A Phase 2, Open-label Study of Encorafenib + Binimetinib in Patients With BRAFV600-mutant Non-small Cell Lung Cancer
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: Pfizer

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
CLINICAL STUDY PFIZER C4221008/ARRAY-818-202
Protocol Title:
A Phase 2, Open-label Study of Encorafenib + Binimetinib in Patients with 
BRAFV600-mutant Non-small Cell Lung Cancer
Protocol Number:
Pfizer C4221008/ARRAY-818-202
Compound:
Encorafenib + Binimetinib
Study Phase:
Phase 2
Version 0:
27 November 2018
Version 1:
04 March 2019
Version 2:
03 October 2019
Version 3:
25 August 2020
Version 4:
16 February 2021  
Version 5:
24 September 2021
Sponsor:
Array BioPharma Inc.
(a wholly owned subsidiary of Pfizer Inc.)
USA
Phone: 
Fax: 
EudraCT Number:
2019-000417-37
CONFIDENTIAL INFORMATION
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
PPD
PPD
PPD
CCI

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..............................................9
1. PROTOCOL SUMMARY...................................................................................................14
1.1. Synopsis ..................................................................................................................14
1.2. Study Schema..........................................................................................................18
1.3. Schedule of Activities (SoA)...................................................................................19
2. INTRODUCTION ...............................................................................................................23
2.1. Background .............................................................................................................23
2.1.1. Overview of Non-small Cell Lung Cancer.................................................23
2.1.2. Treatment of BRAF-mutant Non-small Cell Lung Cancer.........................23
2.1.3. Overview of Encorafenib and Binimetinib.................................................24
2.1.4. Clinical Safety of Encorafenib in Combination with Binimetinib .............25
2.1.5. Clinical Safety of Encorafenib....................................................................27
2.2. Benefit/Risk Assessment.........................................................................................27
2.3. Study Rationale .......................................................................................................28
3. OBJECTIVES AND ENDPOINTS.....................................................................................31
4. STUDY DESIGN.................................................................................................................32
4.1. Overall Design.........................................................................................................32
4.2. Discussion of Study Design ....................................................................................32
4.3. Justification for Dose ..............................................................................................32
4.4. Duration of Treatment and Patient Participation.....................................................33
4.5. End of Study Definition ..........................................................................................33
4.6. Study Termination...................................................................................................33
5. STUDY POPULATION......................................................................................................33
5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................36
5.3. Lifestyle Considerations..........................................................................................39
5.3.1. Meals and Dietary Restrictions...................................................................39
5.3.2. Activity .......................................................................................................39
5.4. Screen Failures ........................................................................................................39
6. STUDY TREATMENT.......................................................................................................39

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
6.1. Study Treatments Administered..............................................................................40
6.1.1. Encorafenib.................................................................................................40
6.1.2. Binimetinib .................................................................................................40
6.2. Preparation/Handling/Storage/Accountability ........................................................41
6.3. Randomization and Blinding...................................................................................42
6.3.1. Randomization and Blinding......................................................................42
6.3.2. Patient Numbering......................................................................................42
6.4. Study Treatment Compliance..................................................................................42
6.5. Concomitant Therapy..............................................................................................43
6.5.1. Permitted Concomitant Therapy Requiring Caution and/or Action...........43
6.5.1.1. CYP and UGT Substrates and Inhibitors ..................................43
6.5.1.2. Transporter Substrates and Inhibitors .......................................44
6.5.1.3. Drugs with a Conditional or Possible Risk to Prolong QT 
Interval and/or Induce Torsade de Pointes ........................................44
6.5.2. Prohibited Concomitant Therapy................................................................45
6.6. Dose Modification...................................................................................................45
6.6.1. Dose Interruptions ......................................................................................45
6.6.2. Dose Modifications.....................................................................................46
6.7. Criteria for Permanent Discontinuation of Study Treatment ..................................47
6.8. Criteria for Study Discontinuation ..........................................................................49
6.9. Intervention after the End of the Study...................................................................49
6.10. Enrollment of Additional Patients.........................................................................49
6.11. Lost to Follow up ..................................................................................................49
7. STUDY VISITS AND ASSESSMENTS ............................................................................50
7.1. Study Visits .............................................................................................................50
7.1.1. Screening ....................................................................................................50
7.1.1.1. BRAFV600 Mutation Testing.......................................................51
7.1.2. Treatment Period ........................................................................................51
7.1.3. End of Treatment and/or Early Termination ..............................................51
7.1.4. Post-treatment Follow-up ...........................................................................52
7.1.4.1. 30-Day Safety Follow-up..........................................................52
7.1.4.2. Disease Follow-up.....................................................................53
7.1.4.3. Survival Follow-up....................................................................53

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
7.1.5. Unscheduled Visits.....................................................................................53
7.2. Efficacy Assessments..............................................................................................54
7.2.1. Radiological Tumor Evaluation..................................................................54
7.2.2. Tumor Imaging During Screening..............................................................55
7.2.3. Tumor Imaging During Treatment .............................................................55
7.2.4. Independent Radiology Review..................................................................55
7.2.5. Performance Status.....................................................................................56
7.3. Safety Assessments .................................................................................................56
7.3.1. Patient Demographics and Other Baseline Characteristics ........................56
7.3.2. Disease Characteristics and Treatment History..........................................56
7.3.3. Physical Examinations................................................................................56
7.3.4. Dermatological Examinations ....................................................................57
7.3.5. Ophthalmic Examinations ..........................................................................57
7.3.5.1. Additional Ophthalmic Testing.................................................57
7.3.6. Vital Signs ..................................................................................................58
7.3.7. Electrocardiograms.....................................................................................58
7.3.8. Echocardiogram/Multi-gated Acquisition ..................................................59
7.3.9. Clinical Laboratory Assessments ...............................................................59
7.3.9.1. Serology ....................................................................................61
7.3.9.2. Pregnancy Testing.....................................................................61
7.4. Other Study Procedures...........................................................................................61
7.4.1. Distribution of Dosing Diary......................................................................61
7.5. Adverse Events and Serious Adverse Events..........................................................62
7.5.1. Time Period and Frequency for Collecting AE and SAE Information.......62
7.5.1.1. Reporting SAEs to Pfizer Safety...............................................63
7.5.1.2. Recording Nonserious AEs and SAEs on the CRF...................63
7.5.2. Method of Detecting AEs and SAEs ..........................................................64
7.5.3. Follow-up of AEs and SAEs.......................................................................64
7.5.4. Regulatory Reporting Requirements for SAEs...........................................64
7.5.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................64
7.5.5.1. Exposure During Pregnancy......................................................65
7.5.5.2. Exposure During Breastfeeding ................................................66

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
7.5.5.3. Occupational Exposure .............................................................67
7.5.6. Cardiovascular and Death Events...............................................................67
7.5.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................67
7.5.8. Adverse Events of Special Interest.............................................................67
7.5.8.1. Lack of Efficacy........................................................................67
7.5.9. Medical Device Deficiencies......................................................................67
7.5.10. Medication Errors.....................................................................................67
7.6. Treatment of Overdose............................................................................................68
7.7. Product Complaints.................................................................................................69
7.8. Pharmacokinetics ....................................................................................................69
7.9. Pharmacodynamics..................................................................................................70
7.10. Biomarkers ............................................................................................................70
7.10.1. Circulating Tumor DNA Biomarker Analysis..........................................71
7.10.2. Circulating Serum Biomarker Analysis....................................................71
7.11. Genetics.................................................................................................................71
7.12. Patient-Reported Outcomes...................................................................................72
7.13. Health Economics .................................................................................................72
8. STATISTICAL CONSIDERATIONS ................................................................................72
8.1. Statistical Hypotheses .............................................................................................72
8.2. Sample Size Determination.....................................................................................72
8.3. Populations for Analyses.........................................................................................73
8.4. Statistical Analyses .................................................................................................73
8.4.1. Primary Analyses........................................................................................73
8.4.2. Secondary Analyses....................................................................................73
8.4.2.1. Duration of Response................................................................73
8.4.2.2. Disease Control Rate.................................................................74
8.4.2.3. Progression-free Survival..........................................................74
8.4.2.4. Overall Survival ........................................................................74
8.4.2.5. Time to Response......................................................................74
8.4.3. Safety Analyses ..........................................................................................75
8.4.4. Pharmacokinetic Analyses..........................................................................75
8.4.5. Other Analyses............................................................................................75

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
8.5. Interim Analyses .....................................................................................................76
9. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......76
9.1. Regulatory, Ethical, and Study Oversight Considerations......................................76
9.2. Investigator Responsibilities ...................................................................................76
9.3. Financial Disclosure................................................................................................77
9.4. Informed Consent Process.......................................................................................78
9.5. Data Protection........................................................................................................78
9.6. Committees..............................................................................................................79
9.6.1. Safety Monitoring.......................................................................................79
9.7. Dissemination of Clinical Study Data.....................................................................79
9.7.1. Data Sharing ...............................................................................................79
9.8. Data Quality Assurance...........................................................................................80
9.9. Source Documents...................................................................................................81
9.10. Study and Site Closure ..........................................................................................81
9.11. Publication Policy .................................................................................................82
10. REFERENCES ..................................................................................................................83
11. APPENDIX 1: CONTRACEPTIVE GUIDANCE............................................................88
12. APPENDIX 2: RECOMMENDED DOSE MODIFICATIONS FOR 
ENCORAFENIB-RELATED* ADVERSE EVENTS .......................................................91
13. APPENDIX 3: RECOMMENDED DOSE MODIFICATIONS FOR 
BINIMETINIB-RELATED* ADVERSE EVENTS ..........................................................95
14. APPENDIX 4: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ..............................99
14.1. Definition of AE....................................................................................................99
14.2. Definition of SAE................................................................................................100
14.3. Recording/Reporting and Follow-up of AEs and/or SAEs .................................102
14.4. Reporting of SAEs ..............................................................................................104
15. APPENDIX 5: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS...............................................................................................................105
16. APPENDIX 6: ECG FINDINGS OF POTENTIAL CLINICAL CONCERN................107
17. APPENDIX 7: SNELLEN EQUIVALENCE (VISUAL ACUITY CONVERSION 
CHART)............................................................................................................................109
18. APPENDIX 8: ALTERNATIVE MEASURES DURING PUBLIC 
EMERGENCIES...............................................................................................................110

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
18.1. Eligibility.............................................................................................................110
18.2. Telehealth Visits..................................................................................................110
18.3. Alternative Facilities for Safety Assessments.....................................................111
18.3.1. Laboratory Testing..................................................................................111
18.3.2. Imaging...................................................................................................111
18.3.3. Electrocardiograms.................................................................................111
18.4. Study Treatment ..................................................................................................111
18.5. Home Health Visits .............................................................................................112
18.6. Adverse Events and Serious Adverse Events......................................................112
18.7. Efficacy Assessments..........................................................................................113
18.8. Steering Committee.............................................................................................113
19. APPENDIX 9: PROTOCOL AMENDMENT SUMMARY OF CHANGES.................114

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
LIST OF TABLES
Table 1.
Primary and Select Secondary Objectives and Endpoints........................16
Table 2.
Study Design Elements.............................................................................17
Table 3.
Schedule of Activities...............................................................................19
Table 4.
Anti-tumor Activity of Encorafenib and Binimetinib in BRAF
V600E Xenograft Model ..........................................................................28
Table 5.
Objectives and Endpoints .........................................................................31
Table 6.
Study Treatments......................................................................................40
Table 7.
Dose Reductions for Encorafenib.............................................................47
Table 8.
Dose Reductions for Binimetinib .............................................................47
Table 9.
Eastern Cooperative Group Performance Status Scoring.........................56
Table 10.
Timing of ECGs........................................................................................59
Table 11.
Summary of Clinical Laboratory Tests.....................................................60
Table 12.
Serial Pharmacokinetic Blood Sample Timing in Patients Enrolled 
under Protocol Versions 0 through 3........................................................70
Table 13.
Pharmacokinetic Blood Sample Timing in Patients Enrolled under 
Protocol Version 4 or later........................................................................70
Table 14.
Populations for Analysis...........................................................................73
LIST OF FIGURES
Figure 1.
Overall Study Design................................................................................18
Figure 2.
Effects of Encorafenib and Binimetinib in DFCI-306 Mice (BRAF
V600E, EGFR del19, T790M)..................................................................28

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study protocol. 
Abbreviation or 
special term
Explanation
AE
adverse event
AESI
adverse event of special interest
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase 
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase 
ATP
adenosine triphosphate
AUC
area under the curve
BCRP
breast cancer resistance protein
β-HCG 
beta human chorionic gonadotropin
BID
twice daily
BUN
blood urea nitrogen
BRAF
serine/threonine-protein kinase B-Raf
BRAF
B-RAF proto-oncogene, serine/threonine-protein kinase
C1D1
Cycle 1 Day 1
CDx
companion diagnostic
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
CK or CPK
creatine (phospho)kinase
CNS
central nervous system
COVID-19
coronavirus disease 2019
CR
complete response
CRF
case report form
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
Abbreviation or 
special term
Explanation
CYP
cytochrome P450 enzyme (2B6, 2C9, 2C19, 3A4 refer to isoforms)
DCR
disease control rate
DILI
drug-induced liver injury
dL
deciliter(s)
DMC
Data Monitoring Committee
DOR
duration of response
DVT
deep vein thrombosis
EC
ethics committee (includes institutional review board, research ethics board, and 
institutional ethics committee)
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperation Oncology Group
eCRF
electronic case report form
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
EDC
electronic data capture
EOT
end of treatment
ERK
extracellular signal-related kinase
ESMO
European Society of Medical Oncology
EU
European Union
EUA
Emergency Use Authorization
FAS
Full Analysis Set
FDA
US Food and Drug Administration
FDG
fluorodeoxyglucose
FNA
fine needle aspiration
FSH
follicle stimulating hormone
g
gram(s)
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
h
hour(s)
HBV
hepatitis B virus
HCV
hepatitis C virus
HFSR
hand-foot skin reaction
HIPAA
Health Information Portability and Accountability Act of 1996

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
Abbreviation or 
special term
Explanation
HIV
human immunodeficiency virus
HRT 
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
INR
international normalized ratio
IPM
Investigational Product Manual
IRB
institutional review board
IRR
independent radiology review
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWRS
Interactive Voice/Web Response System
L
liter(s)
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LVEF
left ventricular ejection fraction
m
meter(s)
MedDRA
Medical Dictionary for Regulatory Activities
MEK
mitogen-activated protein kinase
min
minute(s)
mg
milligram(s)
mL
milliliter(s)
mmHg
millimeters of mercury
MRI
magnetic resonance imaging
ms
millisecond(s)
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
next-generation sequencing
NSAID
nonsteroidal anti-inflammatory drug

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
Abbreviation or 
special term
Explanation
NSCLC
non-small cell lung cancer
OAT
organic anion transporter (1 and 3 refer to family members)
OATP
organic anion transporting polypeptide (1B1, 1B3 refer to family members)
OCT
organic cation transporter (2 refers to family member)
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death protein ligand 1
PDF
portable document format
PE
pulmonary embolism
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
pH
hydrogen ion concentration
PK
pharmacokinetic(s)
PKS
Pharmacokinetics (PK) Set
PPS
Per-protocol Set
PR
partial response
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
PVC
premature ventricular contraction
Q8W
every 8 weeks
Q12W
every 12 weeks
QD
once daily
QT
QT interval
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula.
RBC
red blood cell(s)
RECIST v1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RPED
retinal pigment epithelial detachment
RVO
retinal vein occlusion

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
Abbreviation or 
special term
Explanation
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV2
severe acute respiratory syndrome coronavirus 2
SD
stable disease
SoA
schedule of activities
SS
Safety Set
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TDP
Torsades de Pointes
TPS
tumor proportion score
TTR
Time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase (1A1 refers to family member)
ULN
upper limit of normal
v
version
WBC
white blood cell(s)
WOCBP
woman of childbearing potential

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title:
A Phase 2, Open-label Study of Encorafenib + Binimetinib in Patients with BRAFV600-mutant 
Non-small Cell Lung Cancer
Protocol Number: Pfizer C4221008/ARRAY-818-202
Rationale:
Approximately 1% to 8% of patients with NSCLC have mutations in BRAF (Barlesi et al, 
2016; Davies et al, 2002; Cardarella et al, 2013; Baik et al, 2017; Lin et al, 2014), with half 
of these driven by the BRAFV600E mutation (Zheng et al, 2015). Based on a parallel-group 
trial of the BRAF inhibitor dabrafenib with or without the MEK inhibitor trametinib, the 
combination of dabrafenib plus trametinib is now a standard-of-care regimen for the 
treatment of this molecular subtype of NSCLC either as first-line therapy for metastatic 
disease, or after progression on first-line platinum-based therapy with or without a PD-1/PD-
L1 inhibitor (Planchard et al, 2017; NCCN Guidelines; Planchard et al, 2018). In this study, 
for patients treated with the combination of dabrafenib plus trametinib, the confirmed ORR 
for both treatment-naïve patients (64% [95% CI 46, 79]) and patients who progressed 
following first-line platinum-based therapy (63.2% [95% CI 49.3, 75.6]) was nearly twice 
that of those treated with dabrafenib monotherapy (33% [95% CI 23, 45]) (Planchard et al, 
2016a; Planchard et al, 2016b; Planchard et al, 2017). The median DOR for patients who 
were previously treated was 9.0 months (95% CI 6.9, 18.3), and 10.4 months (95% CI 8.3, 
17.9) for treatment-naïve patients (Planchard et al, 2016a; Planchard et al, 2017). PFS and 
OS results were similarly better for combination therapy as compared to dabrafenib 
monotherapy (Planchard et al, 2017).
Nonclinical data have demonstrated the enhanced activity of combining BRAF and MEK 
inhibition in BRAFV600-driven tumors (Stuart et al, 2012; Flaherty et al, 2012; Joshi et al, 
2015; Khunger et al, 2018). This combination has been validated clinically by the efficacy 
observed for the combination in BRAFV600E-mutant NSCLC (Planchard et al, 2017), and also 
in the treatment of BRAFV600E/K-mutant melanoma where the combination of BRAF and 
MEK inhibition is an established standard-of-care based on 4 pivotal trials of various 
BRAF/MEK inhibitor combinations (Long et al, 2014; Ascierto et al, 2016; Robert et al, 
2016; Dummer et al, 2018a).
Encorafenib is a potent and selective BRAF inhibitor and binimetinib is a potent and 
selective MEK inhibitor. In a Phase 3 study of encorafenib with or without binimetinib 
compared to vemurafenib (a standard-of-care BRAF inhibitor comparator) in patients with 
advanced BRAFV600E/K-mutant melanoma (Study CMEK162B2301; COLUMBUS trial), the 
combination was shown to improve PFS, OS and ORR compared to vemurafenib treatment 
(Dummer et al, 2018a; Dummer et al, 2018b). Median PFS, median OS and confirmed ORR 
for the combination of encorafenib plus binimetinib were 14.9 months (95% CI 11.0, 18.5), 
33.6 months (95% CI 24.4, 39.2) and 63.0% (by central review; 95% CI 55.8, 69.9)/75.0% 

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
(by local review; 95% CI 68.3, 81.0), respectively. These results compared favorably to the 
PFS, OS and ORR of 7.3 months (95% CI 5.6, 8.2), 16.9 months (95% CI 14.0, 24.5) and 
40.3% (by central review; 95% CI 33.3, 47.6)/49.0% (by local review; 95% CI 41.9, 56.5), 
respectively, for vemurafenib, which performed almost identically on all endpoints compared 
to its performance in other pivotal trials in BRAFV600-mutant melanoma where it was used as 
a control (Larkin et al, 2014; Robert et al, 2015). These data compare favorably with results 
from trials of dabrafenib plus trametinib in a similar melanoma setting, with median PFS of 
11.4 months, median OS of 25.6 months (95% CI 23.1, 34.3) and ORR of 64% by local 
review (95% CI 59, 69) for the combination of dabrafenib plus trametinib and median PFS of 
7.3 months, median OS of 18 months (95% CI 15.6, 20.7) and ORR of 51% by local review 
(95% CI 46, 97) for vemurafenib (Robert et al, 2015; Robert et al, 2016).
Although the combination of encorafenib plus binimetinib was not studied in direct 
comparison to the combination of dabrafenib plus trametinib in melanoma, the numerically 
superior outcomes with encorafenib plus binimetinib, particularly when compared to results 
from trials that incorporated a common control arm (vemurafenib) that performed similarly 
across trials, provides reassurance that there is at least comparable efficacy in the setting of 
melanoma. These results also suggest that the efficacy of encorafenib plus binimetinib in 
other BRAFV600-driven settings such as BRAFV600E NSCLC may be similar or potentially 
superior to that observed with dabrafenib and trametinib. 
Importantly, the combination of encorafenib plus binimetinib has a different safety and 
tolerability profile (Flaherty et al, 2017) from dabrafenib plus trametinib. Pyrexia, 
manifesting as a distinctive recurrent febrile syndrome refractory to NSAIDs and associated 
in a minority of patients with chills, dehydration and renal failure, is a significant toxicity 
associated with dabrafenib and trametinib, and is seen in over 50% of patients (Long et al, 
2014). Treatment with encorafenib and binimetinib was associated with a lower incidence of 
pyrexia (18% of patients) in the COLUMBUS trial and these events were generally low 
grade, nonrecurrent and not associated with other manifestations (Dummer et al, 2018a; 
Dummer et al, 2018b); 64% of patients with previously untreated BRAF-mutant metastatic 
NSCLC, and 46% of patients with previously treated BRAF-mutant advanced NSCLC who 
received dabrafenib plus trametinib reported pyrexia (Planchard et al, 2016a; Planchard et al, 
2017).
Therefore, encorafenib plus binimetinib may represent an alternative BRAF/MEK inhibitor 
combination regimen for the treatment of BRAFV600E-mutant NSCLC, and potentially for 
other V600 Class 1 BRAF mutations (e.g. K or D), though very rare. Encorafenib plus 
binimetinib has a differentiated safety profile and may have enhanced efficacy based on 
results observed in the treatment of BRAFV600-mutant melanoma. This study seeks to 
generate data to explore the efficacy and safety of this new combination in NSCLC.

Encorafenib/Binimetinib
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
Clinical Study C4221008 / ARRAY-818-202
Objectives and Endpoints:
Table 1 presents the primary and major/select secondary objectives and endpoints. 
Table 1.
Primary and Select Secondary Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the efficacy of encorafenib + 
binimetinib in treatment-naïve and previously 
treated patients with BRAFV600E-mutant NSCLC as 
measured by ORR
ORR defined as the proportion of patients who 
have achieved a confirmed best overall response 
(CR or PR) as determined by IRR per RECIST 
v1.1 in the treatment-naïve setting
ORR defined as the proportion of patients who 
have achieved a confirmed best overall response 
(CR of PR) as determined by IRR per RECIST 
v1.1 in the previously treated setting
Secondary
To evaluate the efficacy of encorafenib + 
binimetinib in treatment-naïve and previously 
treated patients with BRAFV600E-mutant NSCLC as 
measured by DOR, DCR, PFS, and TTR
Confirmed ORR by Investigator per RECIST v1.1
DOR (by IRR and by Investigator) defined as the 
time from the date of the first documented 
response (CR or PR) that is subsequently 
confirmed (by IRR and by Investigator, 
respectively) to the earliest date of disease 
progression, per RECIST v1.1, or death due to any 
cause
DCR (by IRR and by Investigator), defined as the 
proportion of patients who have a confirmed CR 
or confirmed PR, or SD per RECIST v1.1 
PFS (by IRR and by Investigator), defined as the 
time from the date of first dose of study drug to the 
earliest date of disease progression, per RECIST 
v1.1, or death due to any cause
TTR (by IRR and Investigator), defined as the time 
from the date of first dose to the first 
documentation of objective response (CR or PR) 
which is subsequently confirmed (by IRR and by 
Investigator, respectively)
To evaluate the efficacy of encorafenib + 
binimetinib in treatment-naïve and previously 
treated patients with BRAFV600E-mutant NSCLC 
with respect to OS
OS defined as the time from the date of first dose 
of study drug to the date of death due to any cause
To evaluate the safety and tolerability of 
encorafenib + binimetinib in treatment-naïve and 
previously treated patients with BRAFV600E-mutant 
NSCLC
Incidence and severity of AEs graded according to 
the NCI CTCAE v4.03 and changes in clinical 
laboratory parameters, vital signs, ECGs and 
ECHO/MUGA scans

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Overall Design:
Table 2 presents the study design elements.
Table 2.
Study Design Elements
Study Phase
2
Type of Design
Open-label, multicenter, non-randomized study
Primary Purpose
Treatment: combination treatment with encorafenib + binimetinib in 
patients with BRAFV600E NSCLC
Intervention Model
Single Group
Clinical Indication
BRAFV600mutant NSCLC
Population
Male and female patients at least 18 years of age who have metastatic 
BRAFV600-mutant NSCLC who are either 1) treatment-naïve, OR who 
have received 2) first-line treatment with platinum-based chemotherapy, 
OR 3) first-line treatment with an anti-PD-1/PD-L1 inhibitor given alone, 
or in combination with platinum-based chemotherapy, or in combination 
with immunotherapy (e.g., ipilimumab) with or without platinum-based
chemotherapy.
Number of Patients
At least 60 treatment-naïve patients, and 37 previously treated patients 
with the locally confirmed BRAFV600E mutation will be enrolled and 
treated. It is not expected that more than 107 patients with any BRAFV600
mutation will be enrolled and treated. 
Up to 10 additional patients who have a BRAFV600 mutation other than 
BRAFV600E (BRAFV600x) can be enrolled and treated. 
Study Design
This is an open-label, multicenter, non-randomized, Phase 2 study of the 
combination of encorafenib and binimetinib in patients with 
BRAFV600E-mutant metastatic NSCLC. Although very rare in NSCLC, 
patients with other V600 Class 1 BRAF mutations (e.g. K or D) are also 
allowed. Treatment will be administered in 28-day cycles and will 
continue until disease progression, unacceptable toxicity, withdrawal of 
consent, initiation of subsequent anticancer therapy, death, or the defined 
end of the study. Once the patient discontinues study treatment, the 
treatment period will end, and the patient will enter the follow-up period.
Treatment Regimens
Study treatment with encorafenib and binimetinib will be self-
administered orally without regard to food. 
Patients will receive the following per 28-day (± 3 days) cycle:

Encorafenib: 450 mg (6 × 75 mg capsule) QD

Binimetinib: 45 mg (3 × 15 mg tablet) BID
Alternate starting doses may also be explored based on safety of the 
combination regimen. For an individual patient, the dose of study 

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Table 2.
Study Design Elements
treatment may be reduced or interrupted as appropriate based on 
protocol-defined treatment modifications. 
Estimated Duration 
of Study Patients
After the signing of the ICF, screening assessments may be completed 
over a period of up to 28 days. Patients may continue treatment in 
consecutive 28-day (± 3 days) cycles provided the patient is receiving 
benefit and have not met criteria for study withdrawal. If the patient 
discontinues study treatment, then the treatment period will end, and the 
patient will enter the follow-up period for safety, disease assessments (if 
applicable), subsequent anticancer therapies, and survival. Study 
participation, including post-treatment follow-up is expected to average 
approximately 12-18 months per individual patient.
The end of study will occur 2 years after treatment initiation of the last 
enrolled patient or the point at which all patients have died or withdrawn
consent or have been lost to follow up, whichever occurs first. Any 
patients still receiving study treatment at the end of the study may be 
allowed to continue treatment in accordance with local regulations and 
requirements at the discretion of the Investigator as long as none of the 
treatment discontinuation criteria have been met.
1.2. Study Schema
Figure 1.
Overall Study Design

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1.3. Schedule of Activities (SoA)
Table 3.
Schedule of Activities
Evaluation/ Window
Screening
Treatment Period
Post-Treatment Period
Notes/Protocol 
Section
Screening
Cycle 1
Cycle 
2
Subsequent 
Cycles
Every 
8 
Weeks
Every 
12 
Weeks
EOT
Safety 
Follow-up
Survival 
Follow-
up
Day -28 
to -1
Day 
1
Day 
15
Day 1
± 3D
Day 1
± 3D
± 7D
± 7D
± 3D
30 Days
± 7D
Q12W
± 7D
Administrative Procedures
Informed Consent
X
See Sections 7.1 and
9.4
Inclusion/exclusion 
criteria
X
See Sections 5.1 and 
5.2
Demography and 
medical history
X
See Sections 7.3.1
and 7.3.2
Local documentation of 
BRAFV600 mutation 
status
X
See Section 7.1.1.1
Prior/concomitant 
medication
X
Assess continuously
See Section 6.5
Contact IWRS
X
X
X
X
X
See Section 6.3
Dispense encorafenib
(with dosing diary )
X
X
X
See Sections 6.1 and 
7.4.1
Dispense binimetinib 
(with dosing diary)
X
X
X
See Sections 6.1 and 
7.4.1
Assess study treatment 
compliance
X
X
X
See Section 6.4
Document subsequent 
therapies
X
X
See Sections 7.1.4.1
and 7.1.4.3
Survival status
X
X
See Section 7.1.4.3

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Table 3.
Schedule of Activities
Evaluation/ Window
Screening
Treatment Period
Post-Treatment Period
Notes/Protocol 
Section
Screening
Cycle 1
Cycle 
2
Subsequent 
Cycles
Every 
8 
Weeks
Every 
12 
Weeks
EOT
Safety 
Follow-up
Survival 
Follow-
up
Day -28 
to -1
Day 
1
Day 
15
Day 1
± 3D
Day 1
± 3D
± 7D
± 7D
± 3D
30 Days
± 7D
Q12W
± 7D
Clinical Procedures/Assessments
Tumor tissue sample 
X
Central laboratory 
testing to confirm 
BRAFV600 status. See 
Section 7.1.1.1
Physical exam 
X
X
X
X
X
X
See Section 7.3.3
Vital signs 
X
X
X
X
X
X
See Section 7.3.6
Dermatologic exam
X
X
X
X
X
Post-treatment 
follow-up required. 
See Section 7.3.4. 
ECOG performance 
status
X
X
X
X
X
X
See Section 7.2.5
Full ophthalmic exam
X
Full ophthalmic exams are required only if clinically indicated
see Section 7.3.5
Visual acuity exam
X
X
X
see Section 7.3.5
Triplicate 12-lead ECG
X
X
Predose only. See 
Section 7.3.7 and 
Table 10
Single 12-lead ECG
X
X
X
X
C1D1 2.0 h (± 0.5 h) 
after administration 
of study treatment. 
See Section 7.3.7
and Table 10
ECHO/MUGA
X
X
X
X
See Section 7.3.8

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Table 3.
Schedule of Activities
Evaluation/ Window
Screening
Treatment Period
Post-Treatment Period
Notes/Protocol 
Section
Screening
Cycle 1
Cycle 
2
Subsequent 
Cycles
Every 
8 
Weeks
Every 
12 
Weeks
EOT
Safety 
Follow-up
Survival 
Follow-
up
Day -28 
to -1
Day 
1
Day 
15
Day 1
± 3D
Day 1
± 3D
± 7D
± 7D
± 3D
30 Days
± 7D
Q12W
± 7D
Tumor radiographic 
assessment
X
X
Patients who discontinue 
treatment for reasons other than 
PD will continue to have 
radiographic assessments Q8W 
until PD or meet any of the 
criteria in Section 7.1.4.2
Q8W for 12 months 
then Q12W thereafter.
See Sections 7.2.1, 
7.2.2 and 7.2.3
Adverse event 
assessment
X
Assess continuously
See Section 7.5
Laboratory Assessments
Hematology
X
X
X
X
X
X
See Section 7.3.9
and Table 11
Chemistry
X
X
X
X
X
X
See Section 7.3.9
and Table 11
Coagulation
X
Patients on anticoagulation treatment should have 
parameters monitored throughout the study as clinically 
indicated
See Section 7.3.9
and Table 11
Serum pregnancy test
X
X
See Section 7.3.9.2
and Table 11
Urine pregnancy test
Performed locally on Day 1 of each cycle; or as clinically 
indicated; or per country-specific requirement
See Section 7.3.9.2
and Table 11
Urinalysis
X
See Section 7.3.9
and Table 11
HBV and HCV 
serology testing and 
HIV where applicable
X
See Section 7.3.9.1
and Table 11

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Table 3.
Schedule of Activities
Evaluation/ Window
Screening
Treatment Period
Post-Treatment Period
Notes/Protocol 
Section
Screening
Cycle 1
Cycle 
2
Subsequent 
Cycles
Every 
8 
Weeks
Every 
12 
Weeks
EOT
Safety 
Follow-up
Survival 
Follow-
up
Day -28 
to -1
Day 
1
Day 
15
Day 1
± 3D
Day 1
± 3D
± 7D
± 7D
± 3D
30 Days
± 7D
Q12W
± 7D
PK assessments (for 
patients enrolled under 
Protocol Versions 0 to 
3)
X
X
X
See Section 7.8 and 
Table 12
PK assessments (for 
patients enrolled under 
Protocol Version 4 or 
later)
X
X
X (Cycles 3-
6)
Predose sample only 
See Section 7.8 and 
Table 13
ctDNA blood sample 
  
X
X
X
X
See Section 7.10.1
ctDNA blood sample 
for biomarkers (for 
patients enrolled under 
Protocol Version 4 or 
later)
X
See Section 7.10.1
Proteomic/Metabolic 
serum sample (for 
patients enrolled under 
Protocol Version 4 or 
later)
X
X
X (Cycle 3 
only)
X
See Section 7.10.2

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2. INTRODUCTION
2.1. Background
2.1.1. Overview of Non-small Cell Lung Cancer
Lung cancer is the most commonly occurring cancer in men and the third most commonly 
occurring cancer in women. Worldwide, the World Health Organization (WHO 2018) reports 
the incidence of lung cancer will be about 2.09 million cases in 2018, resulting in an 
expected 1.76 million deaths. More than 40% of NSCLC patients have Stage IV disease at 
initial diagnosis. The 5-year survival rate for those diagnosed with Stage IVMa (e.g., separate 
tumor nodules in a contralateral lobe, tumor with pleural nodules or malignant pleural [or 
pericardial] effusion), lung cancer is approximately 10% and is < 1% for Stage IVMb (e.g., 
distant metastasis in extra-thoracic organs). More than half of people newly diagnosed with 
lung cancer can be expected to die within 1 year of diagnosis (U.S. National Institute of 
Health, National Cancer Institute 2015).
NSCLC is the most common type of lung cancer, accounting for 80% to 85% of all lung 
cancer diagnoses. As with other cancers, NSCLC is a heterogeneous disease comprised of an 
expanding number of biologically distinct and clinically relevant molecular subsets (Jordan 
et al, 2017; Kris et al, 2014). Approximately 1% to 8% of patients with NSCLC have 
mutations in BRAF (Barlesi et al, 2016; Davies et al, 2002; Cardarella et al, 2013; Baik et al, 
2017; Lin et al, 2014), with half of these driven by the BRAFV600E mutation (Class 1) and the 
other half driven by non-V600E mutations distributed throughout exons 11 and 15 
collectively (Class 2 and 3) (Zheng et al, 2015). In 2018, recognizing rapid advances in the 
field of molecular pathology and new options for targeted therapy, updated recommendations 
from several professional organizations included a consensus statement that BRAF testing 
should be performed on all patients with advanced lung adenocarcinoma, irrespective of 
clinical characteristics (Kalemkerian et al, 2018; Lindeman et al, 2018).
2.1.2. Treatment of BRAF-mutant Non-small Cell Lung Cancer
Before the advent of targeted and immune therapies for NSCLC, the ORR for first-line 
platinum-based chemotherapy for Stage IV NSCLC was approximately 30% to 40% with a 
mean survival time of 8 to 10 months (Non-small Cell Lung Cancer Collaborative Group 
1995). The development and application of antibodies targeting PD-1 (nivolumab and 
pembrolizumab) and PD-L1 (atezolizumab, avelumab and durvalumab) have advanced the 
treatment of cancer (Ribas and Wolchok, 2018; Sun et al, 2018). PD-1/PD-L1 inhibitors in 
combination with chemotherapy have recently been approved for the first-line treatment of 
NSCLC patients (KEYTRUDA® [pembrolizumab] prescribing information; TECENTRIQ®
[atezolizumab] prescribing information), and has led to changes in the recommended 
treatment algorithms for NSCLC (NCCN Guidelines; Planchard et al, 2018). However, PD-
1/PD-L1 inhibitors produce durable responses in only about 20% of patients with advanced 
NSCLC (Brahmer et al, 2010; Topalian et al, 2012; Gettinger and Herbst, 2014; Herbst et al, 
2014). The response rate is higher when patients are stratified by partial or complete 
membrane staining for PD-L1 (tumor proportion score, TPS) (Aguilar et al, 2018; Gandhi et 
al, 2018).

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Recently, molecular characterization of a NSCLC tumor has become a key tool for 
facilitating treatment decisions and the clinical management of NSCLC patients (Tsoulos et 
al, 2017). Identification of the unique molecular drivers and development of highly effective 
genotype-specific therapies have transformed the natural history of disease for select 
subgroups of NSCLC patients (Hyman et al, 2018; Leduc et al, 2017; Lee et al, 2017). 
Experience with BRAFV600E melanoma and its treatment with BRAF/MEK inhibitors has 
influenced the treatment of BRAFV600E NSCLC (Khunger et al, 2018). Based on a parallel-
group trial of the BRAF inhibitor dabrafenib with or without the MEK inhibitor trametinib, 
the combination of dabrafenib plus trametinib is now a standard-of-care regimen for the 
treatment of this molecular subtype of NSCLC either as first-line therapy for metastatic 
disease, or after progression on first-line platinum-based therapy with or without a PD-1/PD-
L1 inhibitor (Planchard et al, 2017; NCCN Guidelines; Planchard et al, 2018).
In this study, for patients treated with the combination of dabrafenib plus trametinib, there 
was no statistically significant difference in ORR for treatment-naïve patients (64% [95% CI 
46, 79]) versus patients who progressed following first-line platinum-based therapy (63.2% 
[95% CI 49.3, 75.6]) (Planchard et al, 2016a; Planchard et al, 2016b; Planchard et al, 2017). 
Additionally, for patients treated with the combination, the confirmed ORR for both 
treatment-naïve patients and patients who progressed following first-line platinum-based 
therapy was nearly twice that of those treated with dabrafenib monotherapy (33% [95% CI 
23, 45]). PFS and OS results were similar for patients treated with the combination regardless 
if they were treatment-naïve or progressed following first-line platinum-based therapy 
(Planchard et al, 2017). The median PFS and median OS were 10.9 months (95% CI 7.0, 
16.6) and 24.6 months (95% CI 12.3, not estimable), respectively, for treatment-naïve 
patients and were 10.2 months (95% CI 6.9, 16.7) and 18.2 months (95% CI 14.3, not 
estimable), respectively, for patients who progressed on first-line platinum-based therapy. 
Median PFS and median OS results were also better for combination therapy as compared to 
dabrafenib monotherapy, with PFS and OS of 5.5 months (95% CI 2.8, 7.3) and 12.7 months 
(95% CI 7.3, 16.3), respectively, for monotherapy (Planchard et al, 2017). The median DOR 
for patients who were treatment naïve was 10.4 months (95% CI 8.3, 17.9) and was 9.0 
months (95% CI 6.9, 18.3) for patients who were previously treated.
Some advanced NSCLC patients may be treated with platinum-based chemotherapy with or 
without a PD-1/PD-L1 inhibitor as first-line therapy prior to analysis of their tumor tissue for 
BRAFV600E mutation status. Clinical outcomes for patients with BRAFV600E mutations who 
have progressed on a PD-1/PD-L1 inhibitor regimen is unknown and warrant further clinical 
investigation so it follows that these patients should be studied in future clinical trials of 
BRAF/MEK inhibitor combinations.
2.1.3. Overview of Encorafenib and Binimetinib
Encorafenib is a potent and selective ATPcompetitive inhibitor of BRAFV600-mutant kinase. 
Mutations in the BRAF gene, such as BRAFV600E, can result in constitutively activated BRAF 
kinase that may stimulate tumor cell growth. Encorafenib inhibited in vitro growth of tumor 
cell lines expressing BRAF V600 E, D and K mutations.
Binimetinib is a potent and selective allosteric, ATP-uncompetitive inhibitor of MEK1/2. 
MEK proteins are upstream regulators of the ERK pathway. In vitro, binimetinib inhibited 

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ERK phosphorylation in cell-free assays as well as viability and MEK-dependent 
phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in 
vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models.
Encorafenib and binimetinib target 2 different kinases in the RAS/RAF/MEK/ERK pathway. 
Compared with either drug alone, co-administration of encorafenib and binimetinib resulted 
in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater 
anti-tumor activity with respect to tumor growth inhibition in BRAFV600E-mutant human 
melanoma xenograft studies in mice. Additionally, the combination of encorafenib and 
binimetinib delayed the emergence of resistance in BRAFV600E-mutant human melanoma 
xenografts in mice compared to either drug alone.
Encorafenib 450 mg orally QD in combination with binimetinib 45 mg orally BID have 
received marketing approval in several jurisdictions, including the US and EU 
(BRAFTOVITM [encorafenib] prescribing information; MEKTOVI® [binimetinib] 
prescribing information). Regulatory approval of encorafenib and binimetinib in combination 
was based on the Phase 3 COLUMBUS study (Study CMEK162B2301; randomized, 2-part, 
open-label, multicenter, international clinical study) (Dummer et al, 2018a; Dummer et al, 
2018b). Detailed information regarding nonclinical studies and clinical PK are presented in 
the respective Investigator’s Brochures for encorafenib and binimetinib.
2.1.4. Clinical Safety of Encorafenib in Combination with Binimetinib
COLUMBUS results demonstrated improved tolerability in the encorafenib 450 mg QD + 
binimetinib 45 mg BID arm compared with single-agent encorafenib 300 mg QD (Dummer 
et al, 2018a; Dummer et al, 2018b). This is consistent with a body of literature that suggests 
the combination of a BRAF inhibitor and a MEK inhibitor results in improved tolerability 
compared with either agent alone (Flaherty et al, 2012; Long et al, 2014; Robert et al, 2015; 
Larkin et al, 2014; Ascierto et al, 2016).
Among patients receiving encorafenib plus binimetinib combination therapy in the 
COLUMBUS study, the most common adverse reactions (≥20% of patients, all grades) were
fatigue (43%), nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), 
arthralgia (26%), myopathy (23%), hyperkeratosis (23%), rash (22%), headache (22%), 
constipation (22%), visual impairment (20%) and serous retinopathy (20%). Most of these 
toxicities were generally reversible and manageable by supportive medical care, dose 
modifications or discontinuation. Other clinically important adverse reactions occurring in 
< 10% of patients were facial paresis, pancreatitis, panniculitis, drug hypersensitivity and 
colitis. The most common laboratory abnormalities (≥2%, Grade 3 or 4) were increased 
GGT (11%), increased ALT (6%), increased creatine phosphokinase (5%), increased fasting 
glucose (5%), increased creatinine (4%), anemia (4%), hyponatremia (4%), increased AST 
(3%), neutropenia (3%) and lymphopenia (2%). Detailed information regarding clinical 
safety is presented in the respective Investigator’s Brochures for encorafenib and binimetinib.

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Important potential adverse effects associated with the administration of the combination of 
encorafenib and binimetinib established primarily from safety data from the COLUMBUS 
study and, where indicated, from other studies of the combination, include:

New primary malignancies: Based on its mechanism of action, encorafenib may 
promote malignancies associated with activation of RAS through mutation or other 
mechanisms. Cutaneous and non-cutaneous malignancies occurred in patients, 
including cutaneous squamous carcinoma/keratoacanthoma (2.6%; median time to 
first occurrence of 5.8 months) and basal cell carcinoma (1.6%).

Left ventricular dysfunction: Symptomatic or asymptomatic decreases in ejection 
fraction occurred in 7% of patients, with Grade 3 left ventricular dysfunction 
occurring in 1.6% of patients.

Hemorrhage: Hemorrhage occurred in 19% of patients, with events ≥Grade 3 
occurring in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or 
progressive brain metastases occurred in 1.6% of patients. The most frequent 
hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), 
hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Venous thromboembolism: Occurred in 6% of patients, including 3.1% of patients 
who developed pulmonary embolism.

Ocular toxicities: Serous retinopathy is a class effect of MEK inhibitors. It is 
generally asymptomatic or mildly symptomatic and reversible (Urner-Bloch et al, 
2016). Serous retinopathy occurred in 20% of patients. Symptomatic serous 
retinopathy occurred in 8% of patients with no cases of blindness. The median time to 
onset of the first event of serous retinopathy (all grades) was 1.2 months. RVO is a 
known class-related adverse reaction of MEK inhibitors and may occur in patients 
treated with binimetinib in combination with encorafenib. In patients with BRAF
mutation-positive melanoma across multiple clinical trials, 0.1% of patients 
experienced RVO.

Pneumonitis/Interstitial Lung Disease: Pneumonitis occurred in 0.3% of patients 
with BRAF mutation-positive melanoma across multiple clinical trials.

Hepatotoxicity: The incidence of Grade 3 or 4 increases in liver function laboratory 
tests was 6% for ALT, 2.6% for AST and 0.5% for alkaline phosphatase. No patient 
experienced Grade 3 or 4 serum bilirubin elevation. 

CK Elevation/Rhabdomyolysis: Asymptomatic elevations of laboratory values of 
serum CK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of 
patients with BRAF mutation-positive melanoma across multiple clinical trials.

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
QTc Prolongation: QT prolongation has been observed in patients treated with 
BRAF inhibitors. Encorafenib is associated with dose-dependent QTc interval 
prolongation in some patients. In the COLUMBUS study, an increase in QTcF to 
> 500 ms was measured in 0.5% of patients.

Embryo-Fetal Toxicity: Encorafenib or binimetinib can cause fetal harm when 
administered to pregnant women.
2.1.5. Clinical Safety of Encorafenib
The maximum well-tolerated dose of encorafenib when given as a single agent is 300 mg 
QD. Encorafenib 300 mg QD as a single agent is associated with an increased risk of certain 
AEs compared to when used in combination with binimetinib. For example, Grade 3 or 4 
dermatologic reactions in the COLUMBUS study occurred in 21% of patients treated with 
single-agent encorafenib compared to 2% of patients treated with encorafenib in combination 
with binimetinib. 
Among patients receiving single-agent encorafenib 300 mg QD across multiple clinical trials 
including COLUMBUS, the most common AEs (≥20%, all grades) were alopecia (50%), 
palmar-plantar erythrodysesthesia syndrome (48%), arthralgia (43%), hyperkeratosis (42%), 
nausea (35%), dry skin (29%), fatigue (28%), myalgia (28%), headache (27%), vomiting 
(25%), rash (23%) and palmoplantar keratoderma (22%).
Encorafenib is primarily metabolized and eliminated by the liver; patients with mild to severe 
hepatic impairment may have increased exposure over the range of inter-patient variability 
exposure.
Detailed information regarding clinical safety of encorafenib used as a single agent is 
presented in the encorafenib Investigator’s Brochure.
2.2. Benefit/Risk Assessment
Data from the COLUMBUS study and preclinical and exposure-response data for 
encorafenib and binimetinib demonstrate that both agents in combination contribute to 
observed efficacy (Dummer et al, 2018a; Dummer et al, 2018b). Co-administration of 
encorafenib 450 mg QD with binimetinib 45 mg BID reduces the incidence of safety findings 
of interest for binimetinib (acneiform dermatitis, peripheral edema and rash) and encorafenib 
(arthralgia, myalgia, vomiting, headache, rash and palmoplantar keratoderma). The reduction 
of encorafenib toxicity with the addition of binimetinib enables a higher dose of encorafenib, 
as well as fewer dose interruptions and reductions, which may enhance the efficacy of the 
combination.
The primary risks of the combination of encorafenib plus binimetinib treatment are well 
characterized and include known class effects of BRAF and MEK inhibitors (see 
Sections 2.1.4 and 2.1.5). The combination of encorafenib plus binimetinib has a lower 
frequency and severity of pyrexia and photosensitivity reactions than the dabrafenib plus 
trametinib and vemurafenib plus cobimetinib combinations, respectively. Pyrexia was 
infrequent with the combination of encorafenib plus binimetinib, not complicated by chills,

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dehydration or renal failure and generally not recurrent. Almost all cases of pyrexia 
presenting as an SAE were associated with secondary causes of infection of progressive 
melanoma. Photosensitivity was infrequent (4.7%) in the encorafenib 450 mg QD plus
binimetinib 45 mg BID arm of the COLUMBUS study.
2.3. Study Rationale
Nonclinical data have demonstrated the enhanced activity of combining BRAF and MEK 
inhibition in BRAFV600-driven tumors (Stuart et al, 2012; Flaherty et al, 2012; Joshi et al, 
2015; Khunger et al, 2018). In a BRAFV600E NSCLC mouse xenograft model, administration 
of encorafenib (20 mg/kg QD) in combination with binimetinib (3.5 mg/kg BID) 
demonstrated enhanced anti-tumor activity (see Figure 2 and Table 4), with respect to tumor 
regression and tumor regrowth delay after dosing cesssation, compared to the single-agent 
activity of each drug. This combination has been validated clinically by the efficacy observed 
for the combination in BRAFV600E-mutant NSCLC (Planchard et al, 2017), and also in the 
treatment of BRAFV600-mutant melanoma where the combination of BRAF and MEK 
inhibition is an established standard-of-care based on 4 pivotal trials of various BRAF/MEK 
inhibitor combinations (Long et al, 2014; Ascierto et al, 2016; Robert et al, 2016; Dummer et 
al, 2018a).
Figure 2.
Effects of Encorafenib and Binimetinib in DFCI-306 Mice (BRAF V600E, 
EGFR del19, T790M)
Table 4.
Anti-tumor Activity of Encorafenib and Binimetinib in BRAF V600E 
Xenograft Model
Treatment
% Tumor Growth 
Inhibition
Maximum 
Regression
Days to 400% Target 
Tumor Volume
Vehicle
-
16.2
Encorafenib 
20 mg/kg QD
100%
13.0%
47.1
Binimetinib
3.5 mg/kg BID
91.7%
0%
36.2

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Table 4.
Anti-tumor Activity of Encorafenib and Binimetinib in BRAF V600E 
Xenograft Model
Treatment
% Tumor Growth 
Inhibition
Maximum 
Regression
Days to 400% Target 
Tumor Volume
Encorafenib + Binimetinib
20 mg/kg QD, 3.5 mg/kg BID
100%
45.7%
56.0
Although the current approved BRAF/MEK inhibitor combination of dabrafenib plus 
trametinib has transformed the standard-of-care treatment for NSCLC in patients who have 
the BRAFV600E mutation, it has liabilities (e.g., pyrexia) that could limit effectiveness 
suggesting that additional therapeutic options are needed. BRAFV600E NSCLC remains an 
aggressive disease that portends a poor prognosis and there remains a need to develop new 
treatment regimens to expand the therapeutic options for patients. 
In the Phase 3 COLUMBUS study of encorafenib with or without binimetinib compared to 
vemurafenib (a standard-of-care BRAF inhibitor comparator) in patients with advanced 
BRAFV600E/Kmutant melanoma, the combination was shown to improve PFS, OS and ORR 
compared to vemurafenib treatment (Dummer et al, 2018a; Dummer et al, 2018b). Median 
PFS, median OS and confirmed ORR for the combination of encorafenib plus binimetinib 
were 14.9 months (95% CI 11.0, 18.5), 33.6 months (95% CI 24.4, 39.2) and 63.0% (by 
central review; 95% CI 55.8, 69.9)/75.0% (by local review; 95% CI 68.3, 81.0), respectively. 
These results compared favorably to the PFS, OS and ORR of 7.3 months (95% CI 5.6, 8.2), 
16.9 months (95% CI 14.0, 24.5) and 40.3% (by central review; 95% CI 33.3, 47.6)/51.0% 
(by local review; 95% CI 41.9, 56.5), respectively, for vemurafenib, which performed almost 
identically on all endpoints compared to its performance in other pivotal trials in 
BRAFV600mutant melanoma where it was used as a control (Larkin et al, 2014; Robert et al, 
2015). These data compare favorably with results from trials of dabrafenib plus trametinib in 
a similar melanoma setting, with median PFS of 11.4 months, median OS of 25.6 months 
(95%CI 23.1, 34.3) and ORR of 64% by local review (95% CI 59, 69) for the combination of 
dabrafenib plus trametinib and median PFS of 7.3 months, median OS of 18 months (95% CI 
15.6, 20.7) and ORR of 51% by local review (95% CI 46, 97) for vemurafenib (Robert et al, 
2015; Robert et al, 2016).
Although encorafenib plus binimetinib was not studied in direct comparison to dabrafenib 
plus trametinib in melanoma, the numerically superior outcomes with encorafenib plus 
binimetinib, particularly when compared to results from trials that incorporated a common 
control arm (vemurafenib) that performed similarly across trials, provides reassurance that 
there is at least comparable efficacy in the setting of melanoma and suggest that the efficacy 
of encorafenib plus binimetinib in other BRAFV600-driven settings such as BRAFV600E
NSCLC may be similar or potentially superior to that observed with dabrafenib and 
trametinib. 
Importantly, encorafenib plus binimetinib has a different safety and tolerability profile 
(Flaherty et al, 2017) from dabrafenib plus trametinib. Pyrexia, manifesting as a distinctive 
recurrent febrile syndrome refractory to NSAIDs and associated in a minority of patients 
with chills, dehydration and renal failure, is a significant toxicity associated with dabrafenib 

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and trametinib, and is seen in over 50% of patients (Long et al, 2014). Treatment with 
encorafenib and binimetinib was associated with a lower incidence of pyrexia (18% of 
patients) in the COLUMBUS trial and these events were generally low grade, nonrecurrent 
and not associated with other manifestations (Dummer et al, 2018a; Dummer et al, 2018b); 
64% of patients with previously untreated BRAF-mutant advanced NSCLC, and 46% of 
patients with previously treated BRAF-mutant metastatic NSCLC who received dabrafenib 
plus trametinib reported pyrexia (Planchard et al, 2016a; Planchard et al, 2017).
Therefore, encorafenib plus binimetinib may represent an alternative BRAF/MEK inhibitor 
combination regimen for the treatment of BRAFV600E-mutant NSCLC. Encorafenib plus 
binimetinib has a differentiated safety profile and may have enhanced efficacy based on 
results observed in the treatment of BRAFV600-mutant melanoma. This study seeks to 
generate data to explore the efficacy and safety of this new combination in NSCLC.

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3. OBJECTIVES AND ENDPOINTS
Table 5.
Objectives and Endpoints
Primary Objective
Primary Endpoint
To evaluate the efficacy of encorafenib + 
binimetinib in treatment-naïve and previously 
treated patients with BRAFV600E-mutant NSCLC as 
measured by ORR
ORR defined as the proportion of patients who 
have achieved a confirmed best overall response 
(CR or PR) as determined by IRR per RECIST 
v1.1 in the treatment-naïve setting
ORR defined as the proportion of patients who 
have achieved a confirmed best overall response 
(CR or PR) as determined by IRR per RECIST 
v1.1 in the previously treated setting.
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of encorafenib + 
binimetinib in treatment-naïve and previously 
treated patients with BRAFV600E-mutant NSCLC as 
measured by DOR, DCR, PFS, and TTR
Confirmed ORR by Investigator per RECIST v1.1
DOR (by IRR and by Investigator) defined as the 
time from the date of the first documented 
response (CR or PR) that is subsequently 
confirmed (by IRR and by Investigator, 
respectively) to the earliest date of disease 
progression,  per RECIST v1.1, or death due to 
any cause
DCR (by IRR and by Investigator), defined as the 
proportion of patients who have a confirmed CR 
or confirmed PR, or SD per RECIST v1.1  
PFS (by IRR and by Investigator), defined as the 
time from the date of first dose of study drug to 
the earliest date of disease progression, per 
RECIST v1.1, or death due to any cause
TTR (by IRR and Investigator), defined as the 
time from the date of first dose to the first 
documentation of objective response (CR or PR) 
which is subsequently confirmed (by IRR and by 
Investigator, respectively)
To evaluate the efficacy of encorafenib + 
binimetinib in treatment-naïve and previously 
treated patients with BRAFV600E-mutant NSCLC 
with respect to OS
OS defined as the time from the date of first dose 
of study drug to the date of death due to any cause 
To evaluate the safety and tolerability of 
encorafenib + binimetinib in treatment-naïve and 
previously treated patients with BRAFV600E-mutant 
NSCLC
Incidence and severity of AEs graded according to 
the NCI CTCAE v4.03 and changes in clinical 
laboratory parameters, vital signs, ECGs and 
ECHO/MUGA scans
Exploratory Objectives
Exploratory Endpoints
To evaluate the PK of encorafenib and its 
metabolite LHY746 and binimetinib in in patients 
with BRAFV600-mutant NSCLC
Plasma concentration-time profiles and PK 
parameter estimates for encorafenib and its 
metabolite LHY746 and binimetinib

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Table 5.
Objectives and Endpoints
To assess blood ctDNA mutation status
Genomic analysis of ctDNA in blood samples
4. STUDY DESIGN
4.1. Overall Design
This is an open-label, multicenter, non-randomized, Phase 2 study to determine the safety, 
tolerability and efficacy of encorafenib given in combination with binimetinib in 
treatment-naïve and previously treated patients with BRAFV600E-mutant metastatic NSCLC. 
Although very rare in NSCLC, patients with other V600 Class 1 BRAF mutations (e.g., K or 
D) are also allowed. Patients who are either treatment-naïve, OR who have received 1) first-
line treatment with standard platinum-based chemotherapy, OR 2) first-line treatment with an 
anti-PD-1/PD-L1 inhibitor given alone, or in combination with platinum-based 
chemotherapy, or in combination with immunotherapy (e.g., ipilimumab) with or without 
platinum-based chemotherapy will be enrolled. Treatment will be administered in 28-day 
(± 3 days) cycles and will continue until the patient meets the protocol-defined criteria for 
treatment withdrawal (see Section 6.7). Once the patient discontinues study treatment, the 
treatment period will end, and the patient will enter the follow-up period for safety, 
subsequent anticancer therapy, disease status, and survival status (see Section 7.1.4). 
4.2. Discussion of Study Design
Due to the rarity of the BRAF mutations in patients with NSCLC (see Section 2.1.1), as well 
as the commercial availability of a BRAF/MEK combination, an adequately powered 
randomized clinical trial is not feasible. Because spontaneous remission is rare, ORR 
provides clear evidence of antitumor activity. Recent advances in the treatment of NSCLC 
patients with unique molecular drivers (e.g., ROS1 rearrangements and BRAF V600E-
mutations), has been founded on regulatory approvals based on non-randomized clinical 
trials demonstrating clinically meaningful and durable ORR (Shaw et al, 2016; Planchard et 
al, 2016). Thus, the primary endpoint of the study is ORR, defined as the proportion of 
patients with CR or PR according to RECIST v1.1 (Eisenhauer et al, 2009).
The patient population was selected based on the mechanisms of action of both encorafenib 
and binimetinib (see Section 2.1.3) that might result in a potentially therapeutic approach for 
the treatment of NSCLC patients with a BRAFV600E mutation. Inclusion of patients who had 
progressed on or after prior first-line immunotherapy was based on recent approvals of 
PD-1/PD-L1 antibodies and their progressive use as first-line treatment (see Section 2.1.2).
4.3. Justification for Dose
The regulatory approved dose and administration schedule of encorafenib 450 mg orally QD 
in combination with binimetinib 45 mg orally BID will be used in this study. Regulatory 
approval of encorafenib and binimetinib in combination was based on the Phase 3 
COLUMBUS study (Dummer et al, 2018a; Dummer et al, 2018b; see Sections 2.1.4, 2.2, 
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4.4. Duration of Treatment and Patient Participation
After signing the ICF, screening assessments may be completed over a period of up to 
28 days. Patients may continue to receive study treatment until they meet any of the protocol-
defined criteria for treatment withdrawal (see Section 6.7). If the patient discontinues study 
treatment, then the treatment period will end, and the patient will enter the follow-up period 
for safety, disease assessments (if applicable), subsequent anticancer therapies, and survival 
(see Section 7.1.4). Study participation, including post-treatment follow-up is expected to 
average approximately 12-18 months per individual patient. 
4.5. End of Study Definition
The end of study will occur 2 years after treatment initiation of the last enrolled patient or the 
point at which all patients have died or withdrawn consent or have been lost to follow up, 
whichever occurs first. At the end of the study, access to study treatment will be provided in 
accordance with applicable regulations and requirements to all patients who have not met the 
protocol-defined criteria for treatment withdrawal (see Section 6.7). 
4.6. Study Termination
The Investigator retains the right to terminate study participation at any time, according to 
the terms specified in the study contract. The Investigator is to notify the IRB/IEC in writing 
of the study’s completion or early termination, send a copy of the notification to the Sponsor 
or designee, and retain a copy for the site study regulatory file.
The Sponsor will assess the benefits and risks associated with the study on a continuous basis 
based on information from the study, as well as from routine pharmacovigilance activities for 
encorafenib and binimetinib, and may terminate the study electively if the balance of risks 
and benefits no longer supports continuation of the study, if required by regulatory decision 
or for other reasons (e.g., poor recruitment, changing scientific or clinical landscape). If the 
study is terminated prematurely, the Sponsor will notify the Investigators, the IRB/IEC and 
regulatory bodies of the decision and reason for termination of the study.
5. STUDY POPULATION
Questions regarding patient eligibility should be addressed to the Sponsor or Sponsor’s 
designated agent prior to enrollment. Patients must fulfill all of the following inclusion 
criteria and none of the exclusion criteria to be eligible for enrollment in the study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, are not permitted as they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, and/or patient safety.
5.1. Inclusion Criteria
Patients must meet all of the following criteria to be eligible for enrollment in the study:
1. Able to provide written informed consent. Adult patients under guardianship may 
participate with the consent of their legally authorized guardian if permitted by local 
regulations. 

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2. Age ≥ 18 years at the time of informed consent.
3. Histologically confirmed diagnosis of NSCLC that is currently Stage IV (M1a M1b, 
M1c- AJCC 8th edition).
4. Presence of a BRAFV600E mutation tumor tissue or blood (e.g., ctDNA genetic testing) 
as determined by a local laboratory assay. Other Class 1 BRAFv600 mutations (e.g., K 
or D) will be permitted with prior discussion with the Sponsor. 
Note: Patients must have written documentation from a previous local pathology 
report of BRAFV600 mutation in tumor tissue or blood.
Note: Only PCR and NGS-based local assay results for tumor tissue or blood will be 
acceptable.
5. The Investigator must obtain prior to enrollment adequate tumor tissue for submission 
to a central laboratory for confirmation of BRAFV600 mutation status.
Note: Tumor tissue collected after the patient was diagnosed with metastatic disease 
is preferred.
Note: Tumor tissue sample must not be from locations previously radiated.
Note: Tumor sample must be 1 block or a minimum of 8 unstained slides of 
analyzable tissue is required (up to 15 unstained slides is preferred).
Note: Tumor cells from pleural fluid are permitted provided the sample has been 
centrifuged to generate a formalin-fixed, paraffin-embedded block with sufficient 
tumor nuclei (i.e. >20% tumor nuclei). Liquid samples are not permitted. One block 
or a minimum of 8 unstained slides is required (up to 15 unstained slides is preferred).
Note: FNA is permitted provided sufficient material (1 block or a minimum of 8 
unstained slides is required [up to 15 unstained slides is preferred]) from the same 
sample used to obtain the local BRAF positive result can be sent to the central 
laboratory.
6. Patients who are either treatment-naïve (e.g., no prior systemic therapy for 
advanced/metastatic disease), OR who have received 1) first-line platinum-based
chemotherapy OR 2) first-line treatment with an anti-PD-1/PD-L1 inhibitor given 
alone, or in combination with platinum-based chemotherapy, or in combination with  
or in combination with immunotherapy (e.g., ipilimumab) with or without platinum-
based chemotherapy.
Note: Alternative chemotherapy regimens are acceptable if the patient was platinum 
intolerant or ineligible. 
Note: Patients with early stage disease (e.g., Stages I-III) who have had surgery 
followed by chemotherapy, radiation therapy and/or immunotherapy (e.g., treatment 
in the adjuvant setting), and present with new lesions or evidence of disease 
recurrence (e.g., metastatic disease), within 12 months of completing adjuvant 
treatment would be considered as having received treatment in the first-line setting 
for metastatic disease. These patients will start treatment with 
encorafenib/binimetinib in the previously treated setting. 
Note: Maintenance therapy given after first-line therapy in the metastatic setting will 

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not be considered a separate regimen, provided there was no documentation of 
disease progression between completion of first-line therapy and the start of 
maintenance therapy.
7. Presence of measurable disease based on RECIST v1.1.
Note: Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other locoregional therapy, are not considered measurable unless there has been 
documented progression of the lesion.
Note: If baseline scans from an institution other than the investigational site are used, 
the site must obtain copies of the scans prior to enrollment of the patient, or the scans 
must be repeated at the investigational site and submitted for independent review (see 
Section 7.2.4).
8. ECOG performance status of 0 or 1. 
9. Adequate bone marrow function characterized by the following at screening:
a.
ANC ≥1.5 × 109/L; 
b. Platelets ≥100 × 109/L;
c.
Hemoglobin ≥8.5 g/dL (with or without blood transfusions).
10. Adequate hepatic and renal function characterized by the following at screening:
a.
Total bilirubin ≤ 1.5 × ULN
Note: Patients with documented Gilbert syndrome or hyperbilirubinemia due 
to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following 
discussion and agreement with the Sponsor. 
b. ALT and AST ≤2.5 × ULN, or ≤5 × ULN in presence of liver metastases;
c. Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance
≥ 50 mL/min by Cockcroft-Gault formula; or estimated glomerular filtration 
rate > 50 mL/min/1.73m2.
11. Able to swallow, retain and absorb oral medications.
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests and other study procedures.
13. Female patients of childbearing potential as described in Appendix 1, must have a 
negative serum βHCG test result.
14. Female patients of childbearing potential must agree to use methods of contraception 
that are highly effective or acceptable, as described in Appendix 1, and to not donate 
ova from Screening until 30 days after the last dose of study treatment. 

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15. Male patients must agree to use methods of contraception that are highly effective or 
acceptable, as described in Appendix 1, and to not donate sperm from Screening until 
90 days after the last dose of study drug. 
5.2. Exclusion Criteria 
Patients meeting any of the following criteria are ineligible for enrollment in the study.
1. Patients who have documentation of any of the following: EGFR mutation, ALK 
fusion oncogene or ROS1 rearrangement.
2. Patients who have received more than 1 prior line of systemic therapy in the 
advanced/metastatic setting. Prior therapies can be reviewed with the Sponsor.
Note: Generally, treatments that are separated by an event of progression are 
considered to represent another line of therapy. 
Note: Any therapeutic intervention including systemic therapy, surgery concurrent 
with or followed by systemic therapy, radiation concurrent with systemic therapy, or 
stereotactic radiation/radiosurgery, initiated or added to an existing therapy for 
oligometastatic disease will be considered a new line of therapy.
Note: Palliative radiation to solitary lesions is permitted and will not be considered a 
new line of therapy.
Note: Surgery/radiosurgery for CNS metastases is permitted and will not be 
considered a line of therapy as long as the surgery/radiosurgery was not given with 
systemic therapy (neoadjuvant or adjuvant).
Note: Surgery followed by chemotherapy in the metastatic setting will be considered 
a line of therapy.
3. Previous treatment with any BRAF inhibitor (e.g., dabrafenib, vemurafenib, 
XL281/BMS-908662, etc.), or any MEK inhibitor (e.g., trametinib, cobimetinib,
selumetinib, RDEA119, etc.) prior to screening and enrollment.
4. Receipt of anticancer medications or investigational drugs within the following 
intervals before the first administration of study treatment:
a.
≤ 14 days for chemotherapy, targeted small-molecule therapy, radiation 
therapy, immunotherapy, or antineoplastic biologic therapy (e.g., erlotinib, 
crizotinib, bevacizumab, etc.).
b. ≤ 14 days or 5 half-lives (minimum of 14 days) for investigational agents or 
devices. For investigational agents with long half-lives (e.g., > 5 days), 
enrollment before the fifth half-life requires medical monitor approval. (
Note: COVID-19 vaccinations approved under an Emergency Use Authorization 
(EUA) (or equivalent) are not considered investigational products by regulatory 
authorities. 
c.
Palliative radiation therapy must be complete 7 days prior to the first dose of 
study treatment.

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5. Patients who have had major surgery (e.g., inpatient procedure with regional or 
general anesthesia) ≤6 weeks prior to start of study treatment.
6. Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy and/or 
complications from prior surgical intervention before starting study treatment.
Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (e.g., 
neuropathy, myalgia, alopecia and prior therapy-related endocrinopathies) are 
exceptions.
7. Current use of a prohibited medication (including herbal medications, supplements or 
foods), as described in Section 6.5.2, or use of a prohibited medication ≤ 1 week prior 
to the start of study treatment.
8. Impairment of gastrointestinal function or disease which may significantly alter the 
absorption of oral study treatment (e.g., uncontrolled nausea, vomiting or diarrhea, 
malabsorption syndrome, small bowel resection).
9. Impaired cardiovascular function or clinically significant cardiovascular diseases, 
including any of the following:
a.
History of acute myocardial infarction, acute coronary syndromes (including 
unstable angina, coronary artery bypass graft, coronary angioplasty or 
stenting)
≤ 6 months prior to start of study treatment;
b. Congestive heart failure requiring treatment (New York Heart Association 
Grade ≥2); 
c.
LVEF < 50% as determined by MUGA or ECHO;
d. Uncontrolled hypertension defined as persistent systolic blood pressure 
≥150 mmHg or diastolic blood pressure ≥100 mmHg despite optimal 
therapy;
e.
History or presence of clinically significant cardiac arrhythmias (including 
uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular 
tachycardia);
f.
Triplicate average baseline QTcF interval ≥ 480 ms or a history of prolonged 
QT syndrome.

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10. History of thromboembolic or cerebrovascular events ≤12 weeks prior to the first 
dose of study treatment. Examples include transient ischemic attacks, cerebrovascular 
accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein 
thrombosis or pulmonary emboli.
Note for all countries except Korea: Patients with either deep vein thrombosis or 
pulmonary emboli that do not result in hemodynamic instability are allowed to enroll 
if  they are stable, asymptomatic and on stable anticoagulants for at least 2 weeks. 
Note: Patients with thromboembolic events related to indwelling catheters or other 
procedures may be enrolled.
11. History or current evidence of RVO or current risk factors for RVO (e.g., 
uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes); history of retinal degenerative disease.
12. Concurrent neuromuscular disorder that is associated with the potential of elevated 
CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral 
sclerosis, spinal muscular atrophy).
13. Evidence of active noninfectious pneumonitis or history of interstitial lung disease.
14. Evidence of HBV or HCV infection.
Note: Patients with laboratory evidence of cleared HBV or HCV infection may be 
enrolled.
Note: Patients with no prior history of HBV infection who have been vaccinated 
against HBV and who have a positive antibody against hepatitis B surface antigen as 
the only evidence of prior exposure may enroll.
15. Known history of a positive test for HIV or known AIDS. Testing for HIV must be 
performed at sites where mandated locally.
16. Active infection requiring systemic therapy.
17. Patients with symptomatic brain metastasis, leptomeningeal disease or other active 
CNS metastases are not eligible.
Note: Patients with previously treated brain metastases may participate provided they 
are stable for at least 28 days prior to the first dose of study treatment and any 
neurologic symptoms must have returned to baseline. Patients with untreated brain 
metastases may participate provided the lesions are < 5 mm and are clinically stable 
and asymptomatic.
Note: Patients must have no evidence of new or enlarging brain metastases or CNS 
edema. 
18. Concurrent or previous other malignancy within 2 years of study entry, except 
curatively treated basal or squamous cell skin cancer, prostate intraepithelial 
neoplasm, carcinoma in-situ of the cervix, Bowen’s disease and Gleason ≤ 6 prostate 
cancer. Patients with a history of other curatively treated cancers must be reviewed 
with the Sponsor prior to entering the study.

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19. Known sensitivity or contraindication to any component of study treatment 
(binimetinib and encorafenib), or their excipients.
20. Pregnancy or breastfeeding or patients who plan to become pregnant during the 
duration of the study.
21. Other severe, acute or chronic medical or psychiatric condition(s) or laboratory 
abnormality that may increase the risk associated with study participation or study 
treatment administration or that may interfere with the interpretation of study results 
and, in the judgment of the Investigator, would make the patient an inappropriate 
candidate for the study.
5.3. Lifestyle Considerations
Please refer to Appendix 1 for guidance on contraceptive use for males and females of 
childbearing potential.
5.3.1. Meals and Dietary Restrictions
Patients must avoid consumption of grapefruit, pomegranates, star fruits, Seville oranges or 
products containing the juice of each during the entire study and preferably 7 days before the 
first dose of study drugs, due to potential CYP3A4 interaction with encorafenib (see 
Section 6.5.1.1). Orange juice is allowed.
5.3.2. Activity
Strenuous physical activities, such as competitive sports, can result in significant increases in 
CK levels while on binimetinib treatment. Patients should be cautioned not to start a new 
strenuous exercise regimen after first dose of study treatment.
5.4. Screen Failures
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failures to meet the Consolidated Standards 
of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAEs.
Tests with results that fail eligibility requirements may be repeated during Screening if the 
Investigator believes the result to be in error. Additionally, a patient who fails Screening 
(screen failure) may repeat the Screening process 1 time if the Investigator believes that there 
has been a change in eligibility status. 
6. STUDY TREATMENT
Study treatment refers to encorafenib and binimetinib. Detailed information regarding the 
study treatment can be found in Table 6 and in the IPM. Detailed information on study drug 
preparation, handling, storage and accountability will be provided in the Pharmacy Manual.

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Alternate starting doses may also be explored based on the observed safety of the 
combination regimen in NSCLC patients. For an individual patient, the dose of study 
treatment may be reduced or interrupted as appropriate based on protocol-defined treatment 
modifications (see Section 6.6).
6.1. Study Treatments Administered
6.1.1. Encorafenib
Encorafenib will be self-administered orally without regard to food. Encorafenib should be 
taken daily in the morning at approximately the same time (± 2 hours) every day. Patients 
should be directed to take encorafenib and binimetinib together as applicable. Patients will 
swallow the study intervention whole, and will not manipulate by, for example, opening or 
crushing, or chew the study intervention. If a patient vomits at any time after dosing, the dose 
should not be re-administered. Doses of encorafenib that are omitted for AEs or any other 
reason should not be made up during the day, or at the end of the dosing period. Additional 
information regarding encorafenib administration is provided in the IPM.
Encorafenib will begin on Cycle 1 Day 1 and will be self-administered continuously, except 
on study visit days (e.g., Day 1 of each cycle; see Table 3), and days when PK samples will 
be drawn (see Table 12 and Table 13), when the encorafenib dose will be administered at the 
study site under observation of the Investigator. Treatment may continue if the patient has 
not met any of the protocol-defined conditions for treatment withdrawal (see Section 6.7).
6.1.2. Binimetinib
Binimetinib will be self-administered orally without regard to food. Binimetinib should be 
taken 12 ± 2 hours apart in the morning and in the evening at approximately the same times 
every day. Patients should be directed to take binimetinib and encorafenib together as 
applicable. Patients will swallow the study intervention whole, and will not manipulate by, 
for example, opening or crushing, or chew the study intervention. If a patient vomits at any 
time after dosing, the dose should not be re-administered, and the patient should take the next 
scheduled dose. Doses of binimetinib that are omitted for AEs or any other reason should not 
be made up during the day, or at the end of the dosing period. Additional information 
regarding binimetinib administration is provided in the IPM.
Binimetinib will begin on Cycle 1 Day 1 and will be self-administered continuously, except 
on study visit days (e.g., Day 1 of each cycle; see Table 3), and days when PK samples will 
be drawn (see Table 12 and Table 13), when the morning binimetinib dose will be 
administered at the study site under observation of the Investigator. Treatment may continue 
if the patient has not met any of the protocol-defined conditions for treatment withdrawal 
(see Section 6.7).
Table 6.
Study Treatments
Study Treatment Name
Encorafenib
Binimetinib
Type
Drug
Drug

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Table 6.
Study Treatments
Study Treatment Name
Encorafenib
Binimetinib
Dose Formulation
Capsule
Tablet
Unit Dose Strength
75 mg
15 mg
Dosage Levels
450 mg QD
45 mg BID
Route of Administration
Oral
Oral
Sourcing
Encorafenib will be provided 
centrally by the Sponsor or designee
Binimetinib will be provided 
centrally by the Sponsor or designee
Packaging and Labeling
Encorafenib will be provided in 
high-density polyethylene bottles. 
Each bottle will be labeled per local 
regulatory requirements.
Binimetinib will be provided in 
high-density polyethylene bottles. 
Each bottle will be labeled per local 
regulatory requirements.
Former Names or Aliases
LGX818
ONO-7702
W0090
ARRAY-438162
MEK162
ONO-7703
W0074
6.2. Preparation/Handling/Storage/Accountability
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the Investigator and authorized site staff.
The Investigator (or designee), is responsible for study drug accountability, reconciliation, 
and record maintenance (i.e., receipt, reconciliation, and final disposition records). Inventory 
and accountability records must be maintained and readily available for inspection by the 
study monitor and are open to inspection at any time by applicable regulatory authorities. 
The Investigator or designee must maintain records that document:

Delivery of study drugs to the site.

Inventory of study drugs at the site.

Patient use of study drugs including capsule/tablet counts from each supply 
dispensed.

Return of study drugs to the Investigator or designee by the patient.

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The study treatment must be used only in accordance with the protocol. The Investigator will 
also maintain records adequately documenting that the patient was provided with the 
specified study drugs. These records should include dates, quantities, and any available batch 
or serial numbers or unique code numbers assigned to the study drugs and study patients.
Completed accountability records will be archived by the site. The Investigator or designee 
will be expected to collect and retain all used, unused, and partially used containers of study 
drugs until verified by the study monitor (unless otherwise agreed to by the Sponsor). At the 
conclusion of the study, the Investigator or designee will oversee shipment of any remaining 
study drug back to the Sponsor or designee, or destruction of study drug according to 
institutional standard operating procedures.
Detailed information on study drug preparation, handling, storage and accountability will be 
provided in the IPM.
6.3. Randomization and Blinding
6.3.1. Randomization and Blinding
No randomization or blinding mechanisms will be used in this open-label study; however, the 
study treatment will be dispensed using an IWRS. The site will contact the IWRS to enroll 
the patient and to obtain the study drugs. All subsequent cycles will follow this process. The 
IWRS will also be used to order study drug supplies and document when patients are 
discontinued from treatment. Full details will be provided in the Study Manual. 
6.3.2. Patient Numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned 
when the patient enters the screening period and is retained as the primary identifier for the 
patient throughout his/her entire participation in the study. The Patient No. consists of the 4 
digits Center Number (as assigned by the Sponsor or designee to the investigative site) with a 
sequential patient number suffixed to it (the last 4 digits of the Patient ID), so that each 
patient is numbered uniquely across the entire database. Upon signing the informed consent 
form, the patient is assigned to the next sequential Patient No. available to each Investigator 
through IWRS. Once assigned, the Patient No. must not be reused for any other patient and 
the Patient No. for that individual must not be changed, even if the patient is rescreened. If 
the patient fails to be enrolled or start treatment for any reason, the reason will be entered 
into the eCRF. Refer to Section 5.4 for further information on data collected for screen 
failures. The IWRS must be notified within 2 days that a patient did not initiate study drug 
dosing.
6.4. Study Treatment Compliance
Patient compliance with study treatment will be assessed at each visit. Compliance with all 
study-related treatments should be emphasized to the patient by the site personnel, and 
appropriate steps should be taken to optimize compliance during the study. Compliance will 
be assessed by an accounting of returned study drugs (tablet/capsule counts) and patient 
interviews. Patients will be instructed to bring all study drugs (used, partially used, unused 
drug and/or empty containers) with them to study site visits in order for site personnel to 

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assess study drug accountability. Deviation(s) from the prescribed dosage regimen should be 
recorded in source and in the eCRF. 
6.5. Concomitant Therapy
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines and/or herbal supplements) must be recorded in the eCRF. 
Details regarding all prior anticancer treatments will also be recorded in the eCRF. 
Any prior medication received up to 28 days before the first dose of study treatment and 30 
days after the last dose of study treatment, or until the patient begins a new anticancer 
therapy, whichever occurs first will be recorded in the eCRF. Any addition, deletion or 
change in the dose of these medications will also be recorded. Unless specifically prohibited, 
concomitant medications can be administered at the Investigator’s discretion to manage the 
patient’s medical condition. 
All concomitant treatments/procedures (including over-the-counter or prescription 
medications, vitamins and/or herbal supplements) that are required to manage a patient’s 
medical condition during the study will be recorded in the eCRF including:  

Reason for use.

Dates of administration including start and end dates.

Dosage information (using generic drug names when possible), including dose and 
frequency.
COVID-19 vaccines approved under an EUA (or equivalent) are considered allowed 
concomitant medications and standard AE collection and reporting processes should be 
followed. The timing of vaccine dosing relative to the dosing of study medications is at the 
discretion of the investigator although administration should be avoided on the first day of 
study medication dosing.
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy.
6.5.1. Permitted Concomitant Therapy Requiring Caution and/or Action
6.5.1.1. CYP and UGT Substrates and Inhibitors
Encorafenib is a reversible inhibitor of CYP2B6, CYP2C9, CYP3A4 and UGT1A1. It is also 
a time-dependent inhibitor of CYP3A4, and induced CYP2B6, CYP2C9 and CYP3A4 in 
human primary hepatocytes. Permitted medications to be used with caution in this study 
include those that are sensitive substrates of CYP2B6, CYP2C9, CYP3A4 and UGT1A1 or 
those substrates that have a narrow therapeutic index.
There is a potential for encorafenib to induce CYP3A4, which may reduce the 
effectiveness of hormonal contraception methods. Therefore, the use of at least 1 form 

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of non-hormonal contraception is required for females of childbearing potential during 
participation in this study. 
Caution should be used in patients receiving concomitant treatment with other drugs that are 
substrates of CYP3A4 as the efficacy of these drugs could be reduced when administered 
with encorafenib.
Encorafenib has been identified to be metabolized by CYP3A4 and to a lesser extent by 
CYP2C19 in vitro. Concomitant use of moderate CYP3A4 inhibitors should be avoided. 
If use of a moderate CYP3A4 inhibitor is unavoidable, short-term use (≤30 days) following 
discussion with the Sponsor may be permitted with an accompanying dose reduction to one-
half of the encorafenib dose prior to use of the moderate CYP3A4 inhibitor. After the 
inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the encorafenib dose 
that was taken prior to initiating the CYP3A4 inhibitor. 
In vitro, binimetinib has been identified to be primarily metabolized by glucuronidation. 
Strong inducers of UGT1A1 should be taken with caution when co-administered with 
binimetinib.
For tabulated CYP substrates, inhibitors and inducers to be used with caution or avoided, 
please consult with the FDA website: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers.
6.5.1.2. Transporter Substrates and Inhibitors
In vitro data showed that encorafenib is a substrate of the transporter P-gp. Thus, drugs that 
are known to inhibit or induce P-gp should be used with caution. Encorafenib is also a potent 
inhibitor of the renal transporters, OAT1, OAT3 and OCT2, and the hepatic transporters 
OATP1B1 and OATP1B3. The co-administration of drugs that are known to be sensitive or 
narrow therapeutic index substrates of OAT1, OAT3, OCT2, OATP1B1 or OATP1B3 should 
be used with caution.
Binimetinib has also been shown to be a substrate of P-gp and BCRP. It is advised that 
inhibitors and inducers of P-gp and BCRP transporters should be taken with caution when 
co-administered with binimetinib. 
For tabulated transporter substrates, inhibitors and inducers to be used with caution, please 
consult with the FDA website: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers.
6.5.1.3. Drugs with a Conditional or Possible Risk to Prolong QT Interval and/or 
Induce Torsade de Pointes
Investigators should use caution when administering encorafenib with concomitant 
medications with a known, conditional or possible risk to prolong the QT interval and/or 
induce torsade de pointes. Patients receiving such medications must be carefully monitored 
for potentiating of toxicity due to any individual concomitant medication and may require 
dose titration of the concomitant medication. See the CredibleMeds® website: Combined 
List of Drugs That Prolong QT and/or cause Torsades de Pointes (TDP).

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6.5.2. Prohibited Concomitant Therapy
Medications specifically outlined below are not allowed during the study. If there is a clinical 
indication for one of these medications specifically prohibited during the study, 
discontinuation from the study treatment may be required. Patients may receive other 
medications that the Investigator deems to be medically necessary. The Investigator should 
discuss any questions regarding medications with the Sponsor. The final decision on any 
supportive therapy rests with the Investigator and/or the patient’s primary physician. The 
decision to continue the patient in the study requires mutual agreement of the Investigator, 
the Sponsor and the patient.
The following therapies are prohibited during the Screening and Treatment Periods of this 
study (unless otherwise noted). There are no prohibited therapies during the post-treatment 
Follow-up Period.

No additional anticancer agents such as cytotoxic chemotherapy, small-molecule 
targeted agents, biological agents, immune response modifiers or hormonal therapy 
are to be administered to patients while they are receiving study treatment.

Investigational drugs and devices. 

Radiation therapy (not including palliative radiotherapy at focal sites that covers 
≤10% of the bone marrow reserve). 
Note: The patient must have clear measurable disease outside the radiated field. 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on a case-by-case basis after consultation with the Sponsor.  Note:
Administration of palliative radiation therapy will be considered clinical progression 
for the purposes of determining PFS.

Concomitant strong systemic CYP3A4 inhibitors, which could significantly increase 
the exposure of encorafenib.

Concomitant moderate or strong systemic CYP3A4 inducers, which could 
significantly decrease the exposure of encorafenib.
6.6. Dose Modification
6.6.1. Dose Interruptions
Following initiation of therapy, treatment with encorafenib and binimetinib may be delayed 
to allow resolution of toxicity. Patients may resume treatment if no medical condition or 
other circumstance exists that, in the opinion of the Investigator, would make the patient 
unsuitable for further participation in the study.
Individual decisions regarding dose interruptions and modifications should be made using 
appropriate clinical judgment, considering relatedness of the AE to the study treatment and 
the patient’s underlying condition. Adverse events that have a clear alternative explanation, 
or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant 
signs or symptoms may be exempt from dose-reduction rules. The treating Investigator 

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should refer to and follow the labeled guidance and/or institutional guidelines for the 
management of toxicities relating to encorafenib and binimetinib. Detailed guidelines can 
also be found in Appendix 2 and Appendix 3.
Dose interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study treatment (e.g., elective surgery, unrelated medical events, vacation, 
holidays). Patients should be placed back on study treatment within 2 weeks (14 days) of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption will be documented in the patient’s study record. 
If a patient misses > 6 weeks (i.e., 42 consecutive days) of dosing with encorafenib, study 
treatment with encorafenib will be permanently discontinued. Due to the potential for 
limited efficacy of binimetinib alone in the study population, if a patient permanently 
discontinues treatment with encorafenib, they must also permanently discontinue 
treatment with binimetinib.
If a patient misses > 6 weeks (i.e., 42 consecutive days) of dosing with binimetinib, study 
treatment with binimetinib will be permanently discontinued. If a patient discontinues 
treatment with binimetinib, the patient may continue treatment with encorafenib. Due 
to the potential for increased toxicity when binimetinib is discontinued, doses of single-
agent encorafenib may need to be decreased.
6.6.2. Dose Modifications
Doses of encorafenib and binimetinib may be independently reduced for toxicity 
management as outlined in Table 7 and Table 8, respectively. All dose modifications are 
based on the worst preceding toxicity. The treating Investigator should refer to and follow the 
labeled guidance and/or institutional guidelines for the management of toxicities relating to 
encorafenib and binimetinib. Detailed guidelines can also be found in Appendix 2 and 
Appendix 3. 
When the AE that resulted in a dose reduction improves to and remains stable to the patient’s 
baseline for a minimum of 14 days, the dose can be re-escalated to the next higher dose level 
at the discretion of the Investigator, provided there are no other concomitant toxicities that 
would prevent drug re-escalation. There is no limit to the number of times the patient can 
have their dose reduced or re escalated; however:

No dose re-escalation of encorafenib is allowed after a dose reduction due to 
prolonged QTcF ≥ 501 msec

No dose re-escalation of binimetinib is allowed after a dose reduction due to LVEF 
dysfunction 

No dose re-escalation of binimetinib or encorafenib is allowed after a dose reduction 
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Table 7.
Dose Reductions for Encorafenib
Dose Level
Encorafenib
0 (starting dose)
450 mg QD
-1
300 mg QD
-2
225 mga QD
NOTE: Dose reduction should be based on the highest AE grade.
a Dose reduction below 225 mg QD of encorafenib is not allowed.
Table 8.
Dose Reductions for Binimetinib
Dose Level
Binimetinib
0 (starting dose)
45 mg BID
-1
30 mga BID
NOTE: Dose reduction should be based on the highest AE grade.
a Dose reduction below 30 mg BID of binimetinib is not allowed.
6.7. Criteria for Permanent Discontinuation of Study Treatment
A patient may choose to withdraw from study treatment at any time or be withdrawn from 
study treatment by the Investigator or Sponsor, if the patient does not comply with study 
requirements. If a patient is withdrawn from any/all study treatment, reasonable efforts will 
be made to determine the reason for withdrawal, and this information will be recorded in the 
eCRF.
As of IRB/IEC approval of Amendment 3, patients who request to discontinue receipt of 
study treatment will remain in the study and must continue to be followed for protocol-
specified follow-up procedures (see Section 7.1.4.2 and Section 7.1.4.3). The only exception 
to this is when a patient specifically withdraws consent for any further contact with him or 
her or persons previously authorized by the patient to provide this information.  Patients 
should notify the investigator in writing of the decision to withdraw consent from future 
follow-up, whenever possible.  The withdrawal of consent should be explained in detail in 
the medical records by the investigator, as to whether the withdrawal is only from further 
receipt of study treatment or also from study procedures and/or posttreatment study follow-
up, and entered on the appropriate CRF page.  In the event that vital status (whether the 
patient is alive or dead) is being measured, publicly available information should be used to 
determine vital status only as appropriately directed in accordance with local law.

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Patients meeting any of the following criteria must discontinue all study treatment:

Withdrawal of consent. Patients may choose to withdraw from the study at any time 
without penalty of jeopardizing their healthcare or loss of benefits to which the 
patient is otherwise entitled. Patients will have the option of withdrawing consent for 
study treatment but continue in the follow-up period of the study for safety/efficacy 
assessments. 
Note: Consent withdrawn from study treatment means that the patient may choose 
to discontinue study treatment but remain in the study to be followed for safety, 
progression, subsequent therapies and survival. In this case, follow-up data will 
continue to be collected for this patient. 
Note: Consent withdrawn for the study means that the patient has explicitly indicated 
that they do not want to be followed any longer; in this case no further data, except 
data in the public domain, may be solicited from or collected on the patient. 

Unacceptable AEs or failure to tolerate study treatment is defined as:
o
Grade 4 or life-threatening AE as outlined in Appendix 2 and Appendix 3, (except 
with approval from the Sponsor);
o
Toxicity requiring more than the allowed number of dose reductions for 
encorafenib and binimetinib as described in Table 7 and Table 8, respectively;
o
Occurrence of an AE that is related to study treatment and in the judgment of the 
Investigator compromises the patient’s ability to continue study-specific 
procedures, or is considered to not be in the patient’s best interest.

Patient has missed > 6 weeks (i.e., 42 consecutive days) of dosing per Section 6.6.1.

Disease progression per RECIST v1.1.

Clinical progression, as determined by the Investigator in the absence of radiographic 
progression.

Patient becomes pregnant or begins breastfeeding.

Significant protocol deviation that, in the opinion of the Investigator and/or Sponsor, 
renders the patient unsuitable for further study treatment administration.

Patient is noncompliant with study procedures or study treatment that in the judgment 
of the Investigator or Sponsor renders the patient unsuitable for further study 
participation. 

Patient is lost to follow-up.

Death.

Termination of the study by the Sponsor (described in Section 4.6 and Section 9.10).

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If the decision is made to permanently discontinue study treatment the EOT visit should be 
conducted (see Section 7.1.3). Reasonable efforts should be made to have the patient return 
for all applicable follow-up visits (safety and efficacy), as outlined in the Table 3. The date of 
the last dose of study treatment will be recorded in the eCRF. 
6.8. Criteria for Study Discontinuation
Patients will be considered as having discontinued the study if any of the following criteria 
are met:

Patient completes all required follow-up visits.

Patient dies, and the date of death is available or patient is known to have died; 
however, the date of death cannot be obtained.
Note: Every effort must be made to obtain the date of death.

Consent is withdrawn for any further contact related to the study.
Note: Every reasonable effort should be made to determine the reason a patient 
withdraws prematurely, and this information should be documented in the eCRF.

Patient is lost to follow-up.

Termination of the study by the Sponsor (described in Section 4.6 and Section 9.10).

Termination of the study by the local health authority, IRB or IEC.
6.9. Intervention after the End of the Study
At the end of the study, all patients who have otherwise not met the protocol-defined criteria 
for treatment withdrawal (see Section 6.7), will be offered access to study treatment in 
accordance with applicable regulations and requirements (i.e., including where required, 
separate health authority approval for continued access).
6.10. Enrollment of Additional Patients
Additional patients may be enrolled to ensure that there are at least 60 treatment-naïve 
patients and 37 previously treated patients whose tumors have locally confirmed BRAFV600E
mutation, and who have received at least one dose of study treatment. Up to 10 additional 
patients who have a BRAFV600 mutation other than BRAFV600E (BRAFV600x) can be enrolled 
and treated. It is not expected that more than 107 patients with any BRAFV600 mutation will 
be enrolled and treated.
6.11. Lost to Follow up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.

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The following actions must be taken if a patient fails to return to the study site for a required 
study visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether the patient wishes to and/or should continue in the 
study.

Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient. These contact attempts will be 
documented in the patient’s medical record.

Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study and lost to follow-up. 
7. STUDY VISITS AND ASSESSMENTS
The timing of study visits and assessments are summarized in the SoA (Table 3). Protocol
waivers or exemptions are not allowed. Safety concerns should be discussed with the 
Sponsor immediately upon occurrence or awareness to determine if the patient should 
continue or discontinue study treatment. Adherence to the study design requirements, 
including those specified in the SoA, is essential and required for study conduct.
7.1. Study Visits
7.1.1. Screening
Screening is the interval between signing the ICF up to the time at which the patient receives 
the first dose of study treatment (i.e., Cycle 1 Day 1). Screening may not exceed 28 days. 
Assessments that are required to demonstrate eligibility may be performed over the course of 
1 or more days during the Screening process.
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count, 
imaging study) and obtained before signing of the ICF may be utilized for Screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (Table 3). If baseline scans from an 
institution other than the investigational site are used, the site must obtain copies of the scans 
prior to enrollment of the patient, or the scans must be repeated at the investigational site and 
submitted for independent review (see Section 7.2.4).  
All Screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. Tests with results that fail eligibility requirements may be repeated once during 
screening if the Investigator believes the results to be in error. For screening assessments that 
are repeated, the most recent available results before first dose of study treatment will be 
used to determine eligibility.

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See Section 5.4 and Section 6.10 for information regarding screen failures and enrollment of 
additional patients, respectively.
7.1.1.1. BRAFV600 Mutation Testing
Patients will be eligible for the study based on identification of a BRAFV600 mutation in the 
tumor tissue or blood (e.g., ctDNA genetic testing), as determined by a local laboratory 
assay. Patients must have written documentation from a previous local pathology report of 
BRAFV600 mutation in tumor tissue or by genetic blood test. Only PCR and NGS-based local 
assay results will be acceptable for tumor tissue or blood.
The Investigator must confirm prior to enrollment that the patient has adequate tumor 
tissue available for confirmation of BRAFV600 mutation status by the central laboratory.
Results of central confirmation of BRAFV600 mutation status is not required prior to 
enrollment and will not be used for determining patient eligibility.
Archived tumor tissue or a newly obtained core or excisional biopsy sample from all patients 
are required to be submitted to the central testing laboratory. FNA is acceptable provided 
there is sufficient material (1 block or a minimum of 8 unstained slides [up to 15 unstained 
slides is preferred]) from the same sample used to obtain the local BRAF positive result 
available to send to the central laboratory. 
For archival tumor tissue samples, whenever possible the sample sent for central testing 
should be from the same tumor block that was used for local BRAFV600 mutation testing. A 
minimum of 8 slides (up to 15 is preferred) should be submitted to the central laboratory to 
ensure adequate sample for testing. Tumor cells from pleural fluid are permitted provided the 
sample has been centrifuged to generate a formalin-fixed, paraffin-embedded block with 
sufficient tumor nuclei (i.e. >20% tumor nuclei). Liquid samples are not permitted. One 
block or a minimum of 8 unstained slides (up to 15 unstained slides is preferred) must be sent 
to the central laboratory. Further details regarding sample submission including instructions 
for sample preparation and shipping will be provided in the Laboratory Manual.
If a fresh biopsy is taken, the biopsy should be taken from a nontarget lesion when possible.
7.1.2. Treatment Period
The treatment period begins on the day the patient receives the first dose of study treatment 
(i.e., Cycle 1 Day 1) through the point which the patient permanently discontinues all study 
treatment. During the treatment period, patients will have regularly scheduled assessments as 
outlined in the SoA (Table 3).
7.1.3. End of Treatment and/or Early Termination
When the patient permanently discontinues all study treatment (see Section 6.7), whether the 
patient is terminating the study early or has completed the study (see Section 6.8), the EOT 
visit should be conducted. If the EOT visit coincides with a regular study visit, the EOT 
evaluations will supersede those of the scheduled visit, and the data will be entered in the 
EOT visit in the eCRF. 

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If the patient is withdrawn from study treatment and/or study:

The study monitor and Sponsor must be notified.

The primary reason for withdrawal must be documented in the patient’s medical 
record and in the eCRF.
Note: The reason for withdrawal from treatment may be different from the reason for 
withdrawal from study. For example, patients can discontinue treatment for disease 
progression or toxicity, but remain in the study for safety and survival follow-up.

The EOT and safety follow-up visits as outlined in the SoA (Table 3) should be 
performed.

Patients should be followed for safety as outlined in Sections 7.1.4.1 and 7.5.1.1. 

Patients who discontinue study treatment for reasons other than disease progression 
will continue to be followed for disease status as outlined in Section 7.1.4.2.

All patients who discontinue study treatment will continue to be followed for 
subsequent anticancer therapies and survival (see Section 7.1.4.3).

If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records.
7.1.4. Post-treatment Follow-up
Cutaneous squamous cell carcinoma has been observed in patients treated with BRAF 
inhibitors including encorafenib. It is recommended that dermatologic screening for skin 
malignancies be performed every 8 weeks until 6 months after the last dose of encorafenib. 
Patients should be instructed to immediately inform the Investigator if new skin lesions 
develop.
7.1.4.1. 30-Day Safety Follow-up
The safety follow-up period is the interval between the EOT visit and the scheduled follow-
up visit, which should occur 30 days (+ 7 days) after the EOT visit (or after the last dose of 
study treatment if the EOT was not performed). Adverse events and SAEs must be reported 
as outlined in Section 7.5.1.1 and Section 7.5.1.2. Information related to AEs (including 
concomitant medication taken for ongoing AEs) and new anticancer therapies will be 
collected. Reasonable efforts should be made to have the patient return for the safety follow-
up visit and report any AEs that may occur during this period. If the patient is scheduled to 
start a new anticancer therapy before the end of the 30-day follow-up period, the safety 
follow-up visit should be performed before the new anticancer therapy is started. 

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7.1.4.2. Disease Follow-up
Patients who discontinue study treatment for a reason other than disease progression will 
move into the disease status follow-up and should be assessed every 8 weeks (±7 days) by 
radiological imaging to monitor disease status. If the patient discontinues for reasons other 
than disease progression after 12 months of treatment, then radiographic disease assessments 
will be performed every 12 weeks (±7 days). Every effort should be made to collect 
information regarding disease status until:

Initiation of subsequent anticancer therapy

Disease progression

Death

Withdrawal of consent

Patient is lost to follow-up

Defined end of study
7.1.4.3. Survival Follow-up
Once a patient has received the last dose of study treatment, has confirmed disease 
progression, or starts a new anticancer therapy, the patient moves into the survival follow-up 
period and should be contacted by telephone, email, or site visit by the patient or patient’s 
caregiver at least every 12 weeks (±7 days), until withdrawal of consent, the patient is lost to 
follow-up, death or defined end of the study, whichever occurs first. The following 
information will be recorded at each follow-up assessment:

Following the 30-day safety follow-up period, record new SAEs that are considered 
related to study treatment.

Record all subsequent anticancer therapies.

Determine survival status.
If patients withdraw consent for study treatment, they will be asked if they are willing to be 
contacted via telephone for survival status. If the patient refuses to be contacted, attempts to 
determine survival status should be made via access to public records/databases where 
permitted by local laws.
7.1.5. Unscheduled Visits
Unscheduled study visits may occur at any time if medically warranted. Any assessments 
performed at those visits should be recorded in the eCRF.

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7.2. Efficacy Assessments
7.2.1. Radiological Tumor Evaluation
RECIST v1.1 (Eisenhauer et al, 2009) will be applied by the site as the primary measure of 
tumor assessment and response and as the basis for protocol guidelines related to disease 
status (e.g., discontinuation of study treatment). 
Radiological scans of all suspected sites of disease will be performed utilizing the same 
method and technique throughout the study. Target lesions should demonstrate the patient’s 
baseline tumor burden and will be selected based on size (i.e., lesions with the longest 
diameter), and suitability for accurate repeat assessment.
The following should be performed:

Chest, abdomen, and pelvis CT scans (or MRI if CT is contraindicated) scans are 
required for all patients at Screening. An MRI of the brain is also required for all 
patients at Screening. A CT scan of the brain, preferably with IV contrast, may be 
performed if MRI is contraindicated. Additional imaging of anatomical sites (e.g., 
head and neck, etc.) should be performed as applicable based on location of disease 
sites. 

During the study chest, abdomen, and pelvis CT scans (or MRI if CT is 
contraindicated) are required for all patients. If additional imaging of anatomical sites 
(e.g., head and neck) were performed at baseline, they should be continued 
throughout the duration of the study. Additional imaging of anatomical sites (e.g., 
head and neck, etc.) should be performed as applicable based on location of disease 
sites. Subsequent MRIs of the brain will only be performed if there were lesions 
present at baseline. 

Skeletal lesions identified at Screening should continue to be imaged at subsequent 
scheduled visits using localized CT, MRI, or X-ray (using the same method used at 
Screening for all visits for any given lesion). 

Additional imaging evaluations may be performed at any time if there is symptomatic 
evidence suggesting the possibility of disease progression based on clinical symptoms 
or physical examination. If off schedule imaging evaluations are performed in the 
absence of progression, every effort should be made to perform subsequent imaging 
evaluations in accordance with the original imaging schedule or discussed with the 
Sponsor as applicable. 
Chest X-ray or ultrasound should not be used for tumor response assessments in this study.
While FDG-PET scans are not required for this study, sites may perform combined PET/CT 
scans per their local standard of care, provided the CT is of similar diagnostic quality as CT 
performed without PET, including the use of oral and IV contrast media. If acquired 
according to local standard of care, FDG-PET may be relied upon to document PD in 
accordance with RECIST. 

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7.2.2. Tumor Imaging During Screening
Initial tumor imaging must be performed within 28 days before the first dose of study 
treatment. Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within 28 days before the 
first dose of study treatment. 
The patient must have documentation of measurable disease per RECIST v1.1. Any lesions 
that have been subjected to loco-regional therapies (e.g., radiotherapy, ablation, etc.) should 
not be considered measurable, unless they have clearly progressed since the therapy. 
Previously treated lesions that have not progressed should be considered non-measurable and 
assessed as non-target lesions.
7.2.3. Tumor Imaging During Treatment
The first imaging assessment should be performed as follows:

8 weeks after the first dose of study treatment 

Every 8 weeks (56 days ± 7 days) for 12 months, and then every 12 weeks (± 7 days) 
thereafter until disease progression is determined or until any of the criteria in 
Section 7.1.4.2 are met. 

Imaging assessments may be performed more frequently if clinically indicated. 
Imaging should follow calendar days and should not be delayed, irrespective of study 
treatment administration (i.e. delays in cycles or dose holds).
Per RECIST v1.1, responses (PR or CR) should be confirmed by a repeat radiographic 
assessment. The scan for confirmation of response may be performed no sooner than 4 
weeks after the first documented response and no later than the next per-protocol scheduled 
scan, whichever is clinically indicated.
Radiographic disease assessments should be performed until disease progression per RECIST 
v1.1, withdrawal of consent, initiation of subsequent anticancer therapy, patient is lost to 
follow-up, death or defined end of study (see Section 4.5 and Section 6.8).
7.2.4. Independent Radiology Review
All radiographic images from screening and performed during the study are to be sent to a 
central imaging vendor to perform an independent radiographic imaging assessment of tumor 
status. Further details of the IRR are described in the Independent Radiology Review 
Charter. A detailed description of the procedures for the collection and storage of 
radiological scans is provided in the Study Manual. Of note, patient management decisions 
will be made by Investigator assessment and not by the independent central review. Results 
from IRR will not be provided to the Investigator.

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7.2.5. Performance Status
Assessment of ECOG PS (Oken et al, 1982) will be conducted as shown in Table 9 and at the 
time points specified in the SoA (Table 3).
Table 9.
Eastern Cooperative Group Performance Status Scoring
Grade
ECOG Performance Status
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about 
more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
7.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 3).
7.3.1. Patient Demographics and Other Baseline Characteristics
Demographic data and general medical history will be collected at Screening by the 
Investigator or qualified designee and will include relevant medical and surgical history 
within the last 10 years, smoking history and current illnesses.
7.3.2. Disease Characteristics and Treatment History
A disease-targeted medical and treatment history will be collected at Screening. Details 
regarding the patient’s malignancy under study, including date of diagnosis, initial and 
current cancer stage, tumor histology, relevant disease characteristics, and prior treatments 
including systemic, radiation, and surgical procedures, will be recorded.
7.3.3. Physical Examinations
Physical examinations will be performed by trained medical personnel at the time points 
specified in the SoA (Table 3).
At Screening, the physical examination should be comprehensive and include the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. If
indicated based on medical history and/or symptoms, rectal, external genitalia, breast and 
pelvic examinations will be performed. Body weight will be measured as part of the physical 
examination at each visit. Height will be measured only at Screening. 

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For subsequent visits (e.g., Day 1 of each cycle), the physical examinations should be 
targeted as clinically indicated. Investigators should pay special attention to clinical signs 
related to previous serious illnesses.
All physical examinations occurring on dosing days must be performed prior to study drug 
administration. Any treatment-emergent abnormal findings will be recorded as AEs.
7.3.4. Dermatological Examinations
Dermatologic evaluations will be performed at the site by the Investigator to monitor for the
possible development of keratoacanthoma and/or squamous cell carcinoma, as these have 
been reported to occur with selective BRAF inhibitor treatment (Flaherty et al, 2010; Kefford 
et al, 2010; Robert et al, 2011). This assessment may be performed predose or postdose at the 
time points specified in the SoA (Table 3). 
In addition, dermatologic screening for skin malignancies will be performed every 8 weeks 
until 6 months after the last dose of encorafenib (see Section 7.1.4). 
In case of occurrence of keratoacanthoma or squamous cell carcinoma, patients will undergo 
complete surgical excision of the skin lesion following institutional standards. Dermatologic 
evaluations will be performed by a dermatologist as clinically indicated.
7.3.5. Ophthalmic Examinations
Full ophthalmic examination will be performed by an ophthalmologist at Screening 
(Table 3), including best corrected visual acuity, slit lamp examination, intraocular pressure, 
dilated fundoscopy and optical coherence tomography. Examination of the retina is required 
(especially to identify findings associated with RPED, serous detachment of the retina and
RVO). The ophthalmic evaluation should be repeated at any point during the treatment 
period as clinically indicated.
During the treatment period, visual acuity testing will be performed on Day 1 of each cycle. 
7.3.5.1. Additional Ophthalmic Testing
Patients with clinical suspicion of retinal abnormalities of any grade (e.g., RPED, serous 
detachment of the retina, RVO, photopsia, metamorphopsia, impairment of visual acuity) 
must complete at least one of the following additional assessments:

For non-vascular abnormalities: optical coherence tomography (spectral domain 
optical coherence tomography recommended)

For vascular abnormalities: fluorescein angiography of the central 30 degrees. 
Images/results of the ophthalmic examinations (at a minimum, optical coherence tomography 
and/or fluorescein angiography) must be sent to the investigational site and be maintained in 
the patient’s source document file. These images/results must be made available upon 
Sponsor request.

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7.3.6. Vital Signs
Vital sign measurements (should be taken before blood collection for laboratory tests or at 
least 30 minutes after blood collection for laboratory tests), will be measured per institutional 
standards as part of the physical examination at the time points specified in SoA (Table 3). 
Vital sign assessments include the following:

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure will be assessed with the patient in a recumbent, semi recumbent, or 
sitting position. Manual techniques will be used only if an automated device is not 
available. Blood pressure and pulse measurements will be preceded by at least 5 
minutes of rest.
All vital sign measurements occurring on dosing days must be performed prior to study drug 
administration. Abnormal vital sign results identified after the first dose of study treatment 
constitute an AE if they are considered clinically meaningful, induce clinical signs or 
symptoms, require concomitant therapy, or require changes in study drug/treatment.
7.3.7. Electrocardiograms
A triplicate ECG (3 serial ECGs conducted within approximately 5 to 10 minutes total time) 
will be performed at Screening to confirm patient eligibility and predose on Cycle 1 Day 1 to 
serve as a baseline measurement of cardiac function. A single ECG will be performed at all 
remaining time points specified in the SoA (Table 3). Timing for when ECGs should be 
performed is outlined in Table 10.
Prior to performing the 12-lead ECG, patients will rest in the supine position for at least 
5 minutes. When an ECG is to be performed at the same time point as a blood collection, the 
ECG is to be performed first.  
Interpretation of the tracing will be made by a qualified physician and documented in the 
eCRF. QT interval values will be corrected for heart rate using the Fridericia formula 
(QTcF). Clinically significant abnormalities present when the patient signed the informed 
consent/assent but prior to the first dose of study treatment should be recorded as medical 
history in the eCRF. New or worsened clinically significant findings occurring after the first 
dose of study treatment must be recorded as an AE in the eCRF.
An abnormal ECG (e.g., ECG of > 500 ms or with a change in QTcF from baseline of 
≥60 ms) may be repeated if it cannot be interpreted by the Investigator. ECG tracings will be 
made available if requested by the Sponsor.

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Table 10.
Timing of ECGs
Visit
Anytime
Before Morning 
Dose of Study 
Treatment
2 hours (± 15 min) 
After Morning Dose 
of Study Treatment
Triplicate ECGs
Screening
X
Cycle 1 Day 1
X
Single ECGs
Cycle 1 Day 1
X
Cycle 2 Day 1
X
X
Every 12 Weeks (Cycle X Day 1)
X
X
EOT
X
7.3.8. Echocardiogram/Multi-gated Acquisition
Cardiac ejection fraction will be assessed by transthoracic ECHO or MUGA at the time 
points specified in SoA (Table 3). The same method should be used throughout the study. 
Patients who develop signs/symptoms of CHF at any point during the study are required to 
have an evaluation of LVEF measurements by ECHO or MUGA and should be monitored 
per institutional guidelines.
7.3.9. Clinical Laboratory Assessments
Blood and urine samples for the laboratory tests listed in Table 11 will be collected at the 
time points specified in the SoA (Table 3).
A central laboratory will perform all clinical laboratory assessments (i.e., blood chemistries, 
hematology, coagulation, serology, serum pregnancy and urinalysis), PK assessments (see 
Section 7.8) and biomarker assessments (see Section 7.10). Additional testing may be 
required by the Sponsor based on emerging safety data. Additional tests may also be 
performed if clinically indicated. 
All protocol-required laboratory assessments outlined in Table 11 must be conducted in 
accordance with the Laboratory Manual. Information regarding collection, processing, and 
shipping of laboratory assessments is provided in the Laboratory Manual. The Investigator 
must review the laboratory report and document this review. The laboratory reports must be 
filed with the source documents. 
Local site laboratories may be utilized, in addition to the central laboratory, if more rapid 
results are required for treatment decisions or for patient safety. Local site laboratory results 
obtained during the study will not be captured in the eCRF unless the Investigator determines 
they are needed to clarify why a treatment decision was made or an AE was recorded.

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If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered 
clinically significant by the Investigator (e.g., SAE or AE or dose modification), then the 
results of the specific laboratory assessment must be recorded in the eCRF.
Screening laboratory assessments for hematology and serum chemistry must be performed 
within 7 days of Cycle 1 Day 1. After Cycle 1, predose laboratory procedures can be 
conducted up to 72 hours (within a 3-day window) before study treatment administration, and 
results should be reviewed by the Investigator or qualified designee and found to be 
acceptable before a treatment is initiated.
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the Investigator to be more severe than expected for 
the patient's condition. All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator.
Table 11.
Summary of Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Coagulation
Others
Hemoglobin
Hematocrit
RBC
Platelets
WBC
Neutrophils/ANC
Lymphocytes
Monocytes
Eosinophils
Basophils
Albumin
Alkaline 
phosphatase
ALT
Amylase
AST
Bicarbonate or 
CO2
Total bilirubin
BUN or urea
Calcium
Chloride
CK (If total CK 
≥3 × ULN, then 
measure 
isoenzymes, serum 
creatinine and 
myoglobin in 
blood weekly)
Creatinine
Glucose
LDH
Lipase
Magnesium
Phosphate
Potassium
Appearance
Color
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Nitrite
Leukocytes
PT 
INR
PTT or aPTT
At Screening only:
Hepatitis B surface antigen
Hepatitis B surface antigen 
antibody
Hepatitis B core antibody
Hepatitis C antibody
HIV, as applicable per local 
regulations
If applicable:
Only females of 
childbearing potential 
require pregnancy testing.
Serum and urine pregnancy 
tests will be performed as 
per the SoA (Table 3).
Pregnancy tests (serum or 
urine) should be repeated if 
required by local 
regulations or as clinically 
indicated.

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Table 11.
Summary of Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Coagulation
Others
Total protein
Sodium
Uric acid
Direct bilirubin (if 
total bilirubin 
values are above 
ULN)
7.3.9.1. Serology
Hepatitis screening assessments will be performed by the central laboratory at the Screening 
visit to rule out hepatitis infection; required analytes are shown in Table 11. Generally, 
hepatitis tests should be performed early in the screening process due to the length of time 
needed to obtain the results. HIV testing will only be done at sites where mandated locally.
Additional tests may be performed if clinically indicated.
7.3.9.2. Pregnancy Testing
Pregnancy testing (serum and urine) as outlined in the SoA (Table 3) will only be required 
for women of childbearing potential as defined in Appendix 1. Serum pregnancy tests will be 
performed centrally, and urine pregnancy tests will be performed locally. Pregnancy testing 
(serum or urine) should be repeated as medically indicated (e.g., in case of loss of menstrual 
cycle, when pregnancy is suspected), or per country-specific requirement (note that country-
required urine pregnancy testing will be outlined and communicated to the investigational 
sites under separate cover). All blood and urine collections for pregnancy tests occurring on 
dosing days (i.e., Day 1 of each cycle) must be performed with results available prior to 
study treatment administration.
If a urine pregnancy test is positive, the results will be confirmed with a serum pregnancy 
test. If the serum pregnancy test is negative after a urine test was positive, the Investigator 
will assess the potential benefit/risk to the patient and determine whether it is in the patient’s 
best interest to resume study treatment and continue participation in the study. If pregnancy 
is confirmed by a serum pregnancy test, see Section 7.5.5 for reporting requirements.
Patients of nonchildbearing potential as defined in Appendix 1 do not require pregnancy 
tests. 
7.4. Other Study Procedures
7.4.1. Distribution of Dosing Diary
Patients will be provided with a dosing diary at study visits as outlined in Table 3. The 
dosing diary will include the following information:

Date and time of the next visit.

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
Dosing instructions (see Section 6.1).

Reminder that the patient should not take their morning dose of study treatment on 
study visit days (Day 1 of each cycle) and days when PK samples are collected (see 
Table 12 and Table 13).

Date and time of each dose taken daily for both encorafenib and binimetinib.

Information regarding missed/skipped doses.

Instructions to bring all unused study drugs and/or empty containers to the site at each 
visit to assess patient compliance with study treatment (see Section 6.4).
7.5. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 4. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the patient to discontinue the 
study treatment (see Section 6.7).  
Each patient or legally authorized representative will be questioned about the occurrence of 
AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
7.5.1. Time Period and Frequency for Collecting AE and SAE Information
As of IRB/IEC approval of Amendment 3, the time period for actively eliciting and 
collecting AEs and SAEs (“active collection period”) for each patient begins from the time 
the patient provides informed consent, which is obtained before the patient’s participation in 
the study (ie, before undergoing any study-related procedure and/or receiving study 
treatment), through and including a minimum of 30 calendar days, except as indicated below, 
after the last administration of the study treatment. Note: Prior to IRB/IEC approval of
Amendment 3 only study procedure related AEs were required to be reported from the time 
the patient provided informed consent up to the first dose of study treatment.  
During the long-term follow up period in this study for survival, only SAEs will be actively 
elicited and collected after completion of the active collection period described above. The 
SAEs identified during long-term follow-up will be reported to Pfizer Safety on the CT SAE 
Report Form only if considered reasonably related to the study treatment.

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Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
If the patient withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a patient definitively discontinues or temporarily discontinues study treatment because of 
an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the 
CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the patient has concluded 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a patient has completed the study, and he/she considers the event to be reasonably 
related to the study treatment, the investigator must promptly report the SAE to Pfizer using 
the CT SAE Report Form.
7.5.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period as described above in 
Section 7.5.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor within 24 
hours of it being available.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment. Note that a switch to a commercially available version of the study treatment is 
considered as a new anticancer therapy for the purposes of SAE reporting.
7.5.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a patient during the active collection period, 
which begins after obtaining informed consent as described in Section 7.5.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the patient.
If a patient begins a new anticancer therapy, the recording period for nonserious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period. Note that a switch to a 
commercially available version of the study treatment is considered as a new anticancer 
therapy for the purposes of SAE reporting.

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7.5.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences.
7.5.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts.  For each event, the investigator must pursue and obtain 
adequate information until resolution, stabilization, the event is otherwise explained, or the 
patient is lost to follow-up (as defined in Section 6.11). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a patient death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 4.
7.5.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the Investigator 
Brochures for the study and will notify the IRB/EC, if appropriate according to local 
requirements.
7.5.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study treatment under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.

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7.5.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female patient is found to be pregnant while receiving or after discontinuing study 
treatment. 

A male patient who is receiving or has discontinued study treatment exposes a female 
partner prior to or around the time of conception

A female is found to be pregnant while being exposed or having been exposed to 
study treatment due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy:  
o
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study treatment by ingestion. 
o
A male family member or healthcare provider who has been exposed to the study 
treatment by ingestion then exposes his female partner prior to or around the time 
of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred.  The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a patient or a patient’s partner, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred.  Details of the pregnancy will be 
collected after the start of study treatment and until 6 months after the last dose. 

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form.  Since the exposure information does not pertain to the patient enrolled in the 
study, the information is not recorded on a CRF; however, a copy of the completed 
CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).

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Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study treatment. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
followup of birth outcomes will be handled on a case by case basis (eg, followup on preterm 
infants to identify developmental delays).  In the case of paternal exposure, the investigator 
will provide the patient with the Pregnant Partner Release of Information Form to deliver to 
his partner.  The investigator must document in the source documents that the patient was 
given the Pregnant Partner Release of Information Form to provide to his partner.
7.5.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:

A female patient is found to be breastfeeding while receiving or after discontinuing 
study treatment.

A female is found to be breastfeeding while being exposed or having been exposed to 
study treatment (ie, environmental exposure).  An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study treatment by 
inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the patient enrolled in the study, so the information is not recorded on a CRF.  
However, a copy of the completed CT SAE Report Form is maintained in the investigator 
site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.

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7.5.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study treatment, which may or may not lead to the occurrence of an AE.  Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
patient’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
patient enrolled in the study, the information is not recorded on a CRF; however, a copy of 
the completed CT SAE Report Form is maintained in the investigator site file.
7.5.6. Cardiovascular and Death Events
Not applicable
7.5.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable. 
7.5.8. Adverse Events of Special Interest
See Section 2.1.4 Clinical Safety of Combination Encorafenib and Binimetinib for 
descriptions of AESIs.
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 7.5.1 through Section 7.5.1.2. An AESI is to be recorded as an AE or SAE on the 
CRF.  In addition, an AESI that is also an SAE must be reported using the CT SAE Report 
Form.
7.5.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
7.5.9. Medical Device Deficiencies
Not applicable.
7.5.10. Medication Errors
Medication errors may result from the administration or consumption of the study treatment 
by the wrong patient, or at the wrong time, or at the wrong dosage strength.
Exposures to the study treatment under study may occur in clinical trial settings, such as 
medication errors.

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Safety Event
Recorded on the AE 
CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors Only if associated with an 
AE or SAE
Only if associated with an SAE
Medication errors include:

Medication errors involving patient exposure to the study treatment;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study patient.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
If applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of 
the CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
7.6. Treatment of Overdose
There is no antidote known to over dosage either encorafenib or binimetinib. Supportive 
measures should be instituted.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the patient for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study treatment (whichever 
is longer).  Closely monitor the patient for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor Medical Monitor based on the clinical evaluation of the 
patient.

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7.7. Product Complaints
The Sponsor collects product complaints on study treatments used in clinical studies in order 
to ensure the safety of study patients, monitor quality, and facilitate process and product 
improvements.
All product complaints associated with material packaged, labeled, and released by the 
Sponsor (or designee) will be reported to the Sponsor. All product complaints associated with 
other study material will be reported directly to the respective manufacturer.
The Investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the Sponsor contact or 
respective manufacturer as noted in the packaging information. Any AE associated with a 
product complaint should be recorded as described in Section 7.5.1.1.
If the Investigator is asked to return the product for investigation, he/she will return a copy of 
the product complaint communication with the product.
7.8. Pharmacokinetics
For patients enrolled under Protocol Versions 0 through 3, serial blood samples (~4 mL each) 
for plasma PK analysis of encorafenib, its metabolite (LHY746), and binimetinib will be 
collected as shown in Table 12.  
For patients enrolled under Protocol Version 4 or later, blood samples (~4 mL each)for 
plasma concentration of encorafenib, its metabolite (LHY746), and binimetinib will be 
collected as shown in Table 13.
Complete instructions for sample processing, handling and shipment will be provided in the 
Laboratory Manual.
Study visits for PK sampling should be scheduled in the morning so that proper predose and 
postdose PK blood samples can be collected. On the PK visit days, the morning doses of 
encorafenib and binimetinib will be taken at the study site under observation by the 
Investigator or designee at approximately the same time, only after collecting the predose PK 
sample. Predose sampling information will include the date and exact time of the most recent 
previous dose of binimetinib and encorafenib (except Cycle 1 Day 1), including the dose 
amount taken. Postdose sampling information, only needed for days with postdose PK 
sampling (i.e., Cycle 1 Day 1 and Cycle 1 Day 15), will include the date and exact time of 
the morning dose, including the dose amount taken. Except for the Cycle 1 Day 1 PK 
samples, which have to be obtained on the scheduled day, other PK samples may be obtained 
± 1 day from the scheduled date. 
If vomiting occurs within 4 hours following study treatment administration on the day of PK 
sampling, no additional study treatment will be taken in an effort to replace the material that 
has been vomited and it is recommended that no more PK samples be taken after the emesis 
occurs. Any vomiting that occurs will be noted in the PK eCRF. Further doses will be 
administered with premedication with antiemetic medications and PK sampling will be 
performed after premedication with antiemetics.

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In addition, exploratory analyses on remaining plasma samples may be performed using a 
validated or non-validated, semi-quantitative or qualitative liquid chromatography tandem 
mass spectrometry method, if deemed appropriate.
Table 12.
Serial Pharmacokinetic Blood Sample Timing in Patients Enrolled under 
Protocol Versions 0 through 3
Study Visit
Timing of Sample
Cycle 1 Day 1

0.5 hours (± 5 min) post dose

1.5 hours (± 5 min) post dose

3 hours (± 10 min) post dose

6 hours (± 20 min) post dose
Cycle 1 Day 15

Predose (within 30 minutes prior to dose)

0.5 hours (± 5 min) post dose

1.5 hours (± 5 min) post dose

3 hours (± 10 min) post dose

6 hours (± 20 min) post dose
Cycle 2 Day 1

Predose (within 30 minutes prior to dose)
Table 13.
Pharmacokinetic Blood Sample Timing in Patients Enrolled under 
Protocol Version 4 or later
Study Visit
Timing of Sample
Cycle 1 Day 1

Predose (within 30 minutes prior to dose) 
Cycle 2 Day 1

Predose (within 30 minutes prior to dose)
Cycle 3 Day 1

Predose (within 30 minutes prior to dose)
Cycle 4 Day 1

Predose (within 30 minutes prior to dose)
Cycle 5 Day 1

Predose (within30 minutes prior to dose)
Cycle 6 Day 1

Predose (within 30 minutes prior to dose)
7.9. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
7.10. Biomarkers
Patients will be eligible for the study based on identification of a BRAFV600 mutation in the 
tumor or blood as determined by the local laboratory, and are required to also submit archival 
or fresh tissue to confirm BRAFV600 mutation status by a central laboratory (see 

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Section 7.1.1.1). Complete instructions for sample processing, handling and shipment will be 
provided in the Laboratory Manual.
If the patient consents, and in accordance with local laws, any tumor (archival or fresh) or 
blood samples remaining after determination of BRAF-mutation status may be stored for up 
to 5 years (or according to local regulations) after the completion of the study. Research will 
focus on biomarkers relevant to BRAF V600-mutant cancer. Potential future testing of DNA, 
RNA and protein from the biomarker samples, for example, may include somatic mutation 
molecular analyses (i.e., PCR) and IHC assays. No cell lines or model systems will be 
generated from the samples. All samples and data collected in connection with the study will 
be encoded by the study doctor and patient identity for all samples will remain unknown to 
others, including the study Sponsor. Raw data will not be shared and will not be uploaded to 
public databases. Summarized data may be shared as part of a collaborative research projects 
for publications. The decision to perform such exploratory biomarker research studies would 
be based on outcome data from this study or from new scientific findings related to the drug 
class or disease, as well as reagent and assay availability. The Sponsor will be the exclusive 
owner of any data and discoveries resulting from this study. Genetic testing results can be 
provided at the completion of the study upon request.
7.10.1. Circulating Tumor DNA Biomarker Analysis
In addition to the supplied tumor biopsy sample, blood samples will be collected as outlined 
in the SoA (see Table 3). The blood samples will be processed to plasma and purified ctDNA 
analyzed for potential genomic markers of encorafenib and/or binimetinib activity. The blood 
samples may be used for companion diagnostics or for exploratory research investigating 
genetic variants in ctDNA, such as BRAFV600 mutations as well as additional tumor 
mutations. 
The biomarker samples should be drawn prior to PK samples. Complete instructions for 
sample collection, processing, handling and shipment to a central laboratory will be provided 
in the Laboratory Manual. 
Further exploratory biomarker research may be conducted on collected blood (including PK) 
samples. These additional investigations would be dependent upon clinical outcome, reagent 
and sample availability.
Samples may be stored for up to 5 years (or according to local regulations) following 
completion of the study to enable further analysis of biomarker responses to encorafenib and 
binimetinib.
7.10.2. Circulating Serum Biomarker Analysis
After IRB/IEC approval of Protocol Version 4 or later, peripheral blood samples (serum) will 
be collected as specified in the SoA (Table 3) for analysis of potential proteomic or 
metabolomic factors and signals.
7.11. Genetics
See Section 7.10.

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7.12. Patient-Reported Outcomes
Patient-reported outcomes are not evaluated in this study.
7.13. Health Economics 
Health Economics or Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
8. STATISTICAL CONSIDERATIONS
A detailed SAP will be prepared by the Sponsor or designee. This plan may modify the 
statistical methods outlined in the protocol; however, any major modifications of the primary 
endpoint definition or analysis will also be described in a protocol amendment.
8.1. Statistical Hypotheses
The primary endpoint of the study is ORR for treatment-naïve and previously treated patients 
as determined by IRR per RECIST v1.1. The study is designed to test the null hypothesis of 
ORR ≤ 39% for treatment- naïve patients with BRAFV600E NSCLC, which is considered not 
sufficiently clinically meaningful to warrant further study in this indication where similar 
therapies are already available. The alternative hypothesis is ORR >39% with the assumption 
that the true ORR is at least 65%. Hypotheses are based on the results observed in the 
dabrafenib plus trametinib study in BRAFV600E-mutant NSCLC patients, in which the ORR 
per Investigator assessment was 64% (95% CI: 46, 79) for treatment-naïve patients 
(Planchard et al, 2017) and the results observed in patients with NSCLC whose tumors 
expressed PD-L1 levels with a TPS ≥50% and received pembrolizumab as a single agent 
(Keynote-042) in which ORR per IRR was 39% (95% CI: 34, 45) (Mok et al, 2019).
For previously treated patients with BRAFV600E NSCLC, the null hypothesis of ORR ≤ 20% 
will be tested. The alternative hypothesis is ORR >20% with the assumption that the true 
ORR is at least 45%. This hypothesis is based on the ORR of 18% (95% CI: 14, 23) observed 
in previously treated patients with NSCLC whose tumors expressed PD-L1 levels with a TPS 
≥1% and who received pembrolizumab as a single agent (Keynote-010; Herbst et al, 2016).
8.2. Sample Size Determination
The sample size calculation is based on the primary endpoint of ORR as determined by IRR 
per RECIST v1.1. The hypotheses to be tested are described in Section 8.1. With 
60 evaluable treatment-naïve patients with BRAFV600E NSCLC, the power is greater than 
95% to test the null hypothesis that the ORR is less than or equal to 39% versus the 
alternative hypothesis that it is greater than 39% assuming an alternative target rate of 65% 
with a one-sided ≤0.025 based on a single-stage design using exact test. The null hypothesis 
will be rejected if ≥32 confirmed objective responses are observed. With 37 evaluable 
previously treated patients with BRAFV600E NSCLC, there is at least 90% power to test the 
null hypothesis that the ORR is less than or equal to 20% versus the alternative hypothesis 
that it is greater than 20% assuming an alternative target rate of 45% with a one-sided 
≤0.025 based on a single stage design using exact test. The null hypothesis will be rejected 
if ≥13 confirmed objective responses are observed. 

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At least 60 treatment-naïve and 37 previously treated BRAFV600E NSCLC patients will be 
enrolled and treated. It is not expected that more than 107 patients with any BRAFV600
mutation will be enrolled and treated.
8.3. Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 14.
Populations for Analysis
Population
Description
Screened 
All patients who sign the ICF.
Safety Set
The Safety Set (SS) includes all patients who receive at least 1 dose of 
study drug. 
PK Set
The PK Set includes all patients in the SS who have  at least 1 postdose PK 
blood collection after the first dose of study drug with associated 
bioanalytical results. 
8.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the patient 
populations to be included in the analyses and procedures for accounting for missing, unused 
and spurious data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints.
All efficacy endpoints will be evaluated in treatment-naïve and previously treated patients 
with BRAFV600E included in the SS. If sufficient number of patients (as described in the SAP) 
with other types of BRAFV600 mutations will be enrolled in the study, the endpoints may be 
evaluated in patients with all BRAFV600 mutations.
Primary analyses of all tumor related efficacy endpoints will be based on IRR review.  
Additional, sensitivity analyses will be based on Investigator assessment.
8.4.1. Primary Analyses
The primary endpoint is ORR in treatment-naïve and previously treated patients with 
BRAFV600E. It is defined as the proportion of patients who have achieved a confirmed best 
overall response of CR or PR as determined by IRR per RECIST v1.1, relative to the SS. 
The ORR will be calculated with an exact two-sided 95% CI. 
8.4.2. Secondary Analyses
The secondary efficacy endpoints are listed in Table 5. 
8.4.2.1. Duration of Response
DOR, based on IRR and investigator assessments is defined as the time from the date of the 
first documented response (CR or PR) that is subsequently confirmed (by IRR and by 

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Investigator, respectively) to the earliest date of disease progression, as determined by 
Investigator review of radiographic disease assessments and IRR per RECIST v1.1, or death 
due to any cause. If a patient with a CR or PR has neither progressed nor died at the time of 
the analysis cutoff or at the start of any new anticancer therapy, the patient will be censored 
at the date of last adequate tumor assessment. DOR will be calculated for patients who have 
achieved a confirmed overall response (i.e., CR or PR). 
The survival distribution function for DOR will be estimated using the Kaplan-Meier 
method. In addition, descriptive statistics and frequency distribution will be provided. 
8.4.2.2. Disease Control Rate
Disease control rate is defined as the proportion of patients who have achieved a confirmed 
overall response of CR, PR or SD, as determined by Investigator review of radiographic 
disease assessments and IRR per RECIST v1.1. Additional information regarding DCR will 
be specified in the SAP.
DCR will be calculated along with exact two-sided 95% CIs. 
8.4.2.3. Progression-free Survival
Progression-free survival is defined as the time from the date of first dose of study drug to 
the earliest date of disease progression, as determined by IRR and Investigator review of
radiographic disease assessments per RECIST v1.1, or death due to any cause. If a patient 
has not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer 
therapy, PFS is censored at the date of last adequate tumor assessment. 
The survival distribution function for PFS will be estimated using the Kaplan-Meier method. 
8.4.2.4. Overall Survival
Overall survival is defined as the time from the date of first dose of study drug to the date of 
death due to any cause. If a death has not been observed by the date of the analysis cutoff, 
OS will be censored at the date of last contact. 
The survival distribution function for OS will be estimated using the Kaplan-Meier method.
8.4.2.5. Time to Response
Time to Response (TTR) based on IRR and Investigator assessments is defined, for patients 
with an objective response, as the time, in months, from the date of first dose to the first 
documentation of objective response (CR or PR) which is subsequently confirmed (by IRR 
and by Investigator, respectively). Time to response will be calculated for the subgroup of 
patients with a confirmed objective tumor response.
TTR will be summarized using descriptive statistics.  

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8.4.3. Safety Analyses
Safety data will be presented, based on the SS, in tabular and/or graphical format and 
summarized descriptively, where appropriate. Adverse events will be coded using 
MedDRA®. The incidence of AEs will be summarized by system organ class and/or 
preferred term, maximum severity (based on CTCAE grades), type of AE and relation to 
study treatment.
Laboratory parameters will be presented in shift tables of baseline grade vs. maximum grade 
on study. For laboratory parameters that are not gradable by CTCAE, shift tables of normal-
abnormal will be provided. Summaries of clinically notable measurements will also be 
provided. Definitions of clinically notable will be provided in the SAP.
Vital signs, body weight, ECOG PS, ECHO/MUGA and select ophthalmic examination data 
will be summarized.Clinically notable vital sign measurements will be summarized. 
Definitions of clinically notable will be provided in the SAP.
Results for each ECG parameter will be summarized and reviewed for clinically notable 
abnormalities according to predefined criteria as outlined in the SAP. 
8.4.4. Pharmacokinetic Analyses
Plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib will be 
determined using validated bioanalytical methods. Plasma concentration-time profiles for 
encorafenib, LHY746 and binimetinib will be generated for only patients enrolled under 
Protocol Versions 0 through 3. Descriptive summaries for encorafenib, LHY746 and 
binimetinib concentrations will be presented. Trough plasma concentration-visit of 
encorafenib and LHY746 and binimetinib will be reported and summarized for all patients 
treated in this study.
PK parameters will be determined for all PK-evaluable patients enrolled under Protocol 
Versions 0 through 3 using noncompartmental methods using Phoenix WinNonlin Version 
8.0 or higher (Pharsight, Mountain View, CA).  PK parameter estimates will be presented, 
summarized, and reported.  Details of the analyses will be included in the SAP.
After IRB/IEC approval of Protocol Version 4, PK parameters of encorafenib and LHY746 
and binimetinib will be estimated using a population model-based approach. Relationships 
between PK of encorafenib/binimetinib and biomarkers, clinical response and/or safety will 
be conducted using post hoc exposure estimates (eg, Cmax, AUC or Cmin) from population PK 
modeling, if possible and appropriate. Measures of efficacy may include but are not limited 
to ORR and DOR by IRR. Selection of safety measures will be based on frequency of 
observations or by selection of safety measures of interest. Analyses will be described in a 
separate stand-alone modeling plan and a separate report will be produced.
8.4.5. Other Analyses
Biomarker and exposure-response exploratory analyses, if appropriate, will be described in 
the SAP. The biomarker and exposure-response analyses may be presented separately from 
the main CSR.

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8.5. Interim Analyses 
The Sponsor may conduct  2 interim analyses for treatment-naïve patients, after about 90% 
[n=54] of the planned treatment-naïve patients [n=60] will be enrolled and after 6 months 
from the last treatment-naïve patient enrolled into the study. Results of the IA may be 
considered for discussion, based on criteria specified in the SAP, with regulatory authorities. 
9. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
9.1. Regulatory, Ethical, and Study Oversight Considerations
The study will be performed in accordance with the requirements of the applicable regulatory 
authorities in each country where this study is conducted and will also meet all of the 
requirements of ICH GCP guidance. In addition to IRB/IEC and regulatory authority 
approval, all other required approvals (e.g., approval from the local research and 
development board or scientific committee) will be obtained prior to recruitment of patients 
into the study and shipment of study drug.
Amendments to the protocol will be submitted to all applicable regulatory authorities for 
approval prior to implementation. Only the Sponsor may modify the protocol. The only 
exception is when the Investigator considers that a patient’s safety is compromised without 
immediate action. In these circumstances, immediate approval of the chairman of the 
IRB/IEC must be sought, and the Investigator will inform the Sponsor and the full IRB/IEC 
within 5 working days after the emergency occurred. All amendments that have an impact on 
patient’s risk or the study objectives or require revision of the informed consent document 
must receive approval from the IRB/IEC prior to implementation.
9.2. Investigator Responsibilities
The Investigator is the person responsible for the conduct of the study at the investigational 
site. A sub-Investigator is any member of the clinical study team designated and supervised 
by the Investigator to perform critical study-related procedures and/or to make important 
study-related decisions.
The protocol, protocol amendments, ICF, IBs, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. Any amendments to the protocol will 
require IRB/IEC approval before implementation of changes made to the study design, 
except for changes necessary to eliminate an immediate hazard to study patients.
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

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Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
Investigators must apply due diligence to avoid protocol deviations, (with the exception of 
medical emergencies); the Sponsor (or designee) will not pre-authorize deviations. If the 
Investigator believes a change to the protocol would improve the conduct of the study, this 
must be considered for implementation in a protocol amendment approved by the Sponsor 
and by the IRB/IEC. The Investigator is responsible for enrolling patients who have met the 
specified eligibility criteria. All protocol deviations will be recorded.
The Investigator must retain records in accordance with all local, national, and regulatory 
laws, but for the minimum period of at least 2 years after the last marketing application 
approval in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or if not approved, 2 years after the termination of the study 
drug for investigation to ensure the availability of study documentation should it become 
necessary for the Sponsor or a regulatory authority to review.
The Investigator must not destroy any records associated with the study without receiving 
written approval from the Sponsor. The Investigator must notify the Sponsor or designee in 
the event of accidental loss or destruction of any study records. If the Investigator leaves the 
institution where the study was conducted, the Sponsor or designee must be contacted to 
arrange alternative record storage options (if applicable).
All eCRF data entered by the site (including audit trial), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in 
compliance with applicable record retention regulations. The Sponsor will retain the original 
eCRF data and audit trial.
9.3. Financial Disclosure
Before study initiation, all clinical Investigators participating in clinical studies patient to 
FDA Regulation Title 21 CRF Part 54- Financial Disclosure by Clinical Investigators 
(i.e., “covered studies”) and are required to submit a completed Clinical Investigator 
Financial Disclosure form that sufficiently details any financial interests and arrangements 
that apply. For the purpose of this regulation, this applies to the Investigator and any sub-
Investigator who is directly involved in the treatment of or evaluation of research patients, 
including the spouse and each dependent child of the Investigator or sub-Investigator. These 
requirements apply to both US and foreign clinical Investigators conducting covered clinical 
studies. Any new clinical Investigators added to the covered clinical study during its conduct 
must also submit a completed Investigator Financial Disclosure Form.
During the clinical study, any changes to the financial information previously reported by the 
Investigator or sub-Investigator must be reported to the Sponsor or designee. At the 
conclusion of the clinical study, the Investigator and sub-Investigators will remain obligated 
to report to the Sponsor or designee any changes to the financial information previously 
reported, as well as any changes in their financial information for a period of 1 year after the 
completion of the clinical study.

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9.4. Informed Consent Process
It is the Investigator’s responsibility (or designee) to obtain written informed consent from 
each patient after adequate explanation of the aims, methods, anticipated benefits and 
potential hazards of the study and before any study procedures are initiated. The Investigator 
or his/her representative will explain the nature of the study to the patient or his/her legally 
authorized representative and answer all questions regarding the study.
Informed consent must be obtained before any study-related procedures are conducted, 
unless otherwise specified by the protocol. Informed consent must be obtained using the 
IRB/IEC-approved version in a language that is native and understandable to the patient. A 
template will be provided by the Sponsor or designee. The Sponsor or designee must review 
and acknowledge the site-specific changes to the ICF template. The ICF must include a 
statement that the Sponsor or designee and regulatory authorities have direct access to patient 
records.
The ICF must contain all required elements and describe the nature, scope, and possible 
consequences of the study in a form understandable to the patient. The medical record must 
include a statement that written informed consent was obtained before the patient is enrolled 
in the study and the date the written consent was obtained. The authorized person obtaining 
the informed consent must also sign the ICF.
9.5. Data Protection
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets 
that are transferred to the Sponsor will contain the identifier only. Patient names or any 
information which would make the patient identifiable will not be transferred. If the patient’s 
name appears on any record or document, it must be obliterated on the copy of the document 
to be supplied to the Sponsor or designee. Study finding stored on a computer will be stored 
in accordance with local data protection laws.
The Investigator will permit authorized representatives of the Sponsor, regulatory authorities 
and ethics committees to review the portion of the patient’s medical record that is directly 
related to the study. The patient must be informed that his/her personal study-related data 
will be used by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The Investigator and the Sponsor or designee must adhere to applicable data privacy laws 
and regulations. The Investigator and the Sponsor or designee are responsible for ensuring 
that sensitive information is handled in accordance with local requirements (e.g., HIPAA). 
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) 
of protected information must be obtained.

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9.6. Committees
9.6.1. Safety Monitoring
Encorafenib and binimetinib are commercially available for the treatment of advanced 
BRAFV600E/K-mutant melanoma in a number of jurisdictions including the US and EU 
(BRAFTOVITM [encorafenib] prescribing information; MEKTOVI® [binimetinib] 
prescribing information). The dose and administration schedule of encorafenib 450 mg orally 
QD in combination with binimetinib 45 mg orally BID will be used in this study. Over 1,000 
patients have been treated with the combination of encorafenib and binimetinib in completed 
and ongoing clinical trials. Cumulative safety data for these patients is included in the 
respective Investigator’s Brochures for encorafenib and binimetinib, and the primary risks of 
the combination are well characterized (see Sections 2.1.4 and 2.1.5). As the patient 
population for this study is similar to the approved indication (i.e., adult patients with an 
advanced solid tumor), an independent DMC to monitor safety in this open-label study is not 
required to ensure safety. Safety and efficacy data will be monitored at regular intervals 
throughout the study by the Sponsor and a Steering Committee comprised of select study 
Investigators to ensure patient safety. In addition, ongoing global pharmacovigilance 
monitoring by the Sponsor for the marketed products will inform any changes in the safety 
profile of the combination, as well as any necessary changes in safety assessments. Details 
regarding routine safety reviews will be included in the Steering Committee Charter.
9.7. Dissemination of Clinical Study Data
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. By signing this 
protocol, the Investigator and his/her institution agree that the results of the study may be 
used by the Sponsor, for the purposes of national and/or international registration, 
publication, and information for medical and pharmaceutical professions. Information 
regarding this study and study results will be published in accordance with applicable local 
and national regulations. If necessary, the authorities will be notified of the Investigator’s 
name, address, qualifications, and extent of involvement.
It is understood by the Investigator that the Sponsor will use information obtained in this 
clinical study in connection with the clinical development program, and therefore may 
disclose it as required to other clinical Investigators and to regulatory authorities. The 
Investigator understands that he/she has an obligation to provide complete test results and all 
data obtained during this study to the Sponsor. Data analysis performed independently by an 
Investigator will be submitted to the Sponsor before publication or presentation.
9.7.1. Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bonafide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.

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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
9.8. Data Quality Assurance

Data management will be performed in a validated EDC system. All patient data 
relating to the study will be recorded in an eCRF unless transmitted to the Sponsor or 
designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. The Investigator will be provided with access to an EDC system so 
that the eCRF can be completed for each patient.

The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. Following review and approval, the Investigator 
will electronically sign and date the pages. This signature certifies that the 
Investigator has thoroughly reviewed and confirmed all data on the eCRF.

A PDF and/or electronic file of the eCRFs will be provided to the site after all data 
have been monitored and reconciled and will be archived at the site as required by 
any applicable local regulatory requirements.

The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan and in accordance with the signed 
site agreement. Monitoring will include personal visits with the Investigator and study 
staff as well as appropriate communications by telephone, fax, mail, email or use of 
the EDC system, if applicable.

The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations).

Qualified study monitors will perform ongoing source data verification to confirm 
that data entered into the eCRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. Every effort will be made to maintain the anonymity and 
confidentiality of patients during this study.

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
Qualified representatives of the Sponsor or designee may audit the clinical study site 
and study data to evaluate compliance with the protocol, applicable local clinical 
study regulations, and overall study conduct. The Investigator must allow the auditors 
to review original source documents and study documentation for all patients.

Regulatory authorities may conduct and inspection of the study and the site at any 
time during the study. The Investigator and site staff are expected to cooperate with 
the inspectors and allow access to all source documents supporting the eCRFs and 
other study-related documents. The Investigator must immediately notify the Sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for at least 2 years after study completion 
unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor.
9.9. Source Documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. Changes or corrections to eCRFs will be made by the 
Investigator or an authorized member of the study staff according to the policies and 
procedures at the site.
9.10. Study and Site Closure
The Sponsor or designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures or GCP guidelines

Inadequate recruitment of patients by the Investigator

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Discontinuation of further study treatment development
9.11. Publication Policy
The conditions regulating dissemination of the information derived from this study are 
described in the Clinical Trial Agreement. The Sponsor will comply with the requirements 
for publication of study results. Authorship will be determined by mutual agreement and in 
line with International Committee of Medical Journal Editors authorship requirements.

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10. REFERENCES
Aguilar EJ, Rizvi H, Kravets S et al. Comparison of outcomes with PD-L1 tumor proportion 
score (TPS) of 50-74% vs 75-100% in patients with non-small cell lung cancer 
(NSCLC) treated with first-line PD-1 inhibitors. J Clin Oncol 2018;36(15_suppl);9037 
(abstr).
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc. Binimetinib Investigator’s 
Brochure.
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc. Encorafenib Investigator’s 
Brochure.
Ascierto PA, McArthur GA, Dréno B et al. Cobimetinib combined with vemurafenib in 
advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a 
randomised, double-blind, phase 3 trial. Lancet Oncol 2016;17(9):1248-60.
Baik CS, Myall NJ, Wakelee HA. Targeting BRAF-mutant non-small cell lung cancer: from 
molecular profiling to rationally designed therapy. Oncologist 2017;22(7):786-96.
Barlesi F, Mazieres J, Merlio JP et al. Routine molecular profiling of patients with advanced 
non-small-cell lung cancer: results of a 1-year nationwide programme of the French 
Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387(10026):1415-26.
BRAFTOVITM (encorafenib) prescribing information [package insert]. Boulder, CO. Array 
BioPharma Inc.; June 2018. Available at:
<http://www.arraybiopharma.com/documents/Braftovi_Prescribing_information.pdf> 
(Accessed 27 November 2018).
Brahmer JR, Drake CG, Wollner I et al. Phase I study of single-agent anti-programmed 
death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28(19):3167-75.
Cardarella S, Ogino A, Nishino M et al. Clinical, pathologic, and biologic features associated 
with BRAF mutations in non-small cell lung cancer. Clin Cancer Res 2013;19(16):4532-
40.
Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
testing. Available at: 
<http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf> 
(Accessed 27 November 2018).
CredibleMeds®. Combined List of Drugs That Prolong QT and/or cause Torsades de Pointes 
(TDP). Available at:
<https://www.crediblemeds.org/> (Accessed 27 November 2018).
Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 
2002; 417: 949–54.
Dummer R, Ascierto PA, Gogas HJ et al. Encorafenib plus binimetinib versus vemurafenib 
or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, 
open-label, randomised phase 3 trial. Lancet Oncol. 2018a;19(5):603-15.

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Dummer R, Ascierto PA, Gogas HJ et al. Overall survival in patients with BRAF-mutant 
melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib 
(COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 
2018b;19(5):1315–27.
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.
Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic 
melanoma. N Engl J Med 2010;363(9):809-19.
Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma 
with BRAF V600 mutations. N Engl J Med 2012; 367(18):1694–1703.
Flaherty K. In the Pipeline: Encorafenib and binimetinib in BRAF-mutated melanoma. Clin 
Adv in Hematol Oncol 2017;15(10):745-7.
Gandhi L, Rodríguez-Abreu D, Gadgeel S et al. Pembrolizumab plus Chemotherapy in 
Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378(22):2078-92.
Gettinger S and Herbst RS. B7-H1/PD-1 blockade therapy in non-small cell lung cancer: 
current status and future direction. Cancer J 2014;20(4):281-9.
Herbst RS, Soria JC, Kowanetz M et al. Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients. Nature 2014;515(7528):563-7.
Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, 
PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet. 2016;387(10027):1540-50.
Hyman DM, Piha-Paul SA, Won H et al. HER kinase inhibition in patients with HER2- and 
HER3-mutant cancers. Nature 2018;554(7691):189–94.
Jordan EJ, Kim HR, Arcila ME et al. Prospective comprehensive molecular characterization 
of lung adenocarcinomas for efficient patient matching to approved and emerging 
therapies. Cancer Discov 2017;7(6): 596–609.
Joshi M, Rice SJ, Liu X et al. Trametinib with or without vemurafenib in BRAF mutated 
non-small cell lung cancer. PLoS One 2015;10(2):e0118210.
Kalemkerian GP, Narula N, Kennedy EB et al. Molecular testing guideline for the selection 
of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: 
American Society of Clinical Oncology endorsement of the College of American 
Pathologists/International Association for the Study of Lung Cancer/Association for 
Molecular Pathology clinical practice guideline update. J Clin Oncol 2018;36(9):911-9.
Kefford R, Arkenau MP, Brown M et al. Phase 1/2 study of GSK2118436, a selective 
inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and 
other solid tumors. J Clin Oncol 2010;28:(15s_suppl); 8503 (abstr).

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KEYTRUDA® (pembrolizumab) prescribing information [package insert]. South San 
Francisco, CA. Genentech Inc.; November 2018. Available at:
<https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf> 
(Accessed 27 November 2018).
Khunger A, Khunger M, Velcheti V. Dabrafenib in combination with trametinib in the 
treatment of patients with BRAF V600-positive advanced or metastatic non-small cell 
lung cancer: clinical evidence and experience. Ther Adv Respir Dis 2018;12:1–9.
Kris MG, Johnson BE, Berry LD et al. Using multiplexed assays of oncogenic drivers in lung 
cancers to select targeted drugs. JAMA 2014;311(19):1998-2006.
Larkin J, Ascierto PA, Dréno B et al. Combined vemurafenib and cobimetinib in BRAF-
mutated melanoma. N Engl J Med 2014;371(20):1867-76.
Leduc C, Merlio JP, Besse B et al. Clinical and molecular characteristics of non-small cell 
lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French 
Cooperative Thoracic Intergroup (IFCT) program. Ann Oncol 2017;28(11):2715-24.
Lee SH, Lee JK, Ahn MJ et al. Vandetanib in pretreated patients with advanced non-small 
cell lung cancer-harboring RET rearrangement: a phase II clinical trial. Ann Oncol 
2017;28(2):292-7.
Lin L, Asthana S, Chan E et al. Mapping the molecular determinants of BRAF oncogene 
dependence in human lung cancer. Proc Natl Acad Sci USA 2014;111(7):E748–57.
Lindeman NI, Cagle PT, Aisner DL et al. Updated molecular testing guideline for the 
selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: 
Guideline From the College of American Pathologists, the International Association for 
the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol 
Lab Med 2018;142(3):321-46.
Long GV, Stroyakovskiy D, Gogas H et al. Combined BRAF and MEK inhibition versus 
BRAF inhibition alone in melanoma. N Engl J Med 2014;371(20):1877-88.
MEKTOVI® (binimetinib) prescribing information [package insert]. Boulder, CO. Array 
BioPharma Inc.; June 2018. Available at:
<http://www.arraybiopharma.com/documents/Mektovi_Prescribing_information.pdf> 
(Accessed 27 November 2018).
Mok TSK, Wu YL, Kudaba I et al. Pembrolizumab versus chemotherapy for previously 
untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer 
(KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 
2019;393(10183):1819-30.
National Comprehensive Cancer Network®: NCCN Guideline™ Version 1.2019. Non-small 
Cell Lung Cancer. Available at: 
<https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf> (Accessed 27 
November 2018). 
Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung 
cancer: a meta-analysis using updated data on individual patients from 52 randomised 
clinical trials. BMJ 1995;311(7010):899-909.

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Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-55.
Planchard D, Besse B, Groen HJM et al. An open-label phase 2 trial of dabrafenib plus 
trametinib in patients with previously treated BRAF V600E–mutant metastatic non-
small cell lung cancer. Lancet Oncol 2016a;17(7), 984–93.
Planchard D, Kim T M, Mazieres J et al. Dabrafenib in BRAF V600E–mutant advanced non-
small cell lung cancer: an open-label, single arm, multicenter, phase 2 trial. Lancet 
Oncol 2016b;17(5):642–50.
Planchard D, Smit EF, Groen HJM et al. Dabrafenib plus trametinib in patients with 
previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an 
open-label, phase 2 trial. Lancet Oncol 2017;18(10):1307-16.
Planchard D, Popat S, Kerr K et al. Metastatic non-small cell lung cancer: ESMO clinical 
practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 
2018;29(Supplement_4):iv192-iv237.
Ribas A and Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 
2018;359(6382):1350-5.
Robert C, Arnault JP, Mateus C et al. RAF inhibition and induction of cutaneous squamous 
cell carcinoma. Curr Opin Oncol. 2011;23(2):177-82.
Robert C, Karaszewska B, Schachter J et al. Improved overall survival in melanoma with 
combined dabrafenib and trametinib. N Engl J Med 2015;372(1):30-9.
Robert C, Karaszewska B, Schachter J et al. Three-year estimate of overall survival in 
COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib 
(T) in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous 
melanoma. Ann Oncol 2016;27(6): LBA40 (abstr).
Shaw AT, Ou SH, Bang YJ et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. 
N Engl J Med 2014;371:1963–71.
Stuart DD, Li N, Poon DJ et al. Preclinical profile of LGX818: A potent and selective RAF 
kinase inhibitor. Cancer Res 2012;72(8):abstract 3790.
Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. 
Immunity 2018;48(3):434-52.
TECENTRIQ® (atezolizumab) prescribing information [package insert]. South San 
Francisco, CA. Genentech Inc.; July 2018. Available at:
<https://www.gene.com/download/pdf/tecentriq_prescribing.pdf> (Accessed 27 
November 2018).
Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-
1 antibody in cancer. N Engl J Med 2012;366(26):2443-54.
Tsoulos N, Papadopoulou E, Metaxa-Mariatou V et al. Tumor molecular profiling of NSCLC 
patients using next generation sequencing. Oncol Rep 2017;38(6):3419-29.

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Urner-Bloch U, Urner M, Jaberg-Bentele NF et al. MEK inhibitor-associated retinopathy 
(MEKAR) in metastatic melanoma: Long-term ophthalmic effects. Eur J Cancer 
2016;65:130-8.
U.S. Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. Available at:
<https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/drugin
teractionslabeling/ucm093664.htm> (Accessed 27 November 2018).
U.S. National Institute of Health, National Cancer Institute. Surveillance, Epidemiology, and 
End Results (SEER) Cancer Statistics Review, 1975–2015.
World Health Organization. A report about cancer. 2018. Available at:
<http://www.who.int/news-room/fact-sheets/detail/cancer> (Accessed 27 November 
2018).
Zheng G, Tseng LH, Chen G et al. Clinical detection and categorization of uncommon and 
concomitant mutations involving BRAF. BMC Cancer 2015;15:779.

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11. APPENDIX 1: CONTRACEPTIVE GUIDANCE
Female patients of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy from Screening through 30 days after the last dose of study drug/treatment.
Male patients should use a condom during treatment and through 90 days after the end of 
systemic exposure to study treatment. If the male patient has a partner that is of child-bearing 
potential, the partner should also use contraception through 90 days after the end of systemic 
exposure to study treatment. In addition, male patients must refrain from donating sperm 
during the study through 90 days after the end of systemic exposure of study drug/treatment. 
Males who have had a vasectomy ≥ 90 days from the start of treatment qualify as having met 
the requirement for a highly effective birth control method.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). If fertility is unclear (e.g., amenorrhea in adolescents 
or athletes) and a menstrual cycle cannot be confirmed before first dose of study treatment, 
additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy.

Documented bilateral salpingectomy.

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the patient’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
o
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 
HRT. However, in the absence of 12 months of amenorrhea, confirmation 
with more than one FSH measurement is required. 

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
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance:
NOTE: There is a potential for encorafenib to induce CYP3A4, which may reduce the 
effectiveness of hormonal contraception methods. Therefore, the use of at least 1 form 
of non-hormonal contraception is required for females of childbearing potential during 
participation in this study.
The contraception guidelines outlined below are adapted from the recommendations related 
to contraception and pregnancy testing in clinical trials guidance document (Clinical Trials 
Facilitation Group Guidelines 2014). Patients must agree to use highly effective methods of 
contraception if it is mandated locally or when, in the judgment of the Investigator, 
compliance with acceptable methods is likely to be suboptimal. Any of the contraceptive 
methods listed below are permitted on the study and should be communicated to patient and 
their understanding confirmed.
The following methods have been classified as being highly effective (i.e., failure rate < 1% 
per year when used consistently and correctly) in preventing a pregnancy:

Complete abstinence from heterosexual intercourse during the entire period of risk 
associated with the study treatments; the reliability of sexual abstinence should be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral.
o
Intravaginal.
o
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral.
o
Injectable.
o
Implantable.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

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
Bilateral tubal occlusion.

Vasectomised partner (considered highly effective provided the vasectomized male 
has received medical assessment of surgical success and that the male is a female 
patient’s sole sexual partner).
Acceptable birth control methods characterized as having a failure rate of more than 1% per 
year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action.

Male or female condom with or without spermicide.

Cap, diaphragm or sponge with spermicide.

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12. APPENDIX 2: RECOMMENDED DOSE MODIFICATIONS FOR 
ENCORAFENIB-RELATED* ADVERSE EVENTS
Severity of Adverse Event
Dose Modifications
New Primary Malignancies
Non-cutaneous RAS mutation-positive malignancies
Permanently discontinue encorafenib and 
binimetinib.
Uveitis
Grade 1-3
If Grade 1 or 2 does not respond to specific ocular 
therapy, or for Grade 3 uveitis, withhold encorafenib 
and binimetinib for up to 6 weeks.

If improved, resume at same or reduced 
dose.

If not improved, permanently discontinue.
Grade 4 
Permanently discontinue encorafenib and 
binimetinib.
Other Eye Disorders (i.e., non-Uveitis Events)
Grade 1–2
Maintain dose level of encorafenib and binimetinib
and increase frequency of ophthalmic monitoring to 
at least every 14 days until stabilization or 
resolution.
Grade 3
Interrupt dosing of encorafenib and binimetinib and 
refer patient to ophthalmologist within 7 days.

If resolved to Grade ≤ 1 in ≤ 21 days,
resume treatment at 1 reduced dose level of 
encorafenib and binimetinib.

If not resolved to Grade ≤ 1 in ≤ 21 days, 
permanently discontinue encorafenib and 
binimetinib and close follow-up with 
ophthalmic monitoring until stabilization or 
resolution.
Grade 4
Permanently discontinue encorafenib and 
binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or 
resolution.
QTc Prolongation
QTcF > 500 ms and ≤ 60 ms increase from baseline
1st occurrence: 

Temporarily interrupt dosing of encorafenib 
until QTcF < 500 ms. Then resume 
treatment at 1 reduced dose level of 
encorafenib.
2nd occurrence:

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Severity of Adverse Event
Dose Modifications

Temporarily interrupt dosing of encorafenib 
treatment until QTcF < 500 ms. Then 
resume treatment at 1 reduced dose level of 
encorafenib. 
3rd occurrence: 

Permanently discontinue encorafenib and 
binimetinib.
QTcF > 500 ms and > 60 ms increase from baseline
Permanently discontinue encorafenib and 
binimetinib.
Hepatotoxicity
Grade 2 AST or ALT increased
Maintain encorafenib dose.

If no improvement within 4 weeks, 
withhold encorafenib until improved to 
Grade 0-1 or to pretreatment/baseline levels 
and then resume at the same dose.
Grade 3 or 4 AST or ALT increased
See Other Adverse Reactions
Dermatologic (Except Palmar-plantar Erythrodysesthesia Syndrome)
Grade 2
If no improvement within 2 weeks, withhold until 
Grade 0-1. Resume at same dose if first occurrence 
or reduce dose if recurrent.
Grade 3
Withhold until Grade 0-1. Resume at same dose if 
first occurrence or reduce dose if recurrent.
Grade 4
Permanently discontinue encorafenib and 
binimetinib.
Hand-foot Skin Reaction (HFSR)/Palmar-plantar Erythrodysesthesia Syndrome
(Dose Adjustment for Encorafenib ONLY)
Grade 1
Maintain dose of encorafenib. Promptly institute 
supportive measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-style 
modifications.
Grade 2
1st occurrence: 

Maintain dose of encorafenib and HFSR 
should be closely monitored. Promptly 
institute supportive measures, such as 
topical therapy, for symptomatic relief. 
Give instruction on life-style modifications.

If no improvement ≤ 14 days, interrupt 
dosing of encorafenib until resolved to 
Grade ≤ 1. Resume treatment with 
encorafenib at current dose level. Continue 
supportive measures, such as topical 
therapy, for symptomatic relief. Give 
instruction on life-style modifications.

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Severity of Adverse Event
Dose Modifications
Additional occurrence: 

Treatment with encorafenib may be 
maintained or interrupted based upon the 
Investigator’s discretion. Continue 
supportive measures, such as topical 
therapy, for symptomatic relief. Give 
instruction on life-style modifications.
If interrupted dosing of encorafenib per 
Investigator’s judgment, interrupt until 
resolved to Grade ≤ 1. Resume treatment 
with encorafenib at the same dose level or 
1 reduced dose level based upon the 
Investigator’s discretion.
Grade 3
1st or 2nd occurrence:

Interrupt dosing of encorafenib until 
resolved to Grade ≤1. Promptly initiate 
supportive measures, such as topical 
therapy, for symptomatic relief. Give 
instruction on life-style modifications. 
Reassess the patient weekly. Then resume 
treatment at one reduced dose level of 
encorafenib.

Consider referral to dermatologist and 
manage HFSR per dermatologist’s 
recommendation.
> 3rd occurrence:

Interrupt dosing of encorafenib until 
resolved to Grade ≤ 1, decision to resume 
treatment with encorafenib at one reduced 
dose level or permanently discontinue 
encorafenib should be based upon the 
Investigator’s discretion.
Nausea/Vomiting
Grade 1-2
Maintain dose level of encorafenib and binimetinib. 
Promptly institute antiemetic measure.
Grade 3
Interrupt dosing of encorafenib and binimetinib until 
resolved to Grade ≤ 1. Resume treatment at 
1 reduced dose level of encorafenib. Resume 
treatment with binimetinib at the current dose if, in 
the judgment of the Investigator, the toxicity is 
considered to be unrelated to binimetinib, or at 1 
reduced dose level.
Note: Interrupt dosing of encorafenib and 
binimetinib for ≥Grade 3 vomiting or Grade 3 
nausea only if the vomiting or nausea cannot be 
controlled with optimal antiemetics (as per local 
practice).

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Severity of Adverse Event
Dose Modifications
Grade 4
Permanently discontinue encorafenib and 
binimetinib.
Other Adverse Reactions (including renal, hemorrhage)
Recurrent Grade 2 or
First occurrence of any Grade 3
Withhold for up to 4 weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume at 
reduced dose.

If no improvement, permanently 
discontinue encorafenib and binimetinib.
First occurrence of any Grade 4
Permanently discontinue or withhold for up to 4 
weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, then resume at 
a reduced dose. 

If no improvement, permanently 
discontinue encorafenib and binimetinib.
Recurrent Grade 3
Consider permanently discontinuing encorafenib and 
binimetinib.
Recurrent Grade 4
Permanently discontinue encorafenib and 
binimetinib. 
*For adverse events that may be related to both encorafenib and binimetinib, guidance is provided for the other agent 
also.

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13. APPENDIX 3: RECOMMENDED DOSE MODIFICATIONS FOR BINIMETINIB-
RELATED* ADVERSE EVENTS
Severity of Adverse Event
Dose Modifications
Cardiomyopathy
Asymptomatic, absolute decrease in LVEF of > 10% 
from baseline that is also below the LLN
Withhold binimetinib for up to 4 weeks, evaluate 
LVEF every 2 weeks.
Resume binimetinib at a reduced dose if the 
following are present:

LVEF is at or above the LLN and

Absolute decrease from baseline is 10% or 
less and

Patient is asymptomatic.
If LVEF does not recover within 4 weeks 
permanently discontinue binimetinib.
Grade 3-4 (Symptomatic congestive heart failure or 
absolute decrease in LVEF of > 20% from baseline 
that is also below LLN)
Permanently discontinue binimetinib. Closely 
monitor LVEF until resolution or up to 16 weeks.
Venous Thromboembolism
Uncomplicated DVT or PE
Withhold binimetinib.

If improves to Grade 0-1, resume at a 
reduced dose.

If no improvement, permanently 
discontinue binimetinib.
Life threatening PE
Permanently discontinue binimetinib.
Serous Retinopathy
Symptomatic serous retinopathy/
Retinal pigment epithelial detachments
Withhold binimetinib for up to 10 days.

If improves and becomes asymptomatic, 
resume at the same dose.

If not improved, resume at a lower dose 
level or permanently discontinue 
binimetinib.
Retinal Vein Occlusion (RVO)
Any Grade
Permanently discontinue binimetinib.
Uveitis
Grade 1-3
If Grade 1 or 2 does not respond to specific ocular 
therapy, or for Grade 3 uveitis, withhold binimetinib 
and encorafenib for up to 6 weeks.

If improved, resume at same or reduced 
dose.

If not improved, permanently discontinue 
binimetinib.
Grade 4 
Permanently discontinue binimetinib.

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Severity of Adverse Event
Dose Modifications
Other Eye Disorders (i.e., Non-retinal Events, non-Uveitis Events
Grade 1-2
Maintain dose level of encorafenib and binimetinib 
and increase frequency of ophthalmic monitoring to 
at least every 14 days until stabilization or 
resolution.
Grade 3
Interrupt dosing of encorafenib and binimetinib and 
refer patient to ophthalmologist within 7 days.

If resolved to Grade ≤1 in ≤ 21 days,
resume treatment at 1 reduced dose level of 
encorafenib and binimetinib.

If not resolved to Grade ≤ 1 in ≤ 21 days, 
permanently discontinue encorafenib and 
binimetinib and close follow-up with 
ophthalmic monitoring until stabilization or 
resolution.
Grade 4
Permanently discontinue encorafenib and 
binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or 
resolution.
Interstitial Lung Disease
Grade 2
Withhold binimetinib for up to 4 weeks.

If improved to Grade 0-1, resume at a 
reduced dose.

If not resolved within 4 weeks, permanently 
discontinue.
Grade 3 or Grade 4
Permanently discontinue binimetinib.
Hepatotoxicity
Grade 2 AST or ALT increased
Maintain binimetinib dose.

If no improvement within 2 weeks, 
withhold binimetinib until improved to 
Grade 0-1 or to pretreatment/baseline levels 
and then resume at the same dose.
Grade 3 or 4 AST or ALT increased
See Other Adverse Reactions.
Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations
Grade 4 asymptomatic CPK elevation or
Any Grade CPK elevation with symptoms or with 
renal impairment
Withhold binimetinib dose for up to 4 weeks.

If improved to Grade 0-1 resume at a 
reduced dose.

If not resolved within 4 weeks, permanently 
discontinue binimetinib.

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Severity of Adverse Event
Dose Modifications
Dermatologic 
Grade 2
If no improvement within 2 weeks, withhold until 
Grade 0-1. Resume at same dose if first occurrence 
or reduce dose if recurrent.
Grade 3
Withhold until Grade 0-1. Resume at same dose if 
first occurrence or reduce dose if recurrent.
Grade 4
Permanently discontinue binimetinib and 
encorafenib.
Nausea/Vomiting
Grade 1-2
Maintain dose level of encorafenib and binimetinib. 
Promptly institute antiemetic measure.
Grade 3
Interrupt dosing of encorafenib and binimetinib until 
resolved to Grade ≤ 1. Then resume treatment at 
1 reduced dose level of encorafenib. Resume 
treatment with binimetinib at the current dose if, in 
the judgment of the Investigator, the toxicity is 
considered to be unrelated to binimetinib, or at 1 
reduced dose level.
Note: Interrupt dosing of encorafenib and 
binimetinib for ≥Grade 3 vomiting or Grade 3 
nausea only if the vomiting or nausea cannot be 
controlled with optimal antiemetics (as per local 
practice).
If unresolved permanently discontinue binimetinib 
and encorafenib.
Grade 4
Permanently discontinue binimetinib and 
encorafenib.
Other Adverse Reactions
Recurrent Grade 2 or 
First occurrence of any Grade 3
Withhold for up to 4 weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume at 
reduced dose.

If no improvement, permanently 
discontinue binimetinib and encorafenib.
First occurrence of any Grade 4
Permanently discontinue or withhold for up to 4 
weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, then resume at 
a reduced dose. 

If no improvement, permanently 
discontinue binimetinib and encorafenib.
Recurrent Grade 3
Consider permanently discontinuing binimetinib and 
encorafenib.

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Severity of Adverse Event
Dose Modifications
Recurrent Grade 4
Permanently discontinue binimetinib and 
encorafenib.
*For adverse events that may be related to both binimetinib and encorafenib, guidance is provided for the other agent 
also.

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14. APPENDIX 4: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
14.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
patient, temporally associated with the use of study treatment, whether or not 
considered related to the study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator  
Any abnormal laboratory test results that meet any of the conditions below 
must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study treatment or a concomitant medication.  Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as an AE or SAE if they fulfill the definition of an AE or SAE 

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Events Meeting the AE Definition
and meet the requirements as per Section 7.5.  Also, “lack of efficacy” or 
“failure of expected pharmacological action” does not constitute an AE or SAE  
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
patient’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF.  Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs.
14.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are AEs.  If a complication prolongs 

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An SAE is defined as any untoward medical occurrence that, at any dose:
hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered 
serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately lifethreatening or result in death or hospitalization but may 
jeopardize the patient or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These events should 
usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within 
the active collection period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal 
outcome during the study or within the active collection period, then the event 
leading to death must be recorded as an AE on the CRF, and as an SAE with 
CTCAE Grade 5 (see the Assessment of Intensity section).

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.

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14.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 
events (AEs); and (3) exposure to the study treatment under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
treatment under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to Pfizer Safety in lieu of completion of the CT SAE Report Form/AE/SAE 
CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all patient identifiers, with the exception of 

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the patient number, will be redacted on the copies of the medical records before 
submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories per CTCAE Version 4.03: 
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE‑THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

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Assessment of Causality

The investigator may change his/her opinion of causality in light of followup 
information and send an SAE followup report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study treatment caused the 
event, then the event will be handled as “related to study treatment” for reporting 
purposes, as defined by the sponsor.  In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
14.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.

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15. APPENDIX 5: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as DILI.  Patients who experience 
a transaminase elevation above 3 × ULN should be monitored more frequently to determine 
if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 ×
ULN) by several days or weeks.  The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample).  In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased.  This occurrence is still regarded as a potential DILI.  
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or 
ALT values >2 times the baseline values AND >3 × ULN; or >8 × ULN 
(whichever is smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  

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The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.

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16. APPENDIX 6: ECG FINDINGS OF POTENTIAL CLINICAL CONCERN
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm that 
is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia with 1 or 
more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 

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monomorphic/polymorphic ventricular tachycardia (HR >100 bpm (such as torsades 
de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or notifications 
from the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all 
inclusive of what to be reported as AEs/SAEs.

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17. APPENDIX 7: SNELLEN EQUIVALENCE (VISUAL ACUITY CONVERSION 
CHART)
Holladay J. Visual acuity measurements. J Cataract Refract Surg. 2004;30(2) 297-90. 

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18. APPENDIX 8: ALTERNATIVE MEASURES DURING PUBLIC EMERGENCIES
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 global pandemic and will become effective for other public emergencies only 
upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
18.1. Eligibility
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A patient should be excluded if he/she has a positive test result 
for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. Patients with active infections are excluded from study participation as 
per Section 5.2 Exclusion Criteria. Active infection requiring systemic therapy. 
When the infection resolves, the patient may be considered for re-screening. 
18.2. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study patients at scheduled visits per the Schedule of Activities or 
unscheduled visits. Telehealth visits may be used to continue to assess patient safety and 
collect data points. Telehealth includes the exchange of healthcare information and services 
via telecommunication technologies (e.g., audio, video, video-conferencing software) 
remotely, allowing the patient and the investigator to communicate on aspects of clinical 
care, including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit:

Review and record study treatment(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 7.5. 

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the patient is adhering to the contraception method(s) required in the protocol. 
Refer to Appendix 1 and Section 18.3.1 of this appendix regarding pregnancy tests.
Study patients must be reminded to promptly notify site staff about any change in their health 
status.

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18.3. Alternative Facilities for Safety Assessments
18.3.1. Laboratory Testing
If a study patient is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital. The 
following safety laboratory evaluations may be performed at a local laboratory:  

Refer to Section 7.3.9 Clinical Safety Laboratory Assessments, Table 11 for the list of 
safety laboratory evaluations, including pregnancy testing required per protocol.
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible.  The local laboratory reports should be filed in the patientt’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
If a patient requiring pregnancy testing cannot visit a local laboratory for pregnancy testing, a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be used by the 
patient to perform the test at home, if compliant with local regulatory requirements. The 
pregnancy test outcome should be documented in the patient’s source documents/medical 
records and relevant data recorded on the CRF. Confirm that the patient is adhering to the 
contraception method(s) required in the protocol. 
18.3.2. Imaging
If the patient is unable to visit the study site for safety imaging assessments (e.g., 
echocardiogram or MUGA), the patient may visit an alternative facility to have the safety 
imaging assessments performed. Qualified study site personnel must order, receive, and 
review results. 
18.3.3. Electrocardiograms
If the patient is unable to visit the study site for ECGs, the patient may visit an alternative 
facility to have the ECGs performed. Qualified study site personnel must order, receive, and 
review results. 
18.4. Study Treatment
If the safety of a trial patient is at risk because they cannot complete required evaluations or 
adhere to critical mitigation steps, then discontinuing that patient from study treatment must 
be considered.
Study drugs may be shipped by courier to study patients if permitted by local regulations and 
in accordance with storage and transportation requirements for the study drugs. Pfizer does 
not permit the shipment of study drugs by mail. The tracking record of shipments and the 
chain of custody of study drugs must be kept in the patient’s source documents/medical 
records.

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The following is recommended for the administration of study drugs for patients who have 
active [confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion)] SARS-CoV2 infection:

For symptomatic patients with active SARS-CoV2 infection, study drugs should be 
delayed for at least 14 days from the start of symptoms. This delay is intended to allow 
the resolution of symptoms of SARS-CoV2 infection.

Prior to restarting treatment, the patient should be afebrile for 72 hours, and SARS-
CoV2-related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 
hours.  Notify the study team when treatment is restarted.

Continue to consider potential drug-drug interactions as described in protocol 
Section 6.5 for any concomitant medication administered for treatment of SARS-CoV2 
infection.
18.5. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the patient’s location, rather than an in-person study visit at the site. The following 
may be performed during a home health visit:

Physical exam including dermatological lesions and vital signs

Review and record study treatment(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 7.5  

Review and record any new concomitant medications or changes in concomitant
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the patient is adhering to the contraception method(s) required in the protocol. 
Refer to Appendix 1 and Section 18.3.1 of this appendix regarding pregnancy tests.
18.6. Adverse Events and Serious Adverse Events
If a patient has COVID-19 during the study, this should be reported as an adverse event (AE) 
or serious adverse events (SAE) and appropriate medical treatment provided. Temporary 
discontinuation of the study treatment may be medically appropriate until the patient has 
recovered from COVID-19.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study treatment with the study medical monitor. 

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18.7. Efficacy Assessments
If the patient is unable to visit the study site for imaging assessments (e.g., CT, MRI, X-ray, 
FDG-PET), the patient may visit an alternative facility to have the imaging assessments 
performed. Qualified study site personnel must order, receive, and review results. 
18.8. Steering Committee
There will be no impact on the Steering Committee Charter. The Steering Committee will 
continue to be consulted during public health emergencies.

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19. APPENDIX 9: PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Version 5
24 September 2021
Version 4
16 February 2021
Version 3
25 August 2020
Version 2
03 October 2019
Version 1
04 March 2019
Original Version 0
27 November 2018
Version 5 (24 September 2021)
The primary purpose of this amendment is to provide clarification to the eligibility for the 
previously treated patients, and to update the Secondary Objectives and Interim Analysis 
sections to maintain consistency with the SAP. This amendment is considered to be 
substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the 
European Parliament and the Council of the European Union because it significantly impacts 
the scientific value of the study.
Section # and Name
Description of Change
Brief Rationale
List of Abbreviations and 
Definition of Terms
Added TTR
Added abbreviation for Time to 
Response as added in Objectives 
and Endpoints and Section 8.4.2.5
Section 1.1 Synopsis Table 1
Section 3 Objectives and 
Endpoints Table 5
Included TTR as a Secondary 
Objective and Endpoint, and 
update to DOR endpoint.
Protocol sections updated to 
maintain consistency with the 
SAP
Section 5.1 Inclusion Criteria, #6
Updated 2nd note to clarify the 
eligibility for previously treated 
patients
To ensure eligible patients are 
enrolled appropriately into each 
study population group 
Section 8.4.2.1 Duration of 
Response
Updated to include DOR based on 
IRR and Investigator assessments
Protocol section updated to clarify 
DOR will be based on both IRR 
and Investigator assessments
Section 8.4.2.5 Time to Response
New section to describe the TTR 
endpoint and analysis
Protocol section added to maintain 
consistency with the SAP
Section 8.5 Interim Analyses
Updated to accommodate possible 
interim analyses for the study
Protocol section updated to 
maintain consistency with the 
SAP
Version 4 (16 February 2021) 
The primary purpose of this amendment is to support a registrational status of this study by 
revision of the primary objective and corresponding endpoint into 2 subgroups (treatment-
naïve and previously treated) and to update the sample size to describe the 2 subgroups. 
Corresponding statistical analyses sections have been updated to reflect these changes. This 
amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 

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because it significantly impacts the safety or physical integrity of patients and the scientific 
value of the study.
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 2.1.2 Treatment of BRAF-
mutant Non-small Cell Lung 
Cancer
Updated reference data within the 
rationale. 
Data within referenced articles 
have been updated. 
Section 1.1 Synopsis Table 1 
Primary and Select Secondary 
Objectives and Endpoints
Section 3 Objectives and 
Endpoints Table 4
Objectives and endpoints have 
been updated to distinguish 
between treatment naïve and 
previously treated patients, and to 
centralize assessments for the 
primary objective/endpoint.
Following consultation with the 
FDA, the design of the study has 
been revised to allow for 
registration of either or both a 
treatment naïve population and a 
previously treated population.
Section 1.1 Synopsis Table 2 
Study Design Elements
Section 6.10 Enrollment of 
Additional Patients
Updated number of patients to 
reflect new sample sizes for the 2 
subgroups.
Following consultation with the 
FDA, the design of the study has 
been revised to allow for 
registration of either or both a 
treatment naïve population and a 
previously treated population.
Section 1.2 Study Schema 
Figure 1 Overall Study Design
Updated schema to reflect 
changes made within the protocol. 
Due to change in sample size to 
distinguish between two treatment 
groups, schema has been updated. 
Section 1.3 Schedule of Activities 
(SoA) Table 3
Revised PK assessments schedule; 
added schedule of assessments for 
proteomic/metabolic serum 
sample and circulating serum 
biomarker.
Revisions made to reflect updated 
PK and biomarker sample 
schedule. 
Section 4.1 Overall Design
Added description of the 2 
subgroups.
Following consultation with the 
FDA the design of the study has 
been revised to allow for 
registration of either or both a 
treatment naïve population and a 
previously treated population.
Section 5.2 Exclusion Criteria
Reworded Exclusion Criterion 
#13 to reflect criterion in original 
protocol.
Original criterion enhances patient 
safety. All patients enrolled in the 
study will follow the same 
eligibility criteria.
Section 5.2 Exclusion Criteria
Section 6.5 Concomitant Therapy
Added clarifications to Exclusion 
Criterion #4b and Concomitant 
Therapy to clarify administration 
of COVID-19 vaccine.
COVID-19 vaccines approved 
under an EUA or equivalent are 
not considered investigational 
products.
Section 6.1.1 Encorafenib
Section 6.1.2 Binimetinib
Added clarifier to indicate doses 
administered on PK days must be 
performed under observation by 
the Investigator or designee; 
additional instruction to not 
manipulate the study drug
Clarification has been added due 
to presence of protocol deviations 
related to the observation around 
these doses. Additional 
instructions added to maintain 
integrity of study medication.
Section 7.1.1.1 BRAFV600
Mutation Testing
Additional text added to clarify 
requirement for samples to be sent 
to central lab.
To ensure the centralization of 
mutation status confirmation, text 
has been added. 
Section 7.2.4 Independent 
Radiology Review
Updated section to indicate that 
the review of tumor scans will be 
Central radiology review has been 
implemented as part of the 

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Section # and Name
Description of Change
Brief Rationale
both by the Investigator and the 
central radiology review.
primary objective/endpoint of 
ORR to ensure consistency with 
registration. 
Section 7.4.1 Distribution of 
Dosing Diary
Updated to reflect change from 
patient reminder card to dosing 
diary for patient completion.
To ensure complete and accurate 
drug accountability, the protocol 
requirements will include a dosing 
diary for each patient to complete 
to document their doses.
Section 7.8 Pharmacokinetics
Section 7.8 Table 12 Serial 
Pharmacokinetic Blood Sample 
Timing in patients Enrolled under 
Protocol Versions 0 through 3
Section 7.8 Table 13 
Pharmacokinetic Blood Sample 
Timing in patients enrolled under 
protocol version 4 or later
Updated PK collection schedule; 
clarified Table 12 and added 
Table 13 to reflect new schedules.
Approximately 50 patients 
enrolled under the Protocol 
Version 3 have provided serial PK 
samples, which are sufficient to 
characterize PK in this population. 
To reduce patient burden, only 
predose PK samples will be 
collected from future patients for 
exposure-response analysis. FDA 
agreed on the changes of PK 
collection. 
Section 7.10.2 Circulating Serum 
Biomarker Analysis
Added section for additional 
samples collected.
To monitor proteomic correlates 
of response and resistance to 
therapy.
Section 8 Statistical 
Considerations   
Revised to update changes to 
statistical analyses due to sample 
size updates and to support 
registrational status of study.
Following consultation with the 
FDA, the design of the study has 
been revised to allow for 
registration of either or both a 
treatment naïve population and a 
previously treated population
Section 8.1 Statistical Hypotheses
Updated to reflect new 
calculations for the 2 subgroups.
Following consultation with the 
FDA, the design of the study has 
been revised to allow for 
regulatory approval of either or 
both a treatment naïve population 
and a previously treated 
population.
Section 8.2 Sample Size 
Determination
Updated to reflect the sample size 
for each subgroup.
Following consultation with the 
FDA, the design of the study has 
been revised to allow for 
regulatory approval of either or 
both a treatment naïve population 
and a previously treated 
population.
Appendix 7 Snellen Equivalence 
(Visual Acuity Conversion Chart)
Included conversion chart of 
visual acuity reading.
To assist in the consistent 
conversion of values, the 
conversion chart has been 
included.
Version 3 (25 August 2020) The primary purpose of this amendment is to increase the 
sample size to support a potential registrational status of the study, and to provide 
clarification on acceptable methods for BRAF mutation status confirmation. Country specific 
changes per Korean Amendment 2.1 and 2.2 have been incorporated. This amendment is 
considered to be substantial based on the criteria set forth in Article 10(a) of Directive 

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2001/20/EC of the European Parliament and the Council of the European Union because it 
significantly impacts the safety or physical integrity of patients and the scientific value of the 
study. 
Section # and Name
Description of Change
Brief Rationale
Table 2, Study Design Elements
Section 1.2, Study Schema
Section 6.10, Enrollment of Additional 
Patients
Section 8.2, Sample Size Determination 
Revision of sample size 
from approximately 40 
patients to at least 80 
patients with a 
BRAFV600E mutation, but 
no more than 90 patients 
with any other BRAFV600
mutation will be enrolled 
and treated
Current data from Planchard et al, 
2017 have been updated. As such 
the hypothesis and sample size for 
this study has been adjusted based 
on the reported ORR of 64%.
Section 5.1, Inclusion Criteria
Section 5.2, Exclusion Criteria
Section 7.1.1.1 BRAFV600 Mutation Testing
Updated to include 
changes per country 
specific Amendment 2.1 
and 2.2; clarified FNA is 
acceptable for BRAF 
mutation testing. 
Refer to country specific 
Amendments 2.1 and 2.2 for 
rationale.
A FNA is an acceptable method 
for confirmation of BRAF 
mutation with the central lab as 
long as there is sufficient material 
from the same sample used to 
confirm BRAF mutation.
Section 6.7, Criteria for Permanent 
Discontinuation of Study Treatment
Section 7.5
Appendix 4
Appendix 5
Appendix 6
Pfizer master template 
text included
Safety reporting and processes 
have migrated from the Array 
system and processes to the Pfizer 
system and processes.
Section 8.1, Statistical Hypotheses
Section 8.2, Sample Size Determination
Changes made to the 
sample size; hypotheses, 
populations, and analyses 
to support change in 
sample size.
The hypothesis has been updated 
based on the results observed 
from Planchard et al, 2017 which 
showed an ORR per Investigator 
assessment of 64%. 
This amendment incorporates all revisions to date, including changes made at the request of 
country health authorities. 
Version 2 (03 October 2019)The primary purpose of this amendment is to revise patient 
eligibility criteria based on investigator feedback and changes in standard of care for 
identifying BRAF mutation status in this patient population. This amendment is considered to 
be non-substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union because it significantly 
impacts neither the safety or physical integrity of patients nor the scientific value of the 
study.
Section # and Name
Description of Change
Brief Rationale
1.1, Synopsis 
4.1, Overall Design
5.1, Inclusion Criteria
Inclusion of NSCLC patients with 
other V600 Class 1 BRAF mutations 
(e.g., K or D)
Encorafenib binds to V600 K and D. 
Although these mutations are much 
less common, patients with these 

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Section # and Name
Description of Change
Brief Rationale
mutations should respond similarly as 
patients with a V600E mutation.
5.1, Inclusion Criteria
Patients must have histologically 
confirmed NSCLC by AJCC 8th
edition (M1a, M1b, or M1c)
Updated to the most recent version of 
AJCC.
5.1, Inclusion Criteria
7.1.1.1, BRAFV600
Mutation Testing
7.12, Biomarkers
Patients can qualify for the study with 
written documentation from a 
previous local pathology report of 
BRAFV600 mutation in tumor tissue or 
by a liquid biopsy (e.g., ctDNA 
genetic testing).
Liquid biopsy results are available 
much more quickly and current
standard oncology practice is to first 
perform mutation analyses on 
peripheral blood samples and base 
targeted therapy on positive results. 
Tissue analyses are more often 
performed to corroborate negative 
results from a liquid biopsy. Liquid 
biopsy tests are as specific as tissue-
based testing but not as sensitive, so 
tissue analyses serve to corroborate 
negative results from liquid biopsy 
testing.  Patients can qualify for the 
study with a positive BRAFV600 result 
in a liquid biopsy and will be required 
to submit tissue for central 
confirmation.
4.1, Overall Design
5.1, Inclusion Criteria
Patients may qualify for the study if 
they have received prior PD-1/PD-L1 
therapy in combination with immune 
therapies (e.g., ipilimumab) with or 
without platinum-based 
chemotherapy.
Emerging clinical data have 
demonstrated clinical benefit in 
patients with NSLC who have been 
treated with the combination of a PD-
1/PD-L1 and other immune therapies 
(e.g., CTLA-4), either with and 
without platinum-based 
chemotherapy. Therefore, patients 
who have received these treatments in 
the 1L setting will be eligible for 
enrollment in the study.
5.1, Inclusion Criteria
7.1.1, Screening
If baseline scans from an institution 
other than the investigational site are 
used, the site must obtain copies of 
the scans prior to enrollment of the 
patient, or the scans must be repeated 
at the investigational site and 
submitted for potential future 
independent review.
To ensure that all baseline scans are 
available for central review.
5.1, Inclusion Criteria
Patients with documented Gilbert 
syndrome or hyperbilirubinemia due 
to non-hepatic cause (e.g., hemolysis, 
hematoma) may be enrolled following 
discussion and agreement with the 
Sponsor.
Patients with these conditions may 
have elevated bilirubin but still be 
suitable candidates for study treatment 
and therefore not excluded from 
enrollment.
5.2, Exclusion Criteria
Modifications to text regarding 
thromboembolic or cerebrovascular 
events.
To provide additional clarification 
regarding exclusion criteria for 

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Section # and Name
Description of Change
Brief Rationale
thromboembolic or cerebrovascular 
events.
5.2, Exclusion Criteria
Removed exclusion of history of 
interstitial lung disease that required 
oral or intravenous glucocorticoid 
steroids for management.
Per investigator feedback, patients 
with NSCLC are likely to have had 
interstitial lung disease from prior 
treatments and excluding these 
patients would limit enrollment in the 
study.
5.2, Exclusion Criteria
Modifications to text regarding 
patients with previously treated brain 
metastases.
Modifications based on investigator 
feedback regarding standard of care 
treatment for patients with brain 
metastases. 
5.2, Exclusion Criteria
Clarification provided for when 
exclusion criteria can be reviewed and 
discussed with the Sponsor.
To provide additional clarification 
regarding exclusion criteria.
6.6.2, Dose 
Modifications
Updated to allow for dose re-
escalation of encorafenib and 
binimetinib after dose reduction and 
to adjust the lowest dose level of 
encorafenib and binimetinib.
Updated as per the current local 
prescribing instructions for 
encorafenib and binimetinib.
7.3.9, Clinical 
Laboratory Assessments
Updated to specify that screening 
laboratory assessments for 
hematology and serum chemistry 
must be performed within 7 days of 
Cycle 1 Day 1.
Clarification.
Table 10, Summary of 
Clinical Laboratory 
Tests
Removed urine testing if total CK ≥ 3 
× ULN and to clarify that only 
hematology and serum chemistry need 
to be done within 7 days of Cycle 1 
Day 1.
The central laboratory vendor does 
not perform urine testing.
7.12, Biomarkers
Clarification added regarding 
biomarker samples for future testing, 
storage, and reporting of results.
To provide additional clarification.
7.3.6 Vital Signs
Clarification added regarding timing 
for the collection of vital signs
To provide additional flexibility for 
sites regarding timing of vital sign 
collection.
8.4.4, Pharmacokinetic 
Analyses
Clarification added regarding PK 
analysis methods
Administrative update
Version 1 (04 March 2019)
This amendment regards the inclusion of patients with moderate hepatic impairment as per 
binimetinib labeling recommendations. This amendment is considered to be substantial based 
on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament 
and the Council of the European Union because it impacts the safety of patients.
Section # and Name
Description of Change
Brief Rationale

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5.1 Inclusion Criteria 
Inclusion criterion 10a was updated to 
only allow patients who have a total 
bilirubin ≤1.5 × ULN in the study.
Patients with moderate to severe 
hepatic impairment (i.e., total 
bilirubin > 1.5 × ULN with indirect 
bilirubin < 1.5 × ULN, with or 
without elevation of AST), will not be 
eligible to initiate treatment at the 
starting binimetinib dose in this 
protocol. Therefore, only patients with 
a total bilirubin ≤1.5 × ULN will be 
eligible for study inclusion.
Protocol Title Page
EudraCT Number is now available 
and has been added to the title page of 
the protocol.
To provide the EudraCT Number for 
the study.