACT) is the main treatment option where 
combination chemotherapy remains the consensus standard of care. Current guidelines advocate the 
doublet combinations with oxaliplatin (5-fluorouracil [5-FU], leucovorin, and oxaliplatin 
[FOLFOX]) or irinotecan (5-FU, leucovorin, and irinotecan [FOLFIRI]) based regimens.2 These 
regimens are shown to be superior to combination of 5-FU and folinic acid alone.24 
 
Targeted therapy, including vascular endothelial growth factor (VEGF) inhibitor benvacizumab or 
epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab and panitumumab), is 
currently recommended by clinical guidelines as selective addition to the chemotherapy regimens, 
taking into account patient’s RAS status.2 Bevacizumab, when given in combination with 
chemotherapy has shown to significantly improve overall survival (OS) compared to chemotherapy 
alone.5 6 The survival benefit was retained in patients who continued using bevacizumab as a 
combination therapy, beyond first-line progression.7 Other biological agents such as cetuximab and 
panitumumab, both of which are EGFR monoclonal antibodies, have demonstrated benefits in 
survival, progression free survival (PFS) and response rate when used as first-line treatment of 
patients with wild-type KRAS (KRASwt) tumors in combination with FOLFIRI and FOLFOX when 
compared to chemotherapy alone, but not with other oxaliplatin-based regimens such as FLOX 

 
 
 
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(combination of fluorouracil, leucovorin and oxaliplatin) and CAPOX (combination of capecitabine 
and oxaliplatin) .3 8  
 
B-Raf proto-oncogene mutant colorectal cancer  
 
BRAF encodes a serine/threonine protein kinase belonging to the RAS/RAF/mitogen activated 
protein kinase (MEK)/extracellular signal-regulated kinase (ERK) kinase pathway that has been 
implicated in pathophysiology proliferation, invasion, and metastasis in CRC.25 Approximately 5% 
to 15% of CRC patients have a mutation in the BRAF gene resulting in a valine-to-glutamate change 
at the residue 600 (V600E), which is nearly always mutually exclusive with the RAS mutation.6 9 26 
27 Multiple clinical trials suggest that BRAF mutation is a poor prognostic factor for mCRC.10 12 28 29  
 
Metastatic CRC patients with BRAF mutation have median OS of 10 to 15 months compared to 21 
to 35 months for patients with BRAF wild-type (BRAFwt) tumors.11-13 Patients with BRAF mutation 
have more adverse histologic features, such as lymphatic invasion, mean number of lymph node 
metastases, perineural invasion, and high tumor budding.30 Studies suggest that BRAF mutant mCRC 
is less likely to present liver-limited metastasis and is associated with increased incidence of 
peritoneal and distant lymph node involvement.12 29 31 32 This pattern of metastatic spread in BRAF 
mutant mCRC may contribute to the poor outcomes.12 33 
 
Considering the prognostic importance of BRAF mutation, the European Society of Medical 
Oncology and the National Comprehensive Cancer Network panel have recommended assessment of 
BRAF mutation status alongside RAS gene mutation status in mCRC patients.2 34 
 
Treatment options for BRAF mutant mCRC patients 
 
To date, there is no agent specifically indicated for patients with BRAF mutant mCRC. Limited data 
from unplanned retrospective analysis of patients receiving first-line treatment have produced 
inconclusive results.3 Because RAS and BRAFV600E mutations are almost always mutually exclusive, 
BRAF mutant mCRC patients are typically treated with standard of care regimens for KRASwt 
tumors, i.e., either oxaliplatin- or irinotecan-based SACT, with or without bevacizumab (anti-VEGF 
antibody) or cetuximab (anti-EGFR antibody) but with substantially poorer outcomes than patients 
with BRAFwt tumors.  
 
A retrospective study reported no differences in PFS irrespective of whether oxaliplatin- or 
irinotecan-based chemotherapy was administered in the first-line setting in patients with BRAF 
mutant CRC (6.4 versus 5.4 months; P=0.99).14 There is insufficient evidence to conclude that BRAF 
is a predictive biomarker for irinotecan or oxaliplatin, as patients benefit regardless of their mutational 
status. 
 
With regards to targeted agents, in a post-hoc analysis of a Phase 3 trial comparing bevacizumab-
based chemotherapy with chemotherapy alone, it was reported that BRAF mutation status predicted 
poor survival overall but had no impact on bevacizumab benefit.35 BRAF mutation status predictive 
value for response and benefit from EGFR-directed treatments, such as cetuximab, remain 
controversial. 
 
Limited data from unplanned retrospective subset analyses of subjects with mCRC treated in the first-
line setting suggest that, although a BRAFV600E mutation confers a poor prognosis regardless of 

 
 
 
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treatment, subjects with disease characterized by this mutation may receive some benefit from the 
addition of cetuximab to front-line therapy.13 36 
 
Retrospective analyses of recent trials have suggested that BRAF mutations are not predictive of 
outcome with EGFR-directed therapies37 in certain settings whereas other analyses have suggested 
that cetuximab and panitumumab are most active in subjects with BRAFwt mCRC26 38. In a recent 
meta-analysis of 7 randomized controlled trials in which subjects received panitumumab or 
cetuximab in different lines of therapy, and with a range of background chemotherapy, no significant 
interaction was noted between the benefits of anti-EGFR therapy (measured as OS and PFS) and the 
presence of BRAF mutations. These results suggest that anti-EGFR therapy may have benefit for 
subjects with BRAFV600E CRC. 
 
In a retrospective analysis of the FIRE-3 trial data, the combination of cetuximab plus FOLFIRI, was 
shown to significantly improve the overall response rate (ORR) in patients with BRAF-mutated 
mCRC compared to bevacizumab plus FOLFIRI (52% versus 40%), although no difference in PFS 
or OS was noticed.39 
 
In the Phase III study TRIBE, BRAF-mutated mCRC patients treated with 5-FU, leucovorin, 
irinotecan (FOLFOXIRI) plus bevacizumab showed a trend towards improved OS with 19.0 months 
compared with 10.7 months (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.24–1.20) and 
PFS (HR 0.57, 95% CI 0.27–1.23) compared with FOLFIRI plus bevacizumab among the 28 patients 
with BRAF mutation.16 FOLFOXIRI plus bevacizumab, however, significantly increases the 
incidence of grade 3 or grade 4 adverse events (AEs) in mCRC patients compared to FOLFIRI plus 
bevacizumab.17  
 
Novel combination approaches 
 
BRAF-mutated mCRC is resistant to single-agent RAF inhibitor, such as vemurafenib, with a low 
ORR of around 5%.40 41 Dual BRAF plus MEK inhibition does not provide substantial activity 
either.42 
 
A 35% response rate observed in a Phase Ib study combining vemurafenib with irinotecan and 
cetuximab in patients with BRAF-mutated metastatic colorectal cancer and advanced cancers led the 
Southwest Oncology Group to set up a randomized controlled trial in BRAFV600E mutant mCRC, 
evaluating irinotecan plus cetuximab with or without vemurafenib.43 Median PFS was 4.4 vs 2.0 
months (HR 0.42; 95% CI 0.26–0.55; P<0.001) and response rates were 16 vs 4% (P=0.09) while 
67% achieved disease control, compared to 22% for the three-drug regimen versus the two-drug 
regimen. Safety was regarded as manageable however neutropenia, anemia and nausea occurred more 
frequently in the arm that included vemurafenib.44 
 
Cancer cells with BRAF mutations are highly dependent on MEK/ERK signaling. Recent studies 
have focused on novel targeted therapy combinations to produce more durable responses to BRAF 
inhibitor. An in vitro study suggested that the combination of BRAF and EGFR could produce 
sustained suppression of MEK-dependent activation of mitogen activated protein kinase signaling 
and overcome EGFR-driven resistance.45 Preliminary results from several clinical trials evaluating 
the combination of BRAF and EGFR inhibitors suggest response rates ranging from 4% to 23%.32 42 
46-49  
 

 
 
 
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The Phase III BEACON CRC, is a randomized, open label, 3-arm study with the objective to evaluate 
the combination of encorafenib, and cetuximab with or without binimetinib vs FOLFIRI, or irinotecan 
plus cetuximab as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 
or 2 prior regimens in the metastatic setting.  
In this randomized clinical trial, 665 patients with BRAF V600E–mutant metastatic colorectal cancer 
that had progressed after one or two prior regimens in the metastatic setting were randomized to 
receive encorafenib/binimetinib/cetuximab, encorafenib/cetuximab, or the investigator’s choice of 
irinotecan or leucovorin, fluorouracil, and irinotecan (FOLFIRI) and cetuximab. 
The treatment combination resulted in a median overall survival of 9.0 months (95% confidence 
interval [CI] = 8.0–11.4 months) in patients treated with the triplet compared to 5.4 months (95% CI 
= 4.8–6.6 months) for the control regimens (hazard ratio = 0.52, 95% CI = 0.39–0.70; P < .0001). 
The objective response rate for the targeted triplet therapy was 26%, compared to 2% for the controls. 
The triplet combination was generally well tolerated with no unexpected toxicities. Grade 3 or higher 
adverse events were seen in 58% of patients on triplet treatment, 50% of those in the doublet group, 
and 61% of those in the standard therapy group. 
50 
Data from the BEACON CRC trial are being used to support regulatory approval of the triplet 
combination in BRAF V600E–mutant metastatic colorectal cancer, and BRAF inhibitor–based 
treatment has recently been included as a treatment option in the National Comprehensive Cancer 
Network© (NCCN©) Guidelines for colon and rectal cancers in the United States. 
In light of the early clinical data of the Phase III BEACON CRC study, a Phase II, open label, single-
arm, multi-center study, the ANCHOR CRC study, is currently ongoing to evaluate the antitumor 
activity of the Triplet combination of encorafenib, binimetinib and cetuximab by assessing the 
confirmed ORR in adult subjects  with previously untreated BRAFV600E mutant mCRC, where a total 
of 90 subjects will be enrolled and the study treatment will be administered in 28-day cycles until 
disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer 
therapy or death. After discontinuation of the study treatment, subjects will be followed for survival 
until 1 year after the start of the treatment of the last subject enrolled. 
 
STUDY RATIONALE 
 
The presence of a BRAFV600E mutation is considered a marker of poor prognosis in patients with 
mCRC, and findings from clinical trials have largely remained inconclusive regarding the efficacy of 
first-line treatment options for BRAFV600E mutant mCRC patients. In the absence of a 
targeted/specific treatment for BRAFV600E mutant mCRC, treatment practices can vary based on local 
practices and guidelines. There is, therefore, an unmet need to document the current practices for 
first-line treatment of BRAFV600E mutant mCRC, and their effectiveness and safety in a real-world 
setting.  
 
This real-world, multicenter, non-interventional study (NIS) will describe the treatment patterns, 
effectiveness and safety of current treatment regimens of BRAFV600E mutant mCRC patients in 
Europe, with the aim to put the clinical study findings of the ongoing Phase 2, single-arm, open label 
trial (ANCHOR) into context of the current treatment landscape excluding investigational therapies. 
Additionally, the NIS output may be used to support future health technology assessment submissions 
and publications.  
 

 
 
 
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2 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
 
The primary objective is to describe first-line treatment patterns in BRAFV600E mutant mCRC patients. 
2.2 
SECONDARY OBJECTIVES 
 
The secondary objectives are: 
 
1. To describe the baseline demographic and clinical profiles of BRAFV600E mutant mCRC 
patients receiving first-line treatment, overall and by treatment regimen  
2. To describe PFS in BRAFV600E mutant mCRC patients receiving first-line treatment, overall 
and by treatment regimen 
3. To describe OS in BRAFV600E mutant mCRC patients receiving first-line treatment, overall 
and by treatment regimen 
4. To describe treatment response in BRAFV600E mutant mCRC patients receiving first-line 
treatment, overall and by treatment regimen 
5. To describe treatment duration (i.e., time from treatment initiation to treatment cessation) in 
BRAFV600E mutant mCRC patients receiving first-line treatment, overall and by treatment 
regimen 
6. To describe BRAF mutation testing procedure and timing in regards with the first-line 
treatment in BRAFV600E mutant mCRC patients 
7. To describe the frequency of relevant AEs in BRAFV600E mutant mCRC patients receiving 
first-line treatment, overall and by treatment regimen. Relevant AEs are defined as AEs 
leading to first-line treatment switch, dose adaptation or discontinuation, or leading to death. 
 
2.3 
EXPLORATORY OBJECTIVES 
 
The exploratory objectives are: 
 
1. To describe the reason(s) for treatment discontinuation or switch in BRAFV600E mutant mCRC 
patients starting first-line treatment 
2. To describe the treatment(s) received, by line of treatment (LOT), after first progression in 
BRAFV600E mutant mCRC patients 
 
3 
RESEARCH METHODS 
3.1 
STUDY DESIGN 
 
This retrospective, multicenter longitudinal study will be conducted in Europe to characterize the 
treatment patterns, effectiveness and safety of current treatment regimens in BRAFV600E mutant 
mCRC patients. The observation period is earlier than the date of inclusion of the patient in the study 
and the study will not provide or recommend any treatment or procedure; patients will continue to be 
treated as per the routine practice.  
For eligible patients, relevant data will be abstracted from their medical records and entered into a 
centrally-designed electronic case report form (eCRF) in anonymized form. No additional clinic visits 

 
 
 
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or examinations, laboratory tests or procedures are mandated or recommended as part of this study. 
Treatment patterns, effectiveness and safety outcomes will be collected using data generated as part 
of the routine clinical practice. 
 
This multicenter, non-interventional study entails review of medical records of adult patients who 
initiated first-line treatment for mCRC between January 1st, 2016 and December 31st, 2018 (both 
dates inclusive) and with a diagnosis of BRAFV600E mutant mCRC discovered a priori or a posteriori 
to first-line treatment initiation. The target countries for patient enrollment will include Germany, 
France, Italy, UK, Spain, Belgium, Austria and the Netherlands. Approximately 300 adult patients 
(≥18 years) from a mix of academic and non-academic sites will be enrolled.  
 
In order to obtain a representative sample of real-world patients undergoing treatment for BRAFV600E 
mutant mCRC in Europe, an evidence-based approach will be adapted to (1) find and select sites 
within a country that meet the right criteria for success and for representability (taking into account 
various site-level factors such as center type [public/private, academic/non-academic], center size, 
center practice, etc.), and (2) identify and mitigate risks that could impact patient enrollment. A 
strategy plan for site selection will be created to ensure site representativeness, and will describe all 
processes related to the representativity survey. The site survey involving a large number of centers 
managing CRC patients will be conducted prior site selection.   
 
A Scientific Committee will regularly oversee the conduct of the study to provide scientific advice 
and guidance with regard to the study methodology, study results and related communication.  
 
3.2 
POPULATIONS 
 
3.2.1 Source population (if applicable) 
 
Not applicable. 
 
3.2.2 Study population  
 
The study population will include mCRC patients harboring a BRAFV600E mutation determined by a 
local assay.at any time during the disease management, residing in one of the target countries 
(see Section 3.1 for target countries) and initiating first-line treatment between January 1st, 2016 and 
December 31st, 2018 (both days inclusive).  
 
3.2.2.1 Inclusion criteria 
 
Patients will be eligible for inclusion if they fulfil all of the following criteria: 
 
• Male or female aged ≥18 years at diagnosis of mCRC  
• Diagnosis of histologically or cytologically confirmed CRC that is metastatic and 
unresectable  
• Presence of BRAFV600E mutation in tumor tissue, as confirmed by a local assay  

 
 
 
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• Initiated first-line treatment with drugs registered for mCRC in the respective country at the 
time of treatment between January 1st, 2016 and December 31st, 2018 (both days inclusive) 
• Provision of informed consent or non-opposition to the patient (or next of kin, if applicable) 
for the use of data, according to local regulations 
 
3.2.2.2 Exclusion criteria 
 
Patients will be excluded from the study if they fulfil any of the following criteria: 
 
• Patients with another concomitant cancer at the time of diagnosis* 
• Patients participating in interventional trials on investigational drugs at the time of initiation 
of first-line treatment 
 
* Except for non-metastatic non-melanoma skin cancers, or in situ or benign neoplasms; a cancer will 
be considered concomitant if it occurs within 5 years of mCRC diagnosis. 
 
For patients who fulfil the eligibility criteria, but do not participate in the study (non-consent, non-
inclusion because of patient selection process), a screening log will be maintained (subject to local 
regulations) to record the reason for non-participation, gender, age at diagnosis (pre-defined 
categories), first line treatments received (if available) and survival status. 
 
3.2.3 Participants recruitment and follow-up 
 
3.2.3.1 Participant selection process 
 
In each participating center, all eligible patients’ medical records will be identified. The following 
steps will be followed for patient selection: 
• Participating sites (wherever feasible) will be asked to list exhaustively all eligible patients in 
an pseudonymized way 
• The pseudonymized patient list will then be given a number of enrollment 
• Medical records will be abstracted by the site staff until reaching the targeted number of 
patients per site or reaching the end of the list 
• The patient will be informed of this data collection according to applicable regulations. If the 
patient has opposed to data collection, the reason will be noted and the next record from the 
enrollment list will be identified.  
 
3.2.3.2 Participant data collection 
 
Patients data will be collected from the start of first-line treatment for mCRC until the end of the 
observation period (date of death or last day of study observation period, ie. January 31st, 2020). 
Patients lost to follow-up will be censored at the date of their last available medical record or the date 
when they were last known to be alive. The data will be anonymized during the entry into the eCRF 
by using an algorithm which generates a random patient number without any indication of the patient, 
centre or country. This anonymization will be maintained in the database used for statistical analysis.  
 

 
 
 
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3.3 
STUDY OUTCOMES 
 
3.3.1 Primary endpoint   
 
The primary endpoints are first-line SACT treatment patterns in BRAFV600E mutant mCRC patients, 
described by: 
• Agent or combination of agents received 
• Duration of treatment 
• Maintenance therapy (if any) 
 
The first-line SACT regimen(s) will be described from the time of treatment initiation (for mCRC) 
until the time of first documented disease progression, treatment discontinuation or switch, whichever 
is earlier.  
 
LOT definition will be connected to treatment progression. The LOT will be defined using a data-
driven approach. In the SAP an algorithm for LOT definition will be specified, which will consider 
the specific treatment(s) received (stop and start dates), progression (as recorded in the patient 
medical record, including date), documented reasons for discontinuation of treatments and gap(s) 
between subsequent treatment regimens.  
 
3.3.2 Secondary endpoints 
 
1. Description of the demographic and clinical profile of patients at the time of treatment 
initiation (for mCRC) 
2. PFS, defined as the length of time between initiation of first-line treatment for mCRC and the 
first documented disease progression (if disease progression is not well documented in a 
patient’s medical record, then the start of the subsequent LOT may be considered as proxy for 
disease progression) or death (whichever is earlier) 
3. OS, defined as the length of time between first-line treatment initiation (for mCRC) and death 
(due to any cause) 
4. ORR, defined as complete response (CR) or partial response (PR), described at the end of 
first-line treatment for mCRC 
5. Time to treatment cessation, defined as the length of time between initiation of firstline 
treatment for mCRC and documented disease progression (or start of subsequent LOT, if 
disease progression is not well documented in the patient medical record), treatment 
discontinuation or switch to another treatment (defined as change from 1 treatment regimen 
to another treatment regimen, e.g. change from FOLFOX-based regimen to FOLFIRI or 
irinotecan-based regimen) 
6. Time to BRAF mutation testing since mCRC diagnosis and since first-line treatment for 
mCRC, and description of testing procedures 
7. Frequency of relevant AEs during first-line treatment for mCRC. Relevant AEs are defined 
as AEs leading to first-line treatment switch, dose adaptation or discontinuation, or leading to 
death. 
 
 
 
 

 
 
 
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3.3.3 Exploratory endpoints 
 
1. Description of reasons for treatment discontinuation or switch at the end of first-line treatment 
for mCRC 
2. Second (and subsequent) line treatment patterns in BRAFV600E mutant mCRC patients, 
defined as treatments received after disease progression following first-line treatment, and 
described by: 
• Agent or combination of agents received 
• Duration of treatment 
 
3.3.4 Exposure definition and measurement 
 
This is a NIS of real-world treatment practices in the adult BRAFV600E mutant mCRC patient 
population. This protocol does not recommend the use of any specific treatments, and no study 
medication will be provided as part of participation in the study.  
 
The exposure of interest will be the first-line SACT (monotherapy, doublet therapy, or triplet therapy 
with or without a targeted therapy [either VEGF inhibitor or EGFR inhibitor]) for the treatment of 
BRAFV600E mutant mCRC. Treatment patterns will be described by LOT. 
 
Line of therapy will be defined as follows: 
• First LOT: the start of first LOT will be defined as the first administration of SACT therapy 
after diagnosis of mCRC to the date of first documented disease progression 
• Second and subsequent LOTs: mCRC treatment(s) received on or after the date of 
documented disease progression following previous LOT to the date of documented disease 
progression on or after the current LOT 
• In the absence of information on disease progression, an algorithm will be specified in the 
SAP based on the specific treatment(s) received (stop and start dates), progression (as 
recorded in the patient medical record, including date), documented reasons for 
discontinuation of treatments and gap(s) between subsequent treatment regimens. 
 
The exposure variables of interest are described in Table 1. 
 

 
 
 
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Table 1 
Study Exposure 
 
Exposure 
Definition and Measurements 
 
Systemic 
anti-cancer 
therapy (SACT)1 for mCRC 
• 
Details on SACT (by LOT) 
o 
LOT2 (e.g., first, second, third, etc.) 
o 
Type of treatment3 (i.e., monotherapy, doublet therapy, triplet therapy) 
o 
Agents used 
▪ 
Chemotherapy regimens (e.g., FOLFOX, FOLFIRI, FOLFOXIRI) 
▪ 
Targeted agents (e.g., benvacizumab, cetuximab, panitumumab) 
▪ 
Duration of treatment: start date and stop date 
o 
Date of documented progression 
o 
Dates and reasons for treatment alteration (e.g., switch, discontinuation, 
dose escalation/reduction) 
o 
Maintenance therapy (if any) of first line treatment: name of agent(s); start 
date and stop date 
• 
Treatment response (as recorded in patient medical record by the treating physician) 
of first-line treatment of mCRC: type of response (CR, PR, PD); date recorded 
1 All SACT treatments received/prescribed for mCRC will be captured. 
2 LOT will be defined algorithmically, using a data-driven approach if disease progression is not well documented in the 
patient medical record. Details will be specified in the SAP. 
3 This will be a derived field, based on the SACT treatments received/prescribed. 
CR: complete response; FOLFOX:5-fluorouracil (5-FU), leucovorin, and oxaliplatin; FOLFIRI: 5-FU, leucovorin, and 
irinotecan; FOLFOXIRI: 5-FU, leucovorin, oxaliplatin, irinotecan; LOT: line of therapy; mCRC: metastatic colorectal 
cancer; PD: progressive disease; PR: partial response; SACT: systemic anti-cancer therapy  
 
3.3.5 Outcome variables and measurements 
 
Outcomes of interest are OS, PFS, and ORR of mCRC treatment. The study outcomes definitions and 
measurements are described in Table 2. 
 
Table 2 
Study Outcomes 
Outcome 
Definition and Measurement(s) 
Progression free survival (PFS)  
• 
PFS is defined as follows: 
o 
In patients where disease progression is well documented in medical 
record: length of time from start of first LOT to documented disease 
progression or death due to any cause, whichever occurs first.  
o 
In patients where disease progression is not well documented in medical 
record: length of time from start of first LOT to subsequent LOT1 or death 
due to any cause, whichever occurs first. 
• 
PFS will be calculated from the start date of LOT to the date of first 
documented disease progression (or start of subsequent LOT, as applicable) 
or date of death. 
• 
Patients with no disease progression (or death) will be censored at the earliest 
of: date of last medical record entry or last day of the observation period. 
• 
Disease progression will be considered present if best response to treatment 
is PD; and absent if best response to treatment is CR or PR. 
Overall survival (OS)  
• 
OS is defined as the length of time from first-line treatment initiation (for 
mCRC) to death (due to any cause). 
• 
OS will be calculated from the date of first-line treatment initiation fto the 
date of death. 

 
 
 
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Outcome 
Definition and Measurement(s) 
• 
If patients are confirmed to be alive, they will be censored at the earliest of: 
date of last medical record entry or last day of the observation period.  
Overall response rate (ORR) 
• 
ORR is defined as the number and percentage of patients whose tumor 
shrinks or disappears after first-line treatment (as available in the medial 
records from the time of treatment initiation until the first documented 
disease progression1).  
• 
ORR will be expressed as the number and percentage of patients with best 
response= CR or PR. The denominator will be total number of treated 
patients with no missing information for best response (patients with NE will 
be included in the denominator). 
Time to treatment cessation 
• 
Time to treatment cessation is defined as the length of time between initiation 
of first-line treatment and documented disease progression (or start of 
subsequent LOT, if disease progression is not well documented in patient 
medical record), treatment discontinuation or switch to another treatment 
(defined as change from 1 treatment regimen to another). 
• 
Time to treatment cessation will be calculated from the date of initiation of 
LOT to the date of disease progression, treatment discontinuation or switch. 
• 
Patients with no disease progression, treatment discontinuation or switch to 
another treatment will be censored at the earliest of: date of last medical 
record entry, last day of the observation period or date of death. 
Relevant Adverse events  
• 
Information on relevant AEs during the study period will be collected based 
on information available in the patient medical records.  
• 
Relevant AEs will be mapped into the (MedDRA) and grouped by SOC and 
PT.  
Relevant AEs are defined as AEs leading to first-line treatment switch, dose 
adaptation or discontinuation, or leading to death. 
Cause of death (for deceased 
patients) 
• 
The primary cause of death will be recorded as available in the medical 
record (cancer-related, non-cancer related, unknown/missing). 
Reasons 
for 
treatment 
discontinuation or switch 
• 
Reasons for treatment alteration, defined as treatment interruptions, switches 
and discontinuation, will be collected at the end of each treatment, based on 
information available in the patient medical records. 
1 For patients in whom disease progression is not well documented, the start date of subsequent LOT will be considered 
instead of the date of disease progression. Detailed derivation of LOT will be provided in the SAP. 
CR: complete response; ICD-10: International Classification of Diseases 10th Revision; mCRC: metastatic colorectal 
cancer; MedDRA: Medical Dictionary for Regulatory Activities; LOT: line of therapy; ORR: overall response rate; OS: 
overall survival; PD: progressive disease; PFS: progression free survival; PR: partial response; PT: preferred term; SOC: 
system organ class. 
 
3.3.6 Confounding variables 
 
Multivariable analysis will be performed adjusting for baseline covariates in this study. Covariates of 
interest include patient demographics and clinical profile, and treatment history of CRC, which will 
be assessed before or at the time of mCRC diagnosis. The baseline covariates are summarized in 
Table 3. 
 
Table 3 
Study Covariates 
Covariates 
Definition  
Age 
Age in completed years at the time of first-line treatment for mCRC (will be 
computed from the date of birth and date of diagnosis of mCRC) 
Gender 
Male, female 
Weight 
Weight in kilograms 
Height 
Height in centimeters 

 
 
 
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Covariates 
Definition  
BMI (kg/m2) 
Calculated using weight and height values 
BMI categories: <18.5, 18.5 - <25, 25 - <30, 30 - <35, ≥35 and unknown/missing 
Tests/investigations 
related 
to 
mCRC diagnosis/treatment 
• 
Records (along with the relevant test dates) of the radiologic, histologic and 
laboratory tests during the time of diagnosis and follow-up will be extracted 
based on available information in patient medical records. 
o 
Tumor Biomarker Assessments (tumor sample or ctDNA): BRAF; 
RAS; MSI; MMR 
o 
Blood 
biomarker 
assessments: 
C-reactive 
protein;  
carcinoembryonic antigen; carbohydrate antigen 19-9 
TNM stage at initial diagnosis  
• 
Tumor/node/metastasis (TNM) stage (I, II, III, IV) at the time of initial 
diagnosis of CRC will be abstracted based on available information in patient 
medical records. 
Histology and location of the 
primary tumor at initial diagnosis 
• 
Histology at the time of initial diagnosis of CRC will be abstracted based on 
available information in patient medical records:  
o 
Adenocarcinoma  
o 
Other carcinoma 
• 
Location of the primary tumor: 
o 
colon left 
o 
colon right 
o 
colon transverse 
o 
rectum 
Metastasis status 
 
Metastasis status will be abstracted based on available information in patient 
medical records:  
o 
Synchronous or Metachronous 
o 
Location: Liver, lungs, lymph nodes, bone, peritoneum, CNS, other 
location(s), unknown 
o 
Number of metastatic sites 
Treatment history 
Prior medications/therapies for CRC (where available in patient medical records): 
• 
Radiation therapy: site of radiation, start and stop date, intent 
• 
Chemoradiation: concurrent or sequential, regimen, start and stop date 
• 
Surgery: date, location, intent   
Comorbidity profile 
Comorbidities of interest: ischemic cardiac disorder, congestive heart failure, 
peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, 
diabetes mellitus with end-organ damage, moderate or severe renal disease, 
moderate or severe liver disease, rheumatic or connective tissue disease, acquired 
immunodeficiency syndrome (AIDS), treated hypertension, heart rhythm 
disorder, others 

 
 
 
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Covariates 
Definition  
Performance status 
• 
Performance status will be evaluated by ECOG: 
o 
0=Fully active, able to carry on all pre-disease performance without 
restriction 
o 
1=Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house work, 
office work 
o 
2=Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
o 
3=Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
o 
4=Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair 
ECOG performance status will be collected at mCRC diagnosis 
Biological parameters 
• 
Routine laboratory tests at the mCRC diagnosis 
BMI: body mass index; BRAF: B-Raf proto-oncogene; CNS: central nervous system; CRC: colorectal cancer; CRP: C-
reactive protein; ctDNA: Circulating tumor DNA; ECOG: Eastern Cooperative Oncology Group; LOT: line of therapy; 
mCRC: metastatic colorectal cancer; MSI: microsatellite instability; MMR: mismatch repair; TNM: Tumor, Node, 
Metastasis.  
 
3.4 
DATA SOURCES AND COLLECTION 
 
The source of collected data will be all elements that can constitute a reliable source of patient-level 
information and that are available at the site. This includes data available in the patients’ medical 
charts (e.g., consultation notes, discharge summaries, laboratory test results, recorded prescription 
data and any other documentation of communication with other health care providers). The site 
investigator will be responsible for ensuring that all the required data is collected and entered into the 
eCRF. 
 
The data collection schedule is presented in Table 4.  
 
 

 
 
 
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Table 4 
Data Collection Schedule 
Data collection 
Date 
of 
enrollment/Dat
a abstraction 
Data 
at 
CRC/mCRC 
diagnosis/Initiatio
n 
of 
first-line 
treatment 
Data 
at 
observational 
period 3 
Discontinu
ation 
Informed consent 1 at NIS entry 2, where 
applicable 
X 
 
 
 
Demographics (age at diagnosis, gender, 
weight, height) 
 
X 4, 
 
 
Diagnosis details (date of diagnosis of 
CRC and mCRC, TNM stage, histology, 
primary tumor location) 
 
X 4,5 
 
 
Performance status: ECOG 
 
X 4 
 
 
Comorbidities 
 
X 4 
 
 
Metastasis details (location, number of 
metastatic sites)  
 
X 4 
 
 
Test 
(tumor 
and 
blood 
biomarker 
assessment, 
radiological 
tests, 
colonoscopy, other laboratory tests) 
 
X 6 
X 6 
 
Local BRAF mutation testing (specimen 
type, date of specimen collected/received, 
date of results reported, and results with 
test type/name) 
 
X 6 
 
 
Prior 
medications/therapies/procedures 
for treatment of CRC 
 
X 
 
 
Systemic anti-cancer therapies for mCRC 
(agent name(s), start date and stop date,  
duration and number of treatment cycles, 
maintenance) 
 
 
X 7 
 
Treatment 
alteration 
(e.g., 
switch, 
discontinuation, dose reduction); dates and 
reasons for treatment alteration 
 
 
X 8 
 
Treatment response for each line of 
treatment treatment: type of response (CR, 
PR, PD); date recorded 
 
 
X  
 
Survival status and date of death (if 
applicable) 
 
 
X 
 
Cause of death (if applicable) 
 
 
X 
 
Relevant AEs  
 
X 8 
X 8 
X 8 

 
 
 
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1. 
Informed consent should be obtained prior to any data collection from the patient (or the patient’s legally authorized 
representative), where required by local regulations. 
2. 
Reason for non-participation, gender, age at diagnosis, first line treatments received (if available) and survival status  
will be collected in the NIS screening log for patients who will not consent to participate in this study, if local 
regulation permits. 
3. 
Observational period: patients will be followed from the start of first-line treatment for mCRC and followed until 
the end of the observation period. Patients lost to follow-up will be censored at the date of their last available medical 
record or the date when they were last known to be alive. 
4. 
Data to be collected at the time of mCRC diagnosis. 
5. 
Data to be collected at the time of initial diagnosis of mCRC/CRC. 
6. 
Information on routine laboratory tests will be collected at the time of  mCRC diagnosis; information on other tests 
(including BRAF mutation) and assessments can be captured throughout the observation period. 
7. 
Data on number of treatment cycles and maintenance therapy to be collected for first-line therapy only. 
8. 
Data to be collected for first-line therapy only. 
AE: adverse event; CR: complete response; CRC: colorectal cancer; ECOG: Eastern Cooperative Oncology Group; 
mCRC: metastatic colorectal cancer; NIS: non-interventional study; PD: progressive disease; PR: partial response; 
TNM: Tumor, Node, Metastasis. 
 
3.5 
STUDY SIZE 
 
The primary objective of this NIS is to assess the treatment patterns of BRAFV600E mutant mCRC 
patients. The sample size was determined based on the precision with which the primary objective 
could be achieved. Precision estimates were calculated around percentages ranging from 1% to 20% 
for sample sizes ranging from 200 to 1000 (Table 5). The range of proportions was determined based 
on projected estimates of patient share as per different regimens in first-line therapy in the UK, 
Germany, France, Spain, and Italy using Oncology Dynamics data which projected proportions of 
different lines of therapy between 1% to 21%.  
 
Table 5 
Precision estimates for a range of proportions and cohort sizes 
Proportion 
Sample size 
200 
300 
400 
500 
600 
700 
800 
900 
1000 
1% 
±1.38% 
±1.13% 
±0.98% 
±0.87% 
±0.80% 
±0.74% 
±0.69% 
±0.65% 
±0.62% 
5% 
±3.02% 
±2.47% 
±2.14% 
±1.91% 
±1.74% 
±1.61% 
±1.51% 
±1.42% 
±1.35% 
10% 
±4.16% 
±3.39% 
±2.94% 
±2.63% 
±2.40% 
±2.22% 
±2.08% 
±1.96% 
±1.86% 
15% 
±4.95% 
±4.04% 
±3.50% 
±3.13% 
±2.86% 
±2.64% 
±2.47% 
±2.33% 
±2.21% 
20% 
±5.54% 
±4.53% 
±3.92% 
±3.51% 
±3.20% 
±2.96% 
±2.77% 
±2.61% 
±2.48% 
 
A sample size of 300 patients will be able to measure treatment regimens prescribed to 5%, 10%, and 
20% patients with a precision of ± 2.5%, ± 3.4%, and ± 4.5%, respectively. This was considered 
adequate to meet the descriptive objectives of this study. 
 
 

 
 
 
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3.6 
Personal data mapping 
 
With regards to the EU Reg n°2016/679 on protection of personal data : 
• all collected data are entered pseudonymously into the eCRF and will be anonymized during 
the database lock. 
• the storage place during the study is predefined as follow: electronic data capture (EDC) of 
the CLINFILE company, servers located in France at the HDS-certified hosting provider, 
Cegedim. 
• the data will be stored during the whole study duration in EDC. At the end of the study, 
CLINFILE will transfer the anonymized database onto a media support (CD/DVD) and then 
delete the database from Cegedim’s servers. The sponsor will archived the media support 
during 10 years after the database transfer. 
 
 
3.7 
DATA MANAGEMENT 
 
All medical data will be confidential. According to the European Union General Data Protection 
Regulation 2016/679, sponsoring pharmaceutical company acting as data controller will ensure 
information of the patients about the use of their health data in completely anonymized form. He will 
also inform the patient that the local care team will keep an identification record of their data entry 
for a short period of time only and that it will not be possible to exercise their rights laid down in the 
GDPR (notably article 15-20) after anonymization by destruction of this record.   
 
All data will be collected and entered directly into the EDC system in an anonymyzed way. All 
participating sites will have access to the data entered regarding the individual site’s own enrolled 
patients. All sites will be fully trained on using the on-line EDC, including eCRF completion 
guidelines and help files. Sites will be responsible for entering extracted patient data into a secure 
online EDC database via the eCRF. Investigators and data entry staff will be able to access their 
account with a username and password. All eCRFs should be completed by designated, trained 
personnel or by the study coordinator, as appropriate. In all cases, the eCRF should be reviewed, 
electronically signed and dated by the Principal Investigator. All changes or corrections to eCRFs 
will be documented in an audit trail and an adequate explanation for such changes or corrections will 
be required. The data will be anonymized during the entry into the eCRF by using an algorithm which 
generates a random patient number without any indication of the patient, centre or country. In order 
to ensure data quality, an enrollment record will be maintained at the site until the eCRFs have been 
remotely monitored and validated. Upon database lock, the enrollement record will be destroyed by 
the care team, rendering the data completely anonymous. 
A data management plan, aligned with the study design, will be created before the start of data 
collection and will describe all functions, processes, and specifications for data collection, cleaning 
and validation to ensure that the data are as clean and accurate as possible when presented for analysis. 
 
 
 
 
 

 
 
 
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3.8 
DATA ANALYSIS 
 
3.8.1 General considerations 
 
All computations and generation of tables, listings and data for figures will be performed using SAS® 
version 9.2 or higher (SAS Institute, Cary, NC, USA). Statistical analyses will be fully described in 
a written Statistical Analysis Plan (SAP), which will be prepared before database lock. The SAP will 
detail the most appropriate statistical methodology and analyses to be performed in accordance with 
the study design and objectives.  
The Full Analysis Set (FAS) containing all patients who fulfil the eligibility criteria, will be used for 
this study. If a patient withdraws consent, the patient’s data collected before the consent withdrawal 
will remain in the dataset. Patients in the FAS will also be included in the safety analysis set. 
 
The study endpoints will be analyzed overall, by country and by pre-defined subgroup(s) of interest 
(e.g., age, gender, primary tumor location, number of metastatic organs). Further details will be 
provided in the SAP. 
 
Analyses will be descriptive in nature, as no hypothesis will be tested. Data will be analyzed according 
to the complete case approach, where patients with missing data for relevant variable(s) will be 
excluded. 
 
Categorical variables will be summarized by frequencies and percentages. Continuous variables will 
be summarized by descriptive statistics (mean, and standard deviation, median, 25th and 75th 
percentiles, minimum and maximum). The number of missing observations for each variable will also 
be reported. 
 
3.8.2 Primary analyses 
 
The first-line treatment patterns of patients, including the regimen received,  duration of treatment, 
maintenance therapy (if any), and concomitant medications/therapies received, will be summarized 
using descriptive statistics. Ninety-five percent CIs will be calculated for point estimates, but no 
statistical adjustments will be made for multiple comparisons. 
 
3.8.3 Secondary analyses 
 
• Demographic and clinical profile 
 
Demographics and baseline clinical characteristics of patients (as outlined in Table 3) will be 
summarized using descriptive statistics. 
 
• Progression free survival 
 
Progression free survival is defined in Table 2. This will be assessed for first-line treatments and 
described graphically by Kaplan-Meier (KM) survival curves. Median PFS, 25th and 75th percentiles, 
and corresponding 95% CI will be reported. Cox regression analysis may be performed to adjust for 
predefined (baseline) covariates and HR and 95% CIs reported. 
 

 
 
 
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• Overall survival 
 
Overall survival is defined in Table 2. This will be described graphically by KM survival curves and 
median OS, 25th and 75th percentiles, and correspondent 95% CI reported. Cox regression analysis 
may be performed to adjust for predefined (baseline) covariates; HRs and 95% CIs will be reported. 
 
• Treatment response  
 
The category of objective response following treatment (CR, PR, and PD) will be summarized by 
first-line SACT treatments (monotherapy, doublet therapy, triplet therapy) and by treatment regimens 
using frequency tables with their associated 95% CIs. Additionally, ORR is defined in Table 2. 
Logistic regression may be used to adjust for predefined (baseline) covariates; odds ratios with 95% 
CIs will be reported. 
 
• Treatment duration (time to treatment cessation) 
 
Time to treatment cessation (defined in Table 2) will be assessed for first-line SACT treatments. This 
will be described graphically by KM survival curves. Cox regression may be used to adjust for pre-
defined (baseline) covariates; HRs and 95% CIs will be reported. 
 
• BRAF Mutation testing 
 
Time from metastatic diagnosis to BRAF mutation testing will be assessed in addition to the time 
from testing to first-line treatment, and all testing procedures will be summarized using descriptive 
statistics. 
 
• Safety analyses 
 
The number and percentage of patients who have at least one of the relevant AE during first-line 
treatment will be summarized.Clopper-Pearson (Exact) 95% CIs for the proportion will be 
constructed around the point estimate of the incidence. Tables with counts and frequencies of relevant 
AEs will be provided and summarized by MedDRA SOC and PT. 
 
3.8.4 Exploratory analyses 
 
• Reason(s) for treatment alteration 
 
The reasons for treatment alteration (dose change, interruptions, switches, discontinuation), as 
recorded in patient medical records, will be described using descriptive statistics.  
 
• Treatment patterns for second (and subsequent) LOT  
 
Second- (and subsequent-) line treatment patterns, in the subset of patients who progress beyond first-
line treatment, will be analyzed based on the methods described in primary analysis (Section 3.8.2). 
 
 
 

 
 
 
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3.8.5 Missing data 
 
Due to the nature of the study, missing data (i.e., data that are not collected or documented in the 
patient’s medical record or EMR) may be observed for some variables. In general, missing data will 
not be imputed (except for dates) and the data will be analyzed according to complete case approach. 
Partial dates will be imputed using the rules described in the SAP. 
 
3.9 
QUALITY CONTROL 
 
A study monitoring plan, including for-cause monitoring, that is appropriate for the study design will 
be developed and implemented. Data quality control (QC) will be performed remotely  and, where 
permissible according to local regulations, at the site level by qualified designated personnel under 
professional secrecy. The extent and nature of monitoring will be decided during the study planning 
based on design, complexity, number of subjects, number of sites, etc.  
 
During a site initiation call, the monitor will provide training on the conduct of the study to the 
investigator, co-investigator(s), and all site staff involved in the study. In order to ensure the integrity 
of the data, eCRFs will be remotely monitored and, where permissible according to local regulations, 
sites will be randomly visited for quality control. Site quality control, if performed, will be performed 
by the contractor to examine compliance with the protocol and adherence to the data collection 
procedures, to assess the accuracy and completeness of submitted clinical data, and to verify that 
records and documents are being properly maintained for the duration of the study.  
 
The monitor will close out each site after the last patient’s final data collection is completed, all data 
have been entered and all outstanding monitoring issues have been resolved or addressed. All 
monitoring procedures and frequency of monitoring visits will be described in the study monitoring 
plan. Monitor contact details for each participating site will be maintained in the Investigator Site 
File. 
 
In most cases, the source documents are contained in the patient’s medical record and data collected 
on the eCRFs must match the data in the medical records. All original source documentation is 
expected to be stored at the site for the longest possible time required by locally applicable 
regulations.   
 
Representatives of the Sponsor’s quality assurance unit/monitoring team and competent regulatory 
authorities must be permitted to inspect all study-related documents and other materials at the site, 
including the Investigator Site File and the completed eCRFs. Patients’ original medical records will 
only be examined if permitted by locally applicable regulations. Audits may be conducted at any time 
during or after the study to ensure the validity and integrity of the study data. 
 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating patients, a record of sent patient information letters 
or all original signed informed consent forms, if applicable. After the database lock, however the 
connection between patient identity and collected data will be destroyed. Copies of all CRFs, source 
documents and adequate documentation of relevant correspondence (e.g., letters, meeting minutes, 
telephone calls reports) should be retained by the investigator according to local regulations, or as 
specified in the study contract, whichever is longer. 

 
 
 
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Each site will receive a study site file at study initiation which contains all documents necessary for 
the conduct of the study and this should be updated throughout the study. This file must be available 
for review in the event the site is selected for monitoring, audits, or inspections and must be safely 
archived for at least 10 years after completing the participation in the study or as per local regulations, 
whichever is longer. In the event that archiving of the file is no longer possible at the site, the site will 
be instructed to notify the Sponsor. 
 
3.10 STUDY MANAGEMENT 
 
3.10.1 Sponsor 
 
Pierre Fabre Médicament will serve as the Sponsor of this study. It is the responsibility of Pierre 
Fabre to ensure proper oversight of the contract research organization (CRO) conducting protocol 
development, implementation and monitoring of the study and compliance with all applicable 
regulatory guidelines and laws. 
 
3.10.2 CRO responsible for the management of the study 
 
Clinact will serve as the CRO of this study. It is the responsibility of Clinact to develop the statistical 
analysis plan and clinical study reports, manage recruitment, training, monitoring, management of 
sites, EDC and data management and analysis under guidance, input, review, and approval of Pierre 
Fabre. 
 
3.10.3 Scientific Committee (SC) 
 
A scientific committee will be established before the study initiation. Three experts, including 2 
clinicians and 1 methodologist, will serve as members on this committee over the study period. The 
role of this committee will be (i) to validate the study documents (i.e. protocol & CRF), (ii) to validate 
the survey results and site selection, (iii) to validate study results and interpretation, and (iv) to be 
involved in the communication and publication plan. 
Three main meetings are planned during the study and remote meetings will be planned during the 
study conduct. More information regarding the roles and responsibilities of the SC , the timing of 
meetings, methods of providing information, frequency and format of meetings, will be detailed in the 
Charter. 
 
3.11 LIMITATIONS OF THE RESEARCH METHODS 
 
3.11.1 Selection bias 
 
Selection bias may arise if the study sample differs substantively from the underlying target 
population of patients with BRAFV600E mutant mCRC. To minimize selection bias, the eligibility 
criteria are selected to be as broad as possible, andall patients meeting the selection criteria will be 
enrolled consecutively.. Furthermore, to the extent possible, patients will be recruited from a diverse 
pool of clinical sites. Finally, where applicable, minimal de-identified information, including the 

 
 
 
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reason for non-participation, will be collected for patients who are not enrolled in the study to assess 
whether there may have any systematic differences between participant and non-participants.  
 
3.11.2 Information bias 
 
Inaccurate assessment of study variables may occur in observational research, especially in medical 
chart review studies. To minimize information bias, clear definitions of the variables of interest will 
be provided to ensure accurate assessment of the desired data elements, and detailed eCRF completion 
guidelines will be provided to the site staff to ensure accurate entry of data into the EDC. The eCRFs 
will include programmable edits to identify missing, out of range, illogical, or potentially erroneous 
data. All eCRFs will be completed by trained site personnel. In addition, routine monitoring will be 
conducted and source data verification may be performed to ensure the quality of the data collected. 
 
 
3.11.3 Follow-up bias 
 
Follow-up bias may occur when differences exist between study participants and patients lost to 
follow-up or discontinued. The study will be operationalized in such a way to minimize patient loss 
to follow-up through careful procedures that are minimally burdensome for the patients and the sites. 
 
 
4 
PROTECTION OF HUMAN SUBJECTS AND LOCAL REGULATORY ASPECTS 
4.1 
ETHICS 
 
To ensure the quality and integrity of research, this study will be conducted under the guidelines of 
good pharmacoepidemiology practices (GPPs) issued by the International Society for 
Pharmacoepidemiology (ISPE), the Declaration of Helsinki and its amendments, the EU General Data 
Protection Regulation (GDPR) and any applicable national guidelines. 
 
The investigator will be responsible for ensuring that the observational study will be performed in 
accordance with the protocol, and applicable regulatory and country-specific requirements. 
4.2 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD 
(IEC/IRB) 
 
Consistent with local regulations and prior to enrollment of patients at a given site, the study protocol 
will be submitted together with its associated documents (e.g., ICF) to the responsible institutional 
review board (IRB)/independent ethics committee (IEC) for its review. Before implementation of any 
substantial changes to the protocol, protocol amendments will also be submitted to the relevant 
IRB/IEC in a manner consistent with local regulations. Pertinent safety information will be submitted 
to the relevant IECs during the course of the study in accordance with local regulations and 
requirements. 
 
This study will be undertaken only after the IRB/IEC have given full approval of the final protocol, 
the ICF and applicable recruiting materials, and the Sponsor had received a copy of this approval. 
 
 

 
 
 
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4.3 
PATIENT INFORMATION 
 
For the patients who are alive at the time of data collection, information of the patient about use of 
their health data in completely anonymized form will be ensured by either sending an information 
letter or, if required, presenting an ICF, which must be signed by the patient (or the patient’s next of 
kin) before his or her participation in the study. The patient will also be informed that the local care 
team will keep a record of their data entry for a short period of time only and that it will not be 
possible to exercise their rights laid down in the GDPR (notably article 15-20) after anonymization 
by destruction of this record. For deceased patients, a waiver of informed consent/authorization will 
be requested from the relevant IRB/IEC, where applicable and in accordance with national 
regulations, for the collection of anonymized data.  
 
4.4 
PRIVACY OF PERSONAL DATA 
 
Confidentiality of patient records will be maintained at all times. All study reports will contain 
aggregate data only and will not identify individual patients, physicians, hospital sites or even 
countries. Medical record abstraction will only be performed after receiving the approval from an 
IRB/IEC or equivalent, as applicable by national regulations. At no time during the study will the 
Sponsor receive patients’ identifying information, except when it is required by regulations in case 
of reporting AEs.  
 
In order to maintain patient confidentiality, each patient will be randomly assigned a unique patient 
identifier upon study enrollment which will guarantee anonymisation of the collected data from the 
moment of data entry. All parties will ensure protection of patient personal data and will not include 
patient names on any study forms, reports, publications or in any other disclosures, except where 
required by law. In accordance with local regulations in each of the countries, patients will be 
informed about data handling procedures and asked for their consent, if applicable by national 
regulations. Data protection and privacy regulations will be observed in capturing, forwarding, 
processing, and storing patient data.  
 
4.4.1 Personal data protection 
 
Pierre Fabre Medicament (PFM) as Sponsor of the study and data controller is responsible for the 
processing of personal data in accordance with the provisions of Regulation 2016/679/EU of the 
European Parliament and of the Council of 27 April 2016 on the protection of natural persons with 
regard to the processing of personal data and the free movement of such data (GDPR), the data 
collected being for research purposes in the field of health, the legal basis of the processing being the 
legitimate interest of the data controller. 
 
 
5 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS 
5.1 
TRAINING 
Not applicable. 
 
 

 
 
 
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5.2 
REPORTING OF ADVERSE EVENTS/ADVERSE DRUG REACTIONS 
 
5.2.1 Definitions  
 
Adverse event (AE); synonym: Adverse experience  
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment [Dir 
2001/20/EC Art 2(m)].  
An AE can, therefore, be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.   
 
Adverse reaction; synonyms: ADR, suspected adverse (drug) reaction, adverse effect, 
undesirable effect 
A response to a medicinal product which is noxious and unintended [DIR 2001/83/EC Art 1(11)]. 
Response in this context means that a causal relationship between a medicinal product and an AE is 
at least a reasonable possibility. An adverse reaction, in contrast to an adverse event, is characterized 
by the fact that a causal relationship between a medicinal product and an occurrence is suspected. For 
regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is 
unknown or unstated by the healthcare professional or consumer as primary source, it meets the 
definition of an adverse reaction. Therefore, all spontaneous reports notified by healthcare 
professionals or consumers are considered suspected adverse reactions, since they convey the 
suspicions of the primary sources, unless the primary source specifically state that they believe the 
event to be unrelated or that a causal relationship can be excluded. 
Adverse reactions may arise from use of the product within or outside the terms of the marketing 
authorization or from occupational exposure [DIR 2001/83/EC Art 101(1)]. Use outside the 
marketing authorization includes off label use, overdose, misuse, abuse and medication errors. 
 
Serious adverse reaction 
 
An adverse reaction which results in death, is life-threatening, requires in-patient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or 
is a congenital anomaly/birth defect is considered a serious adverse reaction [DIR 2001/83/EC Art 
1(12)].  
 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time 
of the reaction; it does not refer to a reaction that hypothetically might have caused death if more 
severe (ICH-E2D Guideline).  
 
Medical and scientific judgement should be exercised in deciding whether other situations should be 
considered serious reactions, such as important medical events that might not be immediately life-
threatening or result in death or hospitalization but might jeopardize the patient or might require 
intervention to prevent one of the other outcomes listed above. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization or development of dependency or abuse (ICH-E2D 
Guideline).  

 
 
 
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Any suspected transmission via a medicinal product of an infectious agent is also considered a serious 
adverse reaction. Misuse of a medicinal product can occur from situations where the medicinal 
product is intentionally and inappropriately used not in accordance with the authorized product 
information.  
 
Overdose 
Administration of a quantity of a medicinal product given per administration or cumulatively which 
is above the maximum recommended dose according to the authorized product information. Clinical 
judgement should always be applied.  
 
Abuse 
Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by 
harmful physical or psychological effects [DIR 2001/83/EC Art 1(16)]. 
 
Medication error 
Are unintentional errors in the prescribing, dispensing or administration of a medicine while under 
the control of a healthcare professional, patient or consumer. They are the most common single 
preventable cause of AEs in medication practice. 
 
Occupational exposure 
For the purpose of reporting cases of suspected adverse reactions, an exposure to a medicinal product 
as a result of one’s professional or non-professional occupation. 
 
5.2.2 Reporting  
 
Within the timeframe of study documentation/data collection, Pierre Fabre has not registered any 
drug used for the treatment of mCRC, therefore no Pierre Fabre-owned drug was authorized for use 
within clinical routine treatment for mCRC or BRAFV600E-mutant mCRC. Moreover, patients 
treated in the frame of interventional clinical studies for mCRC and patients treated with concomitant 
systemic therapies for cancers other than mCRC, will be excluded. Therefore, this NIS is not expected 
to generate any safety reports with regard to Pierre Fabre-owned drugs within the frame of the 
eligibility criteria. 
 
Irrespective of this retrospective anonymized data retrieval, the participating physicians will be 
reminded of their general reporting obligations with regard to adverse drug reactions concerning any 
Pierre Fabre product or drugs of other manufacturers in accordance with the respective national law 
and regulations. 
 
 
5.2.3 Reconciliation 
 
Non applicable.  
 

 
 
 
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6 
TIMELINES 
 
The planned timelines for this study are listed as below in Table 6.  
 
Table 6 
Study timelines 
 
Milestone 
Planned date 
Final protocol  
March 12th, 2020 
Start of data entry  
April 2020 
End of observation period 
January 31st, 2020 
Database lock 
November 2020 
Final report delivered 
December 2020 
 
7 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS (IF 
APPLICABLE) 
 
Pierre Fabre is responsible for any presentation and/or publication arising from this study. The study 
results must be submitted to the review of Pierre Fabre before publication. 
 
Any publication of the results from this study must be consistent with the Pierre Fabre’s publication 
policy and guided by the Uniform Requirements for Manuscripts Submitted to Biomedical Journals: 
Writing and Editing for Biomedical Publication of the International Committee of Medical Journal 
Editors (ICMJE), updated April 2010. 
 
All reporting will be consistent with the STROBE (STrengthening the Reporting of OBservational 
studies in Epidemiology) Initiative checklist. 
 
8 
REGULATORY CONSIDERATIONS 
8.1 
CONFIDENTIALITY 
 
The subject matter and aim of the study, all information, data relating to the study or any product 
studied provided to the contractor and/or their collaborators during the term of this agreement and all 
results of the study (hereinafter collectively called the "Information") will be maintained confidential 
for an unlimited time period by the contractor and/or their collaborators. 
 
In addition, all Information shall not be used by the contractor for any other purpose than the one 
described in this Agreement. 
 
The above obligations shall, however, not apply to: 
• Information which at the time of disclosure to the contractor is part of the public knowledge, 
• Information, which, after disclosure, becomes part of the public knowledge through no fault 
of the contractor 

 
 
 
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• Information which the contractor can establish by competent proof was in its possession prior 
to disclosure hereunder and was not acquired from PFM, directly or indirectly under a secrecy 
obligation 
• 
Information which is subsequently obtained lawfully from a third party without any secrecy 
obligation and was not acquired by such third party from PFM, directly or indirectly under a 
secrecy obligation. 
 
No publication or communication relating to the study or the results thereof, in written or oral form, 
shall be made by the contractor and/or their collaborators, without PFM's prior written consent. 
 
9 
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10 APPENDICES 
 
None