An Open-Label, Multicenter, Phase 1 Study With Expansion Cohorts of Ramucirumab or Necitumumab in Combination With Osimertinib in Patients With Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer After Progression on First-Line EGFR TKI Therapy
Phase: PHASE1
Conditions: Non-small Cell Lung Cancer
Sponsor: Eli Lilly and Company

 
 
 
Protocol: I4T-MC-JVDL(c) 
 
 
An Open-Label, Multicenter, Phase 1 Study with Expansion Cohorts of 
Ramucirumab or Necitumumab in Combination with Osimertinib in Patients 
with Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer 
after Progression on First-Line EGFR TKI Therapy 
 
 
NCT02789345 
 
 
Approval Date: 28-Mar-2018 

I4T-MC-JVDL(c) Clinical Protocol
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Protocol I4T-MC-JVDL(c)
An Open-Label, Multicenter, Phase 1 Study with Expansion
Cohorts of Ramucirumab or Necitumumab in Combination 
with Osimertinib in Patients with Advanced T790M-Positive 
EGFR-Mutant Non-Small Cell Lung Cancer after Progression 
on First-Line EGFR TKI Therapy
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
ramucirumab (LY3009806), necitumumab (LY3012211), and osimertinib (AZD9291) unless 
such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Ramucirumab (LY3009806), Necitumumab (LY3012211), and Osimertinib (AZD9291)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 29 March 2016.
Amendment (a) Electronically Signed and Approved by Lilly 15 November 2016.
Amendment (b) Electronically Signed and Approved by Lilly 9 June 2017.
Amendment (c) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 28-Mar-2018 GMT

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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................19
3.1.
Study Rationale............................................................................................................19
3.2.
Background..................................................................................................................21
3.2.1.
Ramucirumab.......................................................................................................21
3.2.2.
Necitumumab.......................................................................................................21
3.2.3.
Osimertinib ..........................................................................................................22
3.3.
Benefit/Risk Assessment..............................................................................................23
4.
Objectives and Endpoints..................................................................................................25
5.
Study Design.....................................................................................................................26
5.1.
Overall Design .............................................................................................................26
5.1.1.
Dose-Finding Portion:  Dose-Limiting Toxicity Observation................................27
5.1.2.
Dose-Expansion Portion:  Expansion Cohort........................................................28
5.2.
Number of Patients.......................................................................................................28
5.3.
Study Completion and End of Trial Definition .............................................................29
5.4.
Scientific Rationale for Study Design...........................................................................29
5.5.
Justification for Dose ...................................................................................................29
5.5.1.
Dose Selection for Ramucirumab.........................................................................29
5.5.2.
Dose Selection for Necitumumab.........................................................................32
5.5.3.
Dose Selection for Osimertinib.............................................................................33
6.
Study Population...............................................................................................................35
6.1.
Inclusion Criteria..........................................................................................................35
6.2.
Exclusion Criteria ........................................................................................................37
6.3.
Lifestyle Restrictions....................................................................................................40
6.3.1.
Diet......................................................................................................................40
6.3.2.
Contraception.......................................................................................................41
6.4.
Screen Failures.............................................................................................................41
7.
Treatments........................................................................................................................42
7.1.
Treatments Administered .............................................................................................42
7.1.1.
Packaging and Labelling ......................................................................................43
7.2.
Method of Treatment Assignment ................................................................................44
7.2.1.
Selection and Timing of Doses.............................................................................44
7.2.1.1.
Dose-Limiting Toxicity Observation...............................................................44

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7.2.1.1.1.
Definition of Dose-Limiting Toxicities .....................................................46
7.3.
Blinding .......................................................................................................................47
7.4.
Dosage Modification....................................................................................................47
7.4.1.
Ramucirumab Dose Adjustments, Delays, and 
Discontinuation....................................................................................................47
7.4.2.
Necitumumab Dose Adjustments, Delays, and 
Discontinuation....................................................................................................53
7.4.3.
Osimertinib Dose Adjustments, Delays, and Discontinuation ...............................54
7.4.4.
Dose Delays for Reasons Not Related to Study Treatment....................................55
7.5.
Preparation/Handling/Storage/Accountability...............................................................55
7.6.
Treatment Compliance .................................................................................................55
7.7.
Concomitant Therapy...................................................................................................56
7.7.1.
Supportive Care ...................................................................................................56
7.7.1.1.
Infusion-Related Reactions - Ramucirumab and 
Necitumumab .................................................................................................56
7.7.1.1.1.
Infusion-Related Reactions - Ramucirumab ..............................................56
7.7.1.1.2.
Infusion-Related Reactions - Necitumumab ..............................................57
7.7.1.2.
Supportive Care for Ramucirumab..................................................................59
7.7.1.2.1.
Supportive Care by Adverse Event of Special Interest...............................59
7.7.1.2.1.1.
Hypertension.......................................................................................59
7.7.1.2.1.2.
Proteinuria ..........................................................................................59
7.7.1.2.1.3.
Thromboembolic Events .....................................................................59
7.7.1.2.1.4.
Bleeding/Hemorrhage .........................................................................59
7.7.1.2.1.5.
Gastrointestinal Perforation.................................................................60
7.7.1.2.1.6.
Reversible Posterior Leukoencephalopathy 
Syndrome............................................................................................60
7.7.1.2.1.7.
Congestive Heart Failure.....................................................................60
7.7.1.2.1.8.
Fistula Formation................................................................................61
7.7.1.2.1.9.
Surgery and Impaired Wound Healing ................................................61
7.7.1.2.1.10.
Liver Failure and Other Significant Liver Injury .................................61
7.7.1.2.2.
Supportive Care Agents for Ramucirumab -
Guidelines ................................................................................................61
7.7.1.2.2.1.
Antiemetic Agents ..............................................................................61
7.7.1.2.2.2.
Analgesic Agents ................................................................................61
7.7.1.2.2.3.
Appetite Stimulants.............................................................................62
7.7.1.2.2.4.
Granulocyte-Colony Stimulating Factors.............................................62
7.7.1.2.2.5.
Erythroid Growth Factors....................................................................62
7.7.1.2.2.6.
Other Supportive Care Agents.............................................................62

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7.7.1.3.
Supportive Care for Necitumumab by Adverse Event of 
Special Interest ...............................................................................................62
7.7.1.3.1.
Skin Reactions..........................................................................................62
7.7.1.3.2.
Conjunctivitis ...........................................................................................64
7.7.1.3.3.
Electrolyte Abnormalities .........................................................................64
7.7.1.3.4.
Thromboembolic Events...........................................................................64
7.7.1.3.5.
Pneumonia and Sepsis...............................................................................64
7.7.1.3.6.
Cardiorespiratory Disorders......................................................................65
7.7.1.4.
Supportive Care for Osimertinib by Adverse Event of 
Special Interest ...............................................................................................65
7.7.1.4.1.
Diarrhea....................................................................................................65
7.7.1.4.2.
Skin Reactions..........................................................................................66
7.7.1.4.3.
QTc ..........................................................................................................67
7.7.1.4.4.
Interstitial Lung Disease ...........................................................................67
7.8.
Treatment after Study Completion................................................................................68
7.8.1.
Continued Access Period......................................................................................68
8.
Discontinuation Criteria ....................................................................................................70
8.1.
Discontinuation from Study Treatment.........................................................................70
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................70
8.2.
Discontinuation from the Study....................................................................................70
8.3.
Lost to Follow-Up........................................................................................................70
9.
Study Assessments and Procedures ...................................................................................72
9.1.
Efficacy Assessments...................................................................................................72
9.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................72
9.1.1.1.
Baseline Tumor Imaging ................................................................................72
9.1.1.2.
Tumor Imaging during Study Treatment.........................................................73
9.1.2.
Efficacy Assessments during Postdiscontinuation Follow-Up...............................73
9.1.3.
Efficacy Measures................................................................................................73
9.1.4.
Appropriateness of Assessments ..........................................................................74
9.2.
Adverse Events ............................................................................................................74
9.2.1.
Adverse Events of Special Interest .......................................................................75
9.2.1.1.
Infusion-Related Reactions - Ramucirumab and 
Necitumumab .................................................................................................75
9.2.1.2.
Adverse Events of Special Interest - Ramucirumab.........................................75
9.2.1.3.
Adverse Events of Special Interest - Necitumumab.........................................75
9.2.1.4.
Adverse Events of Special Interest – Osimertinib............................................75
9.2.2.
Serious Adverse Events........................................................................................75
9.2.3.
Pregnancy ............................................................................................................76

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9.2.4.
Suspected Unexpected Serious Adverse Reactions ...............................................77
9.2.5.
Complaint Handling.............................................................................................77
9.3.
Treatment of Overdose.................................................................................................77
9.4.
Safety...........................................................................................................................77
9.4.1.
Other Safety Measures .........................................................................................77
9.4.1.1.
Electrocardiograms.........................................................................................77
9.4.2.
Safety Monitoring ................................................................................................78
9.5.
Pharmacokinetics .........................................................................................................78
9.6.
Pharmacodynamics ......................................................................................................79
9.7.
Pharmacogenomics ......................................................................................................79
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................79
9.8.
Biomarkers...................................................................................................................80
9.8.1.
Samples for Non-pharmacogenetic Biomarker Research ......................................80
9.8.2.
Tumor Tissue Samples.........................................................................................80
9.8.3.
Immunogenicity Assessments ..............................................................................81
9.9.
Health Economics ........................................................................................................81
10.
Statistical Considerations ..................................................................................................82
10.1. Sample Size Determination ..........................................................................................82
10.2. General Statistical Considerations ................................................................................82
10.3. Statistical Analyses ......................................................................................................83
10.3.1.
Efficacy Analyses ................................................................................................83
10.3.2.
Safety Analyses....................................................................................................83
10.3.3.
Other Analyses.....................................................................................................83
10.3.3.1.
Patient Disposition..........................................................................................83
10.3.3.2.
Patient Characteristics ....................................................................................83
10.3.3.3.
Concomitant Therapy .....................................................................................84
10.3.3.4.
Postdiscontinuation Therapy...........................................................................84
10.3.3.5.
Treatment Compliance....................................................................................84
10.3.3.6.
Pharmacokinetic Analyses..............................................................................84
10.3.3.7.
Immunogenicity Analyses ..............................................................................84
10.3.3.8.
Biomarker Analysis ........................................................................................84
10.3.4.
Interim Analysis...................................................................................................84
11.
References ........................................................................................................................85

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List of Tables
Table
Page
Table JVDL.1.
Baseline Schedule of Activities ..............................................................12
Table JVDL.2.
On-Study-Treatment Schedule of Activities............................................13
Table JVDL.3.
Post-Treatment Follow-Up Schedule of Activities ..................................17
Table JVDL.4.
Continued Access Schedule of Activities................................................18
Table JVDL.5.
Objectives and Endpoints .......................................................................25
Table JVDL.6.
Dose Finding Portion Treatment Regimens/ Dosing Schedule ................42
Table JVDL.7.
Ramucirumab Dose Reductions
a.............................................................48
Table JVDL.8.
Dose-Modification Guidelines for Ramucirumab for Adverse 
Events at Least Possibly Related to Ramucirumab, including 
Adverse Events of Special Interest..........................................................49
Table JVDL.9.
Dose Adjustments of Necitumumab........................................................54
Table JVDL.10.
Recommended Dose Modifications for Osimertinib................................55
Table JVDL.11.
Necitumumab Infusion-Related Reaction Treatment Guidelines .............58
Table JVDL.12.
Managing Skin Reactions .......................................................................63

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List of Figures
Figure
Page
Figure JVDL.1.
Illustration of study design......................................................................27
Figure JVDL.2.
Predicted Cmin,ss following different dose regimens. ................................32
Figure JVDL.3.
Continued access diagram.......................................................................69

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................90
Appendix 2.
Study Governance, Regulatory, and Ethical Considerations....................95
Appendix 3.
Clinical Laboratory Tests........................................................................98
Appendix 4.
Sampling Schedule for Pharmacokinetics, Immunogenicity, 
Biomarkers, and Pharmacogenetics ........................................................99
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ..........102
Appendix 6.
Creatinine Clearance Formula...............................................................103
Appendix 7.
Protocol JVDL Restricted and Prohibited Concomitant Therapy...........104
Appendix 8.
Protocol Amendment I4T-MC-JVDLc Summary An Open-Label, 
Multicenter, Phase 1 Study with Expansion Cohorts of 
Ramucirumab or Necitumumab in Combination with Osimertinib 
in Patients with Advanced T790M-Positive EGFR-Mutant Non-
Small Cell Lung Cancer after Progression on First-Line EGFR TKI 
Therapy................................................................................................106

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1.
Synopsis
Protocol Title:
An Open-Label, Multicenter, Phase 1 Study with Expansion Cohorts of Ramucirumab or Necitumumab in 
Combination with Osimertinib in Patients with Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung 
Cancer after Progression on First-Line EGFR TKI Therapy
Summary of Study Design:
Study I4T-MC-JVDL is an open-label, multicenter Phase 1 study with an expansion cohort to evaluate the safety 
and preliminary efficacy of ramucirumab or necitumumab in combination with osimertinib.  The dose-limiting 
toxicity (DLT) observation period and expansion cohort (safety and preliminary efficacy) will include patients with 
advanced T790M-positive epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer after 
progression on first-line EGFR tyrosine kinase inhibitor therapy.
Objectives and Endpoints:
Objectives
Endpoints
Phase 1a: 
Dose-
Finding 
Portion
Primary:
To assess the safety and tolerability of 
ramucirumab or necitumumab in combination 
with osimertinib
Dose-limiting toxicities, observed during 2 cycles 
(28 days) for ramucirumab arm (Arm A) and 
1 cycle (21 days) for necitumumab arm (Arm B)
Safety (including but not limited to):
TEAEs, SAEs, and deaths
Secondary:
To assess the PK of ramucirumab or 
necitumumab in combination with osimertinib
PK:  Cmin and approximate Cmax of ramucirumab
and necitumumab in serum
Phase 1b:
Dose-
Expansion 
Portion
Primary:
To assess the safety and tolerability of 
ramucirumab in combination with osimertinib
Safety (including but not limited to):
TEAEs, SAEs, and deaths
Secondary:
To assess the preliminary efficacy of 
ramucirumab in combination with osimertinib*
To assess the PK of ramucirumab in combination 
with osimertinib
Efficacy:  ORR (RECIST 1.1), DCR, DOR, PFS, 
and OS*
PK:  Cmin and approximate Cmax of ramucirumab
in serum
Abbreviations:  Cmax = maximum concentration; Cmin = minimum concentration; DCR = disease control rate; 
DOR= duration of response; ORR = objective response rate; OS = overall survival; PFS = progression-free 
survival; PK = pharmacokinetics; RECIST 1.1= Response Evaluation Criteria In Solid Tumors Version 1.1; 
SAEs = serious adverse events; TEAEs = treatment-emergent adverse events.
*Note:  Patients in the Dose-Finding Portion will be included in the overall preliminary efficacy analyses.

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Treatment Arms and Duration:
Phase 1a:  Dose-Finding Portion (3 + 3 dose de-escalation design)
Length of Study Portion
The duration of the Dose-Finding Portion from first patient enrolled to the last patient completing the
DLT observation period is estimated to be approximately 6 months.

Arm A:  28 days (2 cycles) for ramucirumab in combination with osimertinib for DLT observation

Arm B:  21 days (1 cycle) for necitumumab in combination with osimertinib for DLT observation
All patients will be treated until confirmed progressive disease, unacceptable toxicity, or discontinuation 
for any other reason.
Dosing Schedules

Arm A:
Dose Level 0: ramucirumab 10 mg/kg on Day 1 every 2 weeks (Q2W) and osimertinib 80 mg daily, in 
3 patients
Dose Level -1: ramucirumab 8 mg/kg on Day 1 Q2W and osimertinib 80 mg daily, in 3 patients

Arm B:  
Dose Level 0: necitumumab 800 mg on Days 1 and 8 every 3 weeks (Q3W) and osimertinib 80 mg 
daily, in 3 patients
Dose Level -1: necitumumab 600 mg on Days 1 and 8 Q3W and osimertinib 80 mg daily, in 3 patients
Number of patients: up to 24 DLT-evaluable patients (up to 12 enrolled in each arm)
Phase 1b:  Dose-Expansion Portion
Length of Study Portion
The duration of the Dose-Expansion Portion (excluding the Continued Access Period) from first 
patient enrolled to the completion of the study is approximately 2 years after last patient enrolled, or 
when adequate number of events are observed for survival outcome estimation, whichever comes first.

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Treatment Cohort

Cohort A:  ramucirumab at recommended dose + osimertinib 80 mg daily (22 patients)
Number of patients:  22 evaluable patients
Statistical Analysis:  
For Dose-Finding Portion, a 3+3 dose de-escalation design will be used to assess the safety of ramucirumab or 
necitumumab in combination with osimertinib.  Additional patients will be enrolled to achieve the minimum of 
3 evaluable patients at each dose level for each arm, if dropouts or dose interruptions or reductions occur that result 
in a patient being non-evaluable for DLTs.  Data will be reviewed by dose schedule group (3 patients) for each arm.
For Dose-Expansion Portion, the primary data analysis will be conducted approximately 6 months after last patient 
receives initial dose, and the final analysis will occur upon the completion of the study.  All patients enrolled in the 
Dose-Finding Portion (Arm A) and the Dose-Expansion Portion (Cohort A) will be included for all planned 
analyses.  Patients enrolled in Arm B of the Dose-Finding Portion will be analyzed separately.
Descriptive statistics will be derived where appropriate.  The rate of DLTs will be summarized by arm; dose 
exposure for each study drug will be calculated.

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2.
Schedule of Activities
Table JVDL.1.
Baseline Schedule of Activities
Days before C1D1
28
14
7
Instructions
Procedure
Informed consent
X
ICF must be signed before any protocol-specific 
procedures are performed; if the ICF is revised during 
the course of the study, re-consenting of patients may 
be required if deemed necessary by Lilly or the 
IRB/ERB.
Inclusion/exclusion criteria
X
Physical examination
X
Including height, weight, and vital signs (temperature, 
blood pressure, pulse rate, and respiration rate)
ECOG performance status
X
Medical history
X
Including assessment of preexisting conditions, 
historical illnesses, and habits (such as tobacco and 
alcohol use)
Prior and current medication
X
AE collection
X
CTCAE Version 4.0
Radiologic imaging and measurement 
of palpable or visible lesions
X
RECIST 1.1
Brain scan
X
Baseline brain scan by contrast CT or MRI 
ECG
X
Triplicate, see Exclusion Criterion [40] in Section 6.2.
ECHO or MUGA
X
Hematology
X
Coagulation
X
Clinical chemistry
X
T3, free T4, TSH
X
Urinalysis
X
Tumor tissue
X
It is required to provide a tumor tissue specimen from 
a biopsy taken after disease progression on the most 
recent EGFR TKI treatment.
Pregnancy test
X
Applies only to women of childbearing potential. See 
Appendix 3.
Sample collection
See Appendix 4.
Pharmacokinetics
X
Immunogenicity
X
Pharmacogenetics (whole blood)
X
Biomarkers
X
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CTCAE = Common Terminology Criteria for Adverse 
Events (NCI 2009); ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative 
Oncology Group (Oken et al. 1982); ICF = informed consent form; IRB/ERB = institutional review board / 
ethical review board; MUGA = multiple-gated acquisition; RECIST 1.1 = Response Criteria in Solid Tumors 
Version 1.1 (Eisenhauer et al. 2009); TSH = thyroid-stimulating hormone.
Note:  Baseline Period begins when the ICF (study entry) is signed and ends at the first dose of study treatment (or 
at discontinuation, if no treatment is given).

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Table JVDL.2.
On-Study-Treatment Schedule of Activities
Treatment Period Schedule for Ramucirumab Arm and Cohort
Study Period
Treatment Period
Comments
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Visits will be changed to once every 6 weeks if a patient permanently 
discontinues from ramucirumab but still on treatment with osimertinib.  
Procedure Category
Procedure
Physical Examination
Physical exam 
(including weight)
X
X
X
X
X
X
X
X
X
Patients should be weighed at the beginning of each cycle.  Height 
measurements to be performed at baseline only.
ECOG performance 
status 
X
X
X
X
X
X
X
X
X
Complete prior to treatment infusion.
Vital signs
X
X
X
X
X
X
X
X
X
Includes blood pressure, pulse, respiratory rate, and temperature.  To be 
obtained at every treatment visit, immediately prior to and at the completion 
of each infusion.  If there is a postinfusion observation period, then vital signs 
measurements should also be obtained at the end of the observation period.  
In the event of an IRR, the respiration rate will be collected. Refer to
Section 7.7.1.1 for details.
Lab/Diagnostic Tests
Hematology 
X
X
X
X
X
X
X
X
X
Performed within 3 days prior to treatment on Day 1 of each cycle.  If results 
of the laboratory tests obtained at planned Day 1 of the next cycle require a 
delay in the start of the subsequent cycle, any repeat laboratory tests should 
be obtained, as clinically indicated.
Serum chemistry 
X
X
X
X
X
X
X
X
X
Performed within 3 days prior to treatment on Day 1 of each cycle.  For 
dosing decisions, bilirubin and AST/ALT are required to be collected.  If 
enrollment serum chemistry profile is collected within 4 days of C1D1, the 
profile does not need to be repeated.
Coagulation profile 
X
X
X
X
Performed within 3 days prior to treatment on C1D1.  Beginning at Cycle 4, 
within 3 days prior to treatment on Day 1 of the cycles, coagulation profile 
performed every 4 cycles or more frequently, as clinically indicated if patient 
is on oral anticoagulation therapy.  Coagulation parameters to be tested 
include INR or PT, and PTT/aPTT.
Urinalysis 
X
X
X
X
X
X
X
X
X
While a patient is being treated with ramucirumab collect every cycle, 
dipstick or routine analysis measurements should be done within 3 days prior 
to treatment.  If enrollment urinalysis is collected within 4 days of C1D1, the 
profile does not need to be repeated at C1D1.  Results should be available at 
the time of the next dosing decision.
Pregnancy test 
X
X
X
X
X
Pregnancy test (see Appendix 3, minimum sensitivity 25 IU/L or equivalent 
units of β-hCG).  Within 3 days prior to treatment on Day 1 of every 2 cycles, 
(or per institutional guidelines, whichever is more frequent) pregnancy 
testing for women of childbearing potential will be performed.
ECG
X
X
X
X
X
X
X
X
X
Twelve-lead ECG within 3 days prior to treatment on Day 1 of each cycle
(and if clinically indicated) for first 6 months then every other cycle, at the 
discontinuation of any study drugs, and at the short-term follow-up.
ECHO or MUGA
X
Every 12 weeks from C1D1 and if clinically indicated

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Treatment Period Schedule for Ramucirumab Arm and Cohort
Study Period
Treatment Period
Comments
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Visits will be changed to once every 6 weeks if a patient permanently 
discontinues from ramucirumab but still on treatment with osimertinib.  
Procedure Category
Procedure
Sample collection for 
pharmacokinetics, 
immunogenicity, and 
biomarkers
See Appendix 4.
Immunogenicity blood work to be collected BEFORE the first infusion of 
ramucirumab on C1D1 of treatment.  If a patient experiences an IRR on 
ramucirumab, blood samples for immunogenicity and PK analysis will be 
taken at the following time points:  (1) as soon as possible after the onset of 
the IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
Tumor tissue
X
Patients may be asked to undergo optional collection of an additional biopsy 
specimen after treatment with study drug(s) has been initiated.  See Section 
9.8.2 for additional details.
Adverse Events 
Collection/CTCAE Grading
Toxicity assessment
X
All AEs/SAEs will be collected for up to 30 days after the patient and 
investigator agree that the patient will no longer continue study treatment.
Efficacy Assessment
Imaging/Tumor 
Assessments 
(every 6 wk ± 7 d)
X
X
X
Disease assessment will be every 6 weeks (±7 days) as calculated from the 
first dose of study therapy.  After 24 weeks, tumor assessment will be 
conducted every 12 weeks (± 7 days).  The method used at baseline must be 
used consistently for tumor assessment.  CT scan or MRI of chest and upper 
abdomen including both adrenal glands are required, with pelvic imaging 
performed if clinically indicated.
Concomitant Therapy
Concomitant 
medications
X
X
X
X
X
X
X
X
X
Concomitant medications will be recorded throughout the treatment period, 
including those taken during the 30 days after the last dose of all study 
treatment.
Premedication
Premedication 
X
X
X
X
X
X
X
X
X
Osimertinib (80 mg) will be self-administered per os (by mouth) once daily
with administer diary.
Treatment Administration 
Ramucirumab (I.V.)
X
X
X
X
X
X
X
X
X
Osimertinib (orally)
X
Patient Disposition
X
At the time that the patient is discontinued from any component of the study 
treatment or study participation, information regarding the patient status will 
be collected.
Abbreviations:  β-hCG = beta human chorionic gonadotropin; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; C1D1 = Cycle 1 Day 1; CT = computed 
tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EGFR = epidermal growth factor receptor; INR = International Normalized Ratio; IRR = infusion-related reaction; I.V. = intravenous; MRI = magnetic resonance imaging; MUGA = multiple-gated 
acquisition; PT = prothrombin time; PTT/aPTT = partial thromboplastin time / activated partial thromboplastin time; SAE = serious adverse event; TKI = tyrosine kinase inhibitor; wk = week.

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Treatment Period Schedule for Necitumumab Arm
Comments
Repeat every 3 weeks
Cycle
(3-week 
cycle)
1-X
Relative 
day 
within a 
cycle
1
8
Except for the C1D1 visit, allowable cycle windows are ±3 days, unless indicated otherwise.
Visits will be changed to once every 6 weeks if a patient permanently discontinues from necitumumab but 
still on treatment with osimertinib.  
Procedure Category
Procedure
Physical Examination
Physical exam (including 
weight)
X
Patients should be weighed at the beginning of each cycle.  Height measurements to be performed at 
baseline only.
ECOG performance 
status
X
Complete prior to treatment infusion.
Vital signs
X
X
Includes blood pressure, pulse, respiratory rate, and temperature.  To be obtained at every treatment visit,
immediately prior to and at the completion of each infusion.  If there is a postinfusion observation period, 
then vital signs measurements should also be obtained at the end of the observation period.  In the event of 
an IRR, the respiration rate will be collected.  Refer to Section 7.7.1.1 for details.
Laboratory/
Diagnostic Tests
Hematology
X
X
Additional tests can be used for on-study dosing decisions. Pretreatment laboratory data may not be older 
than 72 hours (Day 1 of each cycle) or 24 hours (Day 8).  Hepatic monitoring tests to be done in the event 
of a treatment-emergent hepatic abnormality.  In case of neutropenia or thrombocytopenia Grade 4 during 
Cycle 1 (dose finding part only), repeat every 2 days until recovery.
Chemistry 
X
X
Additional tests can be used for on-study dosing decisions.  Pretreatment laboratory data may not be older 
than 72 hours (Day 1 of each cycle) or 24 hours (Day 8).  Hepatic monitoring tests to be done in the event 
of a treatment-emergent hepatic abnormality.  In case of Grade 3 elevation of transaminases, bilirubin, or 
change of electrolytes (see DLT criteria), repeat every 2 days until recovery.
Coagulation
X*
* To be performed within 3 days prior to treatment on Day 1 of the cycle for every second cycle starting 
from Cycle 2
T3, free T4, TSH
X*
* To be performed within 3 days prior to treatment on Day 1 of the cycle for every second cycle starting 
from Cycle 2
Urinalysis 
X*
* To be performed within 3 days prior to treatment on Day 1 of the cycle for every second cycle starting 
from Cycle 2
Pregnancy test 
X
Pregnancy test (see Appendix 3, minimum sensitivity 25 IU/L or equivalent units of β-hCG).  Within 
3 days prior to treatment on Day 1 of every 2 cycles (or per institutional guidelines, whichever is more 
frequent), pregnancy testing for women of childbearing potential will be performed.
ECG
X*
* To be performed within 3 days prior to treatment on Day 1 of every cycle for first 6 months, then every 
other cycle
ECHO or MUGA
X*
* Every 12 weeks from C1D1 and if clinically indicated.
Sample collection for 
pharmacokinetics, 
immunogenicity, and 
biomarkers
See Appendix 4.
Immunogenicity blood work to be collected BEFORE the first infusion of necitumumab on C1D1 of 
treatment.  If a patient experiences an IRR on necitumumab, blood samples for immunogenicity and PK 
analysis will be taken at the following time points:  (1) as soon as possible after the onset of the IRR, (2) at 
the resolution of the IRR, and (3) 30 days after the IRR.
Tumor tissue
X
Patients may be asked to undergo optional collection of an additional biopsy specimen after treatment with 
study drug(s) has been initiated.  See Section 9.8.2 for additional details.

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Comments
Repeat every 3 weeks
Cycle
(3-week 
cycle)
1-X
Relative 
day 
within a 
cycle
1
8
Except for the C1D1 visit, allowable cycle windows are ±3 days, unless indicated otherwise.
Visits will be changed to once every 6 weeks if a patient permanently discontinues from necitumumab but 
still on treatment with osimertinib.  
Procedure Category
Procedure
Adverse Events 
Collection/CTCAE 
Grading
Toxicity assessment
X
X
All AEs/SAEs will be collected for up to 30 days after the patient and investigator agree that the patient will 
no longer continue study treatment.
Efficacy Assessment
Imaging/Tumor 
Assessments 
(every 6 wk ± 7 d)
X
Disease assessment per RECIST version 1.1 will be performed every 6 weeks (±7 days) as calculated from 
the first dose of study therapy.  After 24 weeks, tumor assessment will be conducted every 12 weeks 
(± 7 days).  The method used at baseline must be used consistently for tumor assessment.  CT scan or MRI 
of chest and upper abdomen including both adrenal glands are required, with pelvic imaging performed if 
clinically indicated.
Concomitant Therapy
Concomitant medications
X
X
Concomitant medications will be recorded throughout the treatment period, including those taken during 
the 30 days after the last dose of all study treatment.
Treatment 
Administration
Necitumumab (I.V.)
X
X
Osimertinib (80 mg) will be self-administered per os (by mouth) once daily with administer diary.
Osimertinib (orally)
X
Patient Disposition
X
At the time that the patient is discontinued from any component of the study treatment or study 
participation, information regarding the patient status will be collected.
Abbreviations:  β-hCG = beta human chorionic gonadotropin; AE = adverse event; C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
D = Day; ECG = electrocardiogram; ECHO = echocardiogram; EGFR = epidermal growth factor receptor; DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology Group; 
IRR = infusion-related reaction; I.V. = intravenous; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; PK = pharmacokinetic; SAEs = serious adverse events; TKI = tyrosine 
kinase inhibitor; TSH = thyroid-stimulating hormone; wk = week.

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Table JVDL.3.
Post-Treatment Follow-Up Schedule of Activities
Procedure
Short-Term 
Follow-Up
a
Long-Term 
Follow-Upb
Instructions
Physical examination
X
Including weight and vital signs (temperature, blood pressure, pulse rate, and respiration rate)
Concomitant medication
X
AE collection
X
CTCAE Version 4.0
ECOG performance status
X
Radiologic imaging and measurement 
of palpable or visible lesions
X
X
Perform every 6 weeks (7 days) according to RECIST 1.1, by the same method used at baseline and throughout the 
study.  After 24 weeks, tumor assessment will be conducted every 12 weeks (± 7 days), until:

the patient has objective disease progression, or

the study’s final analysis of overall survival.
After the patient has objective disease progression, radiologic tests are no longer required.
Collection of survival information
X
X
Perform every 2 months (±7 days).  If an in-person visit is not possible, confirm survival by contacting the patient 
directly via phone.
Collection of post-study-treatment 
anticancer therapy information
X
X
Perform every 2 months (±7 days) for the first 2 years after discontinuation from study treatment and every 6 months
(±14 days) thereafter until death or study completion.
Hematology
X
Coagulation
X
Clinical chemistry
X
T3, free T4, TSH
X
Urinalysis
X
Sample collection
For all sample collection, see 
Appendix 4.
Pharmacokinetics
Biomarkers
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 
1982); MUGA = multiple-gated acquisition; q = every; RECIST 1.1 = Response Criteria In Solid Tumors Version 1.1 (Eisenhauer et al. 2009); TSH = thyroid-stimulating hormone.
a
Short-term (Safety) follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment, and lasts approximately 30 days (±7 days).  No 
follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent.  ECHO or MUGA may be performed during 
short-term follow-up if clinically indicated.
b
Long-term (Survival) follow-up begins the day after short-term follow-up is completed, and lasts until disease progression on or after the study regimen, all patients will be assessed every 2 months 
(±7 days) to obtain information about survival status and detailed information on any subsequent systemic anticancer therapy and disease progression (for patients not having a radiographic 
progression) for as long as the patient is alive, or until study completion.

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Table JVDL.4.
Continued Access Schedule of Activities
Procedureb
Study Treatment
Follow-Upa
AE collection
X
X
CTCAE Version 4.0
Pharmacokinetics and Immunogenicity
If a patient experiences an IRR, collect blood samples for 
pharmacokinetics and immunogenicity analysis at the following time 
points:  (1) as soon as possible after the onset of the IRR, (2) at the 
resolution of the IRR, and (3) 30 days after the IRR.
Administer study drug
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction.
a
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 30 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.
b
Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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3.
Introduction
3.1.
Study Rationale
Lung cancer is the most common cancer worldwide and the leading cause of cancer-related 
mortality, with an estimated 1.6 million new cases and an estimated 1.4 million cancer-related 
deaths per year (Bray et al. 2012; Bunn 2012). Non-small cell lung cancer (NSCLC) accounts 
for approximately 85% of all lung cancers.  The incidence of epidermal growth factor receptor 
(EGFR) mutations in the Caucasian population is about 10% but can be as high as 40% in East 
Asian populations (Bell et al. 2005; Shigematsu et al. 2005; Jänne et al. 2015).
Molecularly targeted therapies have been proven to be superior to chemotherapy for NSCLC 
patients whose tumors have activating mutations in EGFR (Mok et al. 2009; Zhou et al. 2011; 
Rosell et al. 2012; Sequist et al. 2013). EGFR tyrosine kinase inhibitors (TKIs; for example, 
erlotinib, gefitinib, and afatinib) significantly prolong progression-free survival (PFS) in patients 
with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) 
substitution mutations when compared with platinum-based chemotherapy doublets and have 
become the standard of care in countries where approved. The rationale for such treatment is 
supported by the results of studies such as BR.21 (Shepherd et al. 2005) and IPASS (Mok et al. 
2009).
Despite excellent tumor response to initial targeted therapy, EGFR mutation-positive patients 
eventually develop disease progression after 9 to 12 months of treatment. One important
mechanism of acquired resistance is the T790M gatekeeper EGFR mutation in exon 20, which is 
found in about 50% to 60% of patients upon disease progression from first-line EGFR TKI 
therapy.  This mutation increases the affinity of the kinase for ATP, and thus reduces the 
inhibitor efficacy (Peters et al. 2014).  Prior to the availability of third-generation EGFR TKI 
targeting T790M, these patients are candidates for systemic chemotherapy (NCCN Guideline v.4 
2016) unless oligoprogressive disease is diagnosed.  Of note, existing data for cytotoxic 
chemotherapy in patients with acquired resistance to EGFR inhibitors suggest that benefits are 
also of relatively short duration, with studies showing median PFS (mPFS) of 4.0 to 5.5 months 
(Goldberg et al. 2013; Mok et al. 2014).
Osimertinib, a third-generation EGFR TKI targeting activating EGFR mutations including 
T790M but sparing wild-type EGFR, is an oral, irreversible, selective inhibitor.  Osimertinib 
(TAGRISSO®, package insert [PI] and Summary of Product Characteristics [SmPC]) 80-mg 
once-daily tablet has been recently approved in the United States (US) and European Union (EU) 
for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, who have 
progressed on or after EGFR TKI therapy. Ongoing Phase 1/2 trials showed an overall objective 
response rate (ORR) of 61% in patients with EGFR T790M-positive NSCLC after prior EGFR
TKI therapy, including an ORR of 70% at the 80-mg dose level. ORR was 21% in patients with 
EGFR-mutant NSCLC but negative for T790M (Jänne et al. 2015). Based on these data, several 
Phase 3 registration studies are currently ongoing.

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Separately, necitumumab (PORTRAZZA®, PI), an EGFR-directed monoclonal antibody (mAb), 
has obtained marketing authorization in the US and EU, in combination with gemcitabine and 
cisplatin, for first-line treatment of patients with metastatic squamous NSCLC. Although 
another EGFR mAb cetuximab has been proven to be ineffective with respect to ORR when 
given as single agent to patients with progressive disease (PD) to erlotinib or gefitinib (Hanna et
al. 2006; Neal et al. 2010), the combination of cetuximab with afatinib has demonstrated 
promising results. Among 126 patients with acquired resistance to erlotinib or gefitinib, ORR
was 29% and comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; 
p=0.341). Median PFS was 4.7 months (95% confidence interval [CI]: 4.3-6.4), and the median 
duration of confirmed objective response (OR) was 5.7 months (range: 1.8-24.4). Patients with 
T790M-positive and T790M-negative tumors had median durations of confirmed OR of 
5.6 months (range: 1.8-24.4) and 9.5 months (range: 2.9-14.8), respectively. Median PFS was 
similar for T790M-negative and T790M-positive patients (4.6 vs. 4.8 months; p=0.643)
(Janjigian et al. 2014).
On the basis of the clinical data that suggested modest benefit from continued EGFR TKI 
therapy despite acquired resistance (Goldberg et al. 2013; Yoshimura et al. 2013), synergistic 
effect of combining EGFR mAb and EGFR TKI, and preclinical data that support the use of 
necitumumab together with EGFR TKI (Lilly unpublished data S180914, S089213), we 
hypothesize that simultaneous inhibition of the EGFR signaling pathway using both osimertinib 
and necitumumab would improve efficacy of osimertinib in patients that progress on prior EGFR
TKI and have T790M-positive NSCLC. A separate study of necitumumab in combination with 
osimertinib is being conducted in NSCLC EGFR-mutant patients that progressed on 
first-generation EGFR TKI and are negative for T790M (NCT02496663).
In addition, inhibition of angiogenesis is considered a promising approach to the treatment of 
cancer. Ramucirumab (Cyramza®), a human immunoglobulin G, subclass 1 (IgG1) anti-vascular 
endothelial growth factor (VEGF) Receptor 2 (VEGFR2) mAb, has obtained marketing 
authorization in the US, EU, and Japan for the treatment of advanced gastric or gastroesophageal 
junction (GEJ) adenocarcinoma as monotherapy (REGARD) or in combination with paclitaxel 
(RAINBOW); in the US and EU for the treatment of advanced NSCLC in combination with 
docetaxel (REVEL); and in the US and EU for the treatment of metastatic colorectal cancer 
(mCRC) in combination with FOLFIRI (irinotecan, 5-fluorouracil, and folinic acid; RAISE). 
Recently, ATLAS (Johnson et al. 2013) and BeTa (Herbst et al. 2011) trials reported that the 
combination of the antiangiogenic agent bevacizumab with erlotinib provided additional PFS and 
overall survival (OS) benefit in the subgroup of patients with EGFR mutations. Additionally, the 
JO25567 study, which is a randomized Phase 2 study of erlotinib with or without bevacizumab 
as first-line therapy for patients with EGFR-mutant NSCLC, showed that mPFS was 16.0 months 
(95% CI: 13.9-18.1) with erlotinib plus bevacizumab and 9.7 months (95% CI: 5.7-11.1) with 
erlotinib alone (hazard ratio [HR]: 0.54 [95% CI: 0.36-0.79]; log-rank test p = 0.0015). A 
greater proportion of patients achieved disease control with erlotinib plus bevacizumab (99% vs.
88%; p=0.0177) (Seto et al. 2014). RELAY, a Phase 3 randomized study of erlotinib with or 
without ramucirumab as first-line therapy for patients with EGFR-mutant NSCLC, is ongoing
(NCT02411448).

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Considering the improvement in PFS and disease control rate (DCR) with the combination of 
erlotinib and bevacizumab in EGFR-mutant NSCLC, as well as promising ORR in EGFR-mutant 
lung cancer patients treated with combination of afatinib and cetuximab after progression on 
first-generation EGFR TKI, we would like to examine whether the combination of osimertinib 
and ramucirumab or necitumumab in EGFR-mutant NSCLC after progression on first-line EGFR 
TKI would also lead to improvement in efficacy in patients with acquired T790M. This study 
allows for an efficient and streamlined approach for identifying combinations that may have the 
best success in future randomized controlled trials.
3.2.
Background
3.2.1. Ramucirumab
Ramucirumab (Cyramza®), a human IgG1 anti-VEGFR2 mAb, has obtained marketing 
authorization in the US, EU, and Japan for the treatment of advanced gastric or GEJ (gastric-
GEJ) adenocarcinoma as monotherapy (REGARD) or in combination with paclitaxel 
(RAINBOW), with disease progression on or after prior fluoropyrimidine- and/or platinum-
containing chemotherapy.  Ramucirumab is also approved in the US and EU for the treatment of 
advanced NSCLC in combination with docetaxel (REVEL), with disease progression on or after 
prior platinum-based chemotherapy.  Patients with EGFR or anaplastic lymphoma kinase 
genomic tumor aberrations should have disease progression on approved therapy for these 
aberrations prior to receiving ramucirumab.  Ramucirumab is also approved in the US and EU 
for the treatment of mCRC in combination with FOLFIRI (RAISE) with disease progression on 
or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
In addition, the toxicity profile of ramucirumab has been manageable given as a monotherapy or 
in combination.  In REGARD, a single-agent, placebo-controlled, Phase 3 gastric cancer study, 
25 patients (10.5%) receiving ramucirumab discontinued study treatment due to adverse events 
(AEs).  The most common adverse drug reactions reported in ≥10% of ramucirumab-treated 
patients were abdominal pain, diarrhea, and hypertension.  Clinically relevant reactions 
(including Grade ≥3) associated with antiangiogenic therapy observed in ramucirumab-treated 
patients across clinical trials were proteinuria, infusion-related reactions, and gastrointestinal 
(GI) perforations.
3.2.2. Necitumumab
Necitumumab (LY3012211) is a recombinant human mAb of the IgG1 class, which targets EGFR.  
Necitumumab demonstrates a high affinity to its target and blocks ligand-induced receptor 
phosphorylation and downstream signaling.  In vitro studies further demonstrate that 
necitumumab inhibits EGFR-dependent tumor cell proliferation, and can exert cytotoxic effect in 
tumor cells through antibody-dependent cell cytotoxicity.  Necitumumab (PORTRAZZA®, PI) in 
combination with gemcitabine and cisplatin, has been approved for first-line treatment of 
patients with metastatic squamous NSCLC in the US and EU.
The pivotal, randomized Phase 3 trial SQUIRE (I4X-IE-JFCC) compared gemcitabine/cisplatin 
plus necitumumab (GC+N) versus gemcitabine/cisplatin (GC) as first-line therapy in 1093 

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patients with Stage IV squamous NSCLC (Thatcher et al. 2015).  The study met its primary 
objective, demonstrating a statistically significant improvement in OS in the GC+N Arm 
compared with the GC Arm (HR = 0.84; p = 0.012).  This was supported by a statistically 
significant improvement in PFS (HR = 0.85; p = 0.02).  Several prespecified subgroup analyses 
for OS and PFS showed a consistent treatment effect in favor of GC+N.  Post-progression 
anticancer therapy was similar (47% vs. 45%).  The safety data obtained in SQUIRE overall 
were consistent with the safety profile expected for an anti-EGFR mAb, with skin reactions (any 
grade:  79% vs. 12%, including Grade ≥3:  8.2% vs. 0.6%) and hypomagnesemia (any grade:  
31% vs. 16%, including Grade ≥3:  9.3% vs. 1.1%) being the most frequently reported events 
(pooled terms) occurring at higher rates for patients receiving necitumumab.  The Grade ≥3 
treatment-emergent adverse events (TEAEs) with highest incidence for which incidence was 
higher in the necitumumab arm than in the control arm were hypomagnesemia (8.7% vs. 1.1%), 
rash (3.7% vs. 0.2%), pulmonary embolism (3.5% vs. 1.8%), hypokalemia (3.0% vs. 1.5%), and 
vomiting (2.8% vs. 0.9%).
In another randomized Phase 3 trial, INSPIRE (I4X-IE-JFCB [JFCB]), 947 patients were 
planned to be randomly assigned to necitumumab plus pemetrexed-cisplatin (PC+N) versus 
pemetrexed-cisplatin (PC) as first-line therapy for Stage IV nonsquamous NSCLC (Paz-Ares et 
al. 2015).  Enrollment was halted, following an independent data monitoring committee (IDMC) 
recommendation, after 633 patients because of safety concerns related to thromboembolism as 
well as the overall number of deaths from all causes that were unbalanced against the 
experimental group; the trial continued for patients that had been enrolled.  Based on the final 
analysis, PC+N did not improve the efficacy outcome over PC alone in advanced nonsquamous 
NSCLC (OS HR = 1.01, p=0.96; PFS HR = 0.96, p=0.66).  The addition of necitumumab 
resulted in a higher frequency of Grade ≥3 TEAEs.  Grade ≥3 TEAEs occurring more frequently 
in the necitumumab arm included skin or subcutaneous disorders (14.1 vs. 0.3%), 
thromboembolic events (9.5 vs. 6.4%), hypomagnesaemia (7.6 vs. 2.2%), asthenia (6.9 vs. 1.9%), 
vomiting (6.6 vs. 3.2%), dyspnea (5.3 vs. 2.6%), and diarrhea (4.3 vs. 2.2%).
The randomized Phase 2 trial, I4X-MC-JFCL, compared paclitaxel-carboplatin plus 
necitumumab versus paclitaxel-carboplatin in the first-line treatment of patients with Stage IV 
squamous NSCLC.  The overall efficacy and safety results were generally consistent with those 
of SQUIRE.  Several other Phase 1 and 2 trials of necitumumab are ongoing to evaluate the 
efficacy and safety of necitumumab in combination with chemotherapy or other targeted 
therapies in patients with NSCLC.
For more details regarding the necitumumab development program, reference is made to the 
Investigator’s Brochure (IB).
3.2.3. Osimertinib
Osimertinib (AZD9291) is a novel, third-generation, and irreversible EGFR TKI with selectivity 
against mutant versus wild-type forms of EGFR. Osimertinib is a mono-anilino-pyrimidine 
compound that is structurally and pharmacologically distinct from all other TKIs, including 
another third-generation compound, rociletinib (CO-1686) (Cross et al. 2014).

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Osimertinib (TAGRISSO®, PI and SmPC) 80-mg once-daily tablet has been recently approved in 
the US and EU for the treatment of patients with metastatic EGFR T790M mutation-positive 
NSCLC who have progressed on or after EGFR TKI therapy.
Osimertinib potently inhibits EGFR phosphorylation in activating mutations and resistance cell 
lines in vitro, with much less activity against wild-type EGFR lines.
Preclinical data comparing efficacy of afatinib+cetuximab (A+C) and osimertinib showed that 
both A+C and osimertinib inhibited proliferation of T790M-positive cells in long-term (10-day) 
growth inhibition assays, but osimertinib induced more growth inhibition than A+C (Meador et 
al. 2015). Moreover, xenograft-derived A+C resistant cell lines displayed in vitro and in vivo 
sensitivity to osimertinib, but osimertinib-resistant cell lines demonstrated cross-resistance to 
A+C. Interestingly, addition of cetuximab to osimertinib did not confer additive benefit in any 
preclinical disease setting.
Available data from a Phase 1 clinical trial with osimertinib reveals high response rates in 
patients with EGFR TKI resistance whose tumors harbored EGFR-T790M (ORR 61%; 95% CI:
52%-70%) and lower response rates in patients whose tumors lacked EGFR-T790M (ORR 21%; 
95% CI: 12%-34%). The mPFS was 9.6 months (95% CI: 8.3 to not reached) in EGFR
T790M-positive patients and 2.8 months (95% CI: 2.1 to 4.3) in EGFR T790M-negative 
patients. The most common AEs were diarrhea (47%), rash (40%), nausea (22%), and decreased 
appetite (21%) (Jänne et al. 2015).
Due to its margin of potency between T790M mutant EGFR and wild-type EGFR, the incidence 
and severity of wild-type EGFR AEs (for example, rash and diarrhea) appear to be lower than 
those observed with first- and second-generation EGFR TKIs.
3.3.
Benefit/Risk Assessment
Osimertinib inhibits EGFR tyrosine kinase activity by irreversibly competing with ATP for 
binding in the kinase domain. Necitumumab binds to the extracellular domain of EGFR and 
prevents ligand activation of the receptor.  In EGFR-dependent human xenograft models of lung 
cancer, necitumumab led to significant and durable tumor regression. 
 
 
 
 
 
By binding the extracellular domain of EGFR, necitumumab may provide additional 
antitumor effect via activation of antibody-dependent cellular cytotoxicity and inhibition of the 
autocrine loop of cancer cell signaling (Riemenschneider et al. 2005; Patel et al. 2011).
Phase 1 studies have shown that various combinations of EGFR TKIs and EGFR-directed mAb
can be administered to patients with NSCLC, although efficacy and/or safety profile of such 
combination has not been encouraging (Ramalingam et al. 2008; Janjigian et al. 2011; Wheler et 
al. 2013; Janjigian et al. 2014). However, combined EGFR inhibition with third-generation 
CCI

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EGFR TKI and EGFR-directed mAb has not been prospectively studied in patients with acquired 
resistance to first-generation EGFR TKIs (Janjigian et al. 2011).
On the basis of preclinical data of necitumumab in lung adenocarcinoma harboring a drug 
sensitive L858R and drug resistant T790M mutation, we hypothesize that simultaneous 
inhibition of the EGFR signaling pathway using both osimertinib and necitumumab would 
improve efficacy of osimertinib in tumors that progress on prior first-generation EGFR TKI in 
patients with T790M-positive NSCLC.  Both necitumumab and osimertinib may cause skin rash, 
hence some overlap is expected; however, the rate of rash with third-generation EGFR TKIs is 
believed to be less than that of the first- and second-generation.
Separately, the combination of an EGFR TKI and an antiangiogenic agent has shown promising 
efficacy improvement without significant additional toxicity. Recently, ATLAS (Johnson et al. 
2013) and BeTa (Herbst et al. 2011) trials reported that the combination of bevacizumab with 
erlotinib provided additional PFS and OS benefit in the subgroup of patients with EGFR
mutations. In addition, the JO25567 study, which is a randomized Phase 2 study of erlotinib 
with or without bevacizumab as first-line therapy for patients with EGFR-mutant NSCLC, 
showed that mPFS was 16.0 months (95% CI: 13.9-18.1) with erlotinib plus bevacizumab and 
9.7 months (5.7-11.1) with erlotinib alone (HR: 0.54 [95% CI: 0.36–0.79]; log-rank test 
p=0.0015). A greater proportion of patients achieved disease control with erlotinib plus 
bevacizumab (99% vs. 88%; p=0.0177) (Seto et al. 2014). No significant toxicity was observed 
with the addition of bevacizumab to erlotinib. Similarly, BELIEF, which is a single-arm Phase 2 
study of first-line erlotinib plus bevacizumab in patients with EGFR-mutant NSCLC, showed 
that for all 109 patients, the 1-year PFS is 55.6% (95% CI: 44.7–66.6%), with a median of 13.6 
months, while for patients with T790M-positive NSCLC determined pretreatment by a sensitive
method, 1-year PFS is 60.2% (95% CI: 45.6-74.8%) with a median of 15.4 months (Stahel et al. 
2015). RELAY, a Phase 3 randomized study of erlotinib with or without ramucirumab as first-
line therapy for patients with EGFR-mutant NSCLC, is ongoing (NCT02411448).
Considering the improvement in PFS and DCR with the combination of erlotinib and 
bevacizumab in EGFR-mutant NSCLC, as well as no significant worsening toxicity observed
with the addition of bevacizumab to erlotinib, we anticipate a similarly favorable benefit/risk 
ratio would apply to the same class of agents with similar mechanisms of action. Therefore, we
would like to examine whether the combination of osimertinib and ramucirumab in 
EGFR-mutant T790M-positive NSCLC after progression on first-line EGFR TKI would also 
lead to improvement in efficacy with tolerable toxicity.
This study will provide benefit-risk data on the coadministration of osimertinib with 
ramucirumab or necitumumab. More information about the known benefits, risks, serious 
adverse events (SAEs) and anticipated AEs of ramucirumab, necitumumab, and osimertinib are 
to be found in the IB of each agent.

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4.
Objectives and Endpoints
Table JVDL.5 shows the objectives and endpoints of the study.
Table JVDL.5.
Objectives and Endpoints
Objectives
Endpoints
Phase 1a:  
Dose-
Finding 
Portion
Primary:
To assess the safety and tolerability of 
ramucirumab or necitumumab in combination 
with osimertinib
Dose-limiting toxicities, observed during 2 cycles 
(28 days) for ramucirumab arm (Arm A) and 1 
cycle (21 days) for necitumumab arm (Arm B)
Safety (including but not limited to):
TEAEs, SAEs, and deaths
Secondary:
To assess the PK of ramucirumab or 
necitumumab in combination with osimertinib
PK:  Cmin and approximate Cmax of 
ramucirumab and necitumumab in serum
Phase 1b:  
Dose-
Expansion 
Portion
Primary:
To assess the safety and tolerability of 
ramucirumab in combination with osimertinib
Safety (including but not limited to):
TEAEs, SAEs, and deaths
Secondary:
To assess the preliminary efficacy of 
ramucirumab in combination with osimertinib*
To assess the PK of ramucirumab in combination 
with osimertinib
Efficacy:  ORR (RECIST 1.1), DCR, DOR, PFS, 
and OS*
PK:  Cmin and approximate Cmax of 
ramucirumab in serum
Tertiary/Exploratory:
To explore the association between biomarkers 
and clinical outcomes
Biomarkers:  Genetic and other molecular 
markers (e.g. assessments of DNA, RNA, and 
protein) from tissue and blood samples
Abbreviations:  Cmax = maximum concentration; Cmin = minimum concentration; DCR = disease control rate; 
DNA = deoxyribonucleic acid; DOR= duration of response; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST 1.1 = Response Evaluation Criteria 
In Solid Tumors Version 1.1; RNA = ribonucleic acid; SAEs = serious adverse events; TEAEs = treatment-
emergent adverse events.
*Note:  Patients in the Dose-Finding Portion will be included in the overall preliminary efficacy analyses.

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5.
Study Design
5.1.
Overall Design
Study I4T-MC-JVDL (JVDL) is an open-label, multicenter Phase 1 study with an expansion 
cohort to evaluate the safety and preliminary efficacy of ramucirumab or necitumumab in 
combination with osimertinib in patients with advanced T790M-positive EGFR-mutant NSCLC
who have relapsed after first-line EGFR TKI therapy.
The study consists of the Dose-Finding Portion (dose-limiting toxicity [DLT] observation) and 
the Dose-Expansion Portion (expansion cohort).

Phase 1a:  Dose-Finding Portion consists of 2 arms.  Arm A is the combination of 
ramucirumab and osimertinib and Arm B is the combination of necitumumab and 
osimertinib.

Phase 1b:  Dose-Expansion Portion consists of 1 cohort.  Cohort A is the combination of 
ramucirumab and osimertinib.
Figure JVDL.1 illustrates the study design.

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Abbreviations:  D1 = Day 1; D8 = Day 8; DLT = dose-limiting toxicity; n = number of patients; 
Neci = Necitumumab; Osim = Osimertinib; PK = pharmacokinetics; Ram = ramucirumab.
Note:  The results of the interim analysis will confirm the dosing regimen to be used in the expansion cohort.  Dose 
reductions, delays, and discontinuations may occur per the guidelines in Section 7.4.  
Figure JVDL.1.
Illustration of study design.
5.1.1. Dose-Finding Portion:  Dose-Limiting Toxicity Observation
The Dose-Finding Portion will employ a 3+3 dose de-escalation design with a fixed dose of 
osimertinib at 80 mg once daily (QD).  The DLT observation period is 2 cycles (4 weeks) for 
Arm A and 1 cycle (3 weeks) for Arm B, as shown in Figure JVDL.1.
DLTs will be determined based on the incidence, intensity, and duration of AEs that occur up to 
4 weeks for Arm A and 3 weeks for Arm B following the first dose of both study drugs (see 
Section 7.2.1.1 for selection and timing of doses).  Adverse events will be graded according to 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
Version 4.0 (CTCAE v4.0).
The definition for DLTs and the criteria used to determine progress of the study are provided in 
Section 7.2.1.1.

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5.1.2. Dose-Expansion Portion:  Expansion Cohort
Based on the safety profile observed during the Dose-Finding Portion, the sponsor may 
determine the dosing regimen to be investigated in the Dose-Expansion Portion of the study and 
expand to further evaluation of the combination therapy in this patient population.
The patients in the Dose-Expansion Portion will meet the same eligibility criteria as for 
Dose-Finding Portion of the study. The Dose-Expansion Portion consists of 1 cohort for patients 
with acquired EGFR T790M-positive NSCLC. Only patients with T790M-positive tumors using 
a test validated and performed locally will be assigned to ramucirumab + osimertinib (Cohort A). 
All patients will be treated until PD, intolerable toxicity despite dose reduction, or 
patient/investigator decision to terminate the study participation. Dose reductions, delays, and 
discontinuations may occur per the guidelines in Section 7.4.
The purpose of the Dose-Expansion Portion is to gather additional safety, tolerability, 
pharmacokinetics (PK), and preliminary efficacy information regarding ramucirumab in 
combination with osimertinib.  
Note:  For both study portions, tests for T790M that are currently recommended for the 
use of osimertinib in the US and in the EU, respectively, include the following:

In the US, as approved by the Food and Drug Administration, the cobas® EGFR Mutation 
Test Version 2 is a real-time polymerase chain reaction test for the qualitative detection 
of defined mutations of the EGFR gene in DNA derived from formalin-fixed 
paraffin-embedded tumor tissue from NSCLC patients.  The test is intended to aid in 
identifying patients with NSCLC whose tumors have defined EGFR mutations and for 
whom safety and efficacy of a drug have been established as follows:
•
Tarceva® (erlotinib) - Exon 19 deletions and L858R
•
Tagrisso® (osimertinib) - T790M

In the EU, according to the currently approved SmPC for osimertinib as a treatment for 
locally advanced or metastatic NSCLC, a validated test is recommended to determine 
EGFR T790M mutation status. As indicated in the SmPC, the mutation status should be 
tested using either tumor DNA derived from a tissue sample or circulating tumor DNA 
(ctDNA) obtained from a plasma sample. Only robust, reliable, and sensitive tests with 
demonstrated utility for the determination of T790M mutation status of tumor-derived 
DNA (from a tissue or a plasma sample) should be used.  Positive determination of 
T790M mutation status using either a tissue-based or plasma-based test indicates 
eligibility for treatment with osimertinib. If a plasma-based ctDNA test is used and the 
result is negative, it is advisable to follow-up with a tissue test wherever possible due to 
the potential for false negative results using a plasma-based test.
5.2.
Number of Patients
Approximately 90 patients will be screened and up to 46 patients enrolled.  For the Dose-Finding 
Portion, up to 24 DLT-evaluable patients will be enrolled (12 in each arm).  For the 
Dose-Expansion Portion, 22 evaluable patients will be enrolled into Cohort A.

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5.3.
Study Completion and End of Trial Definition
There will be a database lock to report the primary data analyses approximately 6 months after 
last patient receives initial dose in the Dose-Expansion Portion of the study.
The completion of the study (Study Completion) is defined as approximately 2 years after last 
patient enrolled, or when adequate number of events are observed for survival outcome 
estimation, whichever comes first.  
Investigators will continue to follow the study schedule for all patients until notified by Lilly that 
study completion has occurred.  “End of trial” refers to the date of the last visit or last scheduled 
procedure for the last patient, including patients participating in the continued access period (see 
Section 7.8.1), if applicable.  Section 7.1 describes the maximum duration of study treatment.
5.4.
Scientific Rationale for Study Design
This is a Phase 1, open-label study that will evaluate safety and preliminary efficacy of 
ramucirumab or necitumumab in combination with osimertinib. This Phase 1 study includes a 
3+3, dose de-escalating design for the Dose-Finding Portion followed by the Dose-Expansion 
Portion with 1 cohort. As detailed in Section 3.1, Study Rationale, and Section 3.3, Benefit/Risk 
Assessment, this study enrolls patients with EGFR-mutant NSCLC who recently developed 
disease progression on first-line EGFR TKI therapy. Although the combination of osimertinib 
and ramucirumab or necitumumab may work in patients with either T790M-positive or T790M-
negative NSCLC, the response rates and other efficacy measures are expected to be different, 
and this study only enrolls patients with T790M-positive NSCLC to reduce heterogeneity of 
patients in a study with relatively small sample size.
5.5.
Justification for Dose
5.5.1. Dose Selection for Ramucirumab
Ramucirumab administered at 10 mg/kg on Day 1 on an every-2-week (Q2W) schedule will be 
examined in this study.  This dose regimen of ramucirumab is different compared to the REVEL 
study.  In REVEL, conducted in a second-line NSCLC setting, ramucirumab was administered at 
a dose of 10 mg/kg every 3 weeks (Q3W).  Exposure-response (efficacy/safety) findings from
Phase 3 ramucirumab trials, REGARD, RAINBOW, and REVEL and PK simulations were used 
to guide the dose selection in this study. A recent safety review of the DLT Assessment Period 
data from Phase 1b of the study RELAY concluded that ramucirumab at 10 mg/kg Q2W is safe 
and tolerable for EGFR mutation-positive NSCLC patients.
Efficacy
Exposure-efficacy response analyses performed on data obtained from REGARD, RAINBOW, 
and REVEL demonstrated that an increase in exposure is associated with improvement in 
efficacy in terms of both OS and PFS.
The following 4 exposure measures were tested, and the findings were consistent for all of them:

minimum concentration after first dose administration,

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
minimum concentration at steady state (Cmin,ss),

maximum concentration at steady state, and

average concentration at steady state.
In REGARD (n=72 [number of patients with evaluable PK data]), patients with 
greater-than-median ramucirumab exposure demonstrated longer OS and PFS and significantly 
better treatment effects (smaller HR) as compared to patients with less-than-median 
ramucirumab exposure.
In RAINBOW (n=321 [number of patients with evaluable PK data]), patients with ramucirumab 
exposure greater-than-median (in the third and fourth quartile groups) were associated with 
longer OS and PFS and significantly better treatment effects (smaller HR) as compared to 
patients with ramucirumab exposure lower-than-median (in the first and second quartile groups).
In REVEL (n=376 [number of patients with evaluable PK data]), significantly longer OS and 
PFS favoring ramucirumab were generally observed in the highest exposure quartile group (the 
fourth group), while marginal increases on OS and PFS were observed in other exposure quartile 
groups.
Safety
Weekly doses of ramucirumab ranging from 2 to 16 mg/kg were evaluated in Phase 1 
Study I4T-MC-JVBM (JVBM).  A maximal tolerated dose (MTD) for weekly dosing was 
identified as 13 mg/kg every week.  Every-2-week (6 to 10 mg/kg) and every-3-week (15 to 20 
mg/kg) dose regimens were evaluated in an additional dose-ranging study (Study I4T-MC-JVBN
[JVBN]).  All dose regimens in Study JVBN were well tolerated and no MTD was identified in 
this study.
The same ramucirumab dose regimen (8 mg/kg every 2 weeks) was used in REGARD and 
RAINBOW.  REGARD demonstrated a well-tolerated safety profile in the gastric cancer 
monotherapy setting.  Due to the low incidence of hypertension and neutropenia, no 
safety-exposure relationship was identified.  In RAINBOW, ramucirumab in combination with 
paclitaxel was also well tolerated in patients with gastric cancer, with manageable AEs.  An 
increasing ramucirumab exposure was correlated with increased incidence of Grade ≥3
hypertension, neutropenia, and leukopenia. Of note, there were no Grade 4 or 5 hypertension 
events in RAINBOW.  Hypertension was managed primarily by the use of standard 
antihypertensive medication.  Neutropenia and leukopenia are known risks with paclitaxel 
treatment.  Overall, the safety profile of ramucirumab plus paclitaxel was largely consistent with 
the safety profiles of the individual treatment components and the combination revealed no 
unexpected safety findings.
The safety profile observed in REVEL was consistent with the safety profile for ramucirumab 
established in gastric cancer (REGARD and RAINBOW), as well as the established safety 
profile for docetaxel, and was manageable in the NSCLC population.  An increasing 
ramucirumab exposure was correlated with increased incidence of Grade ≥3 hypertension and 
febrile neutropenia.  Of note, there were no Grade 4 or 5 hypertension events in REVEL.  

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Hypertension was managed primarily by the use of standard antihypertensive medication.  In 
addition, incidence of febrile neutropenia appeared to reach plateau at the third exposure quartile.
These exposure-efficacy and exposure-safety data indicate that there is an opportunity to further 
enhance efficacy of ramucirumab while maintaining an acceptable safety profile.  Based on PK 
simulation, a dose regimen of 10 mg/kg on Day 1 every 2 weeks was selected for Study JVDL
for the following reasons:

This dose regimen may produce Cmin,ss that is higher than the fourth Cmin,ss quartile 
obtained from 10-mg/kg every-3-week regimen in REVEL, in at least 70% of the 
patient population (Figure JVDL.2) and is therefore expected to produce better clinical 
efficacy outcomes relative to the 10-mg/kg every-3-week regimen.

It is expected that ramucirumab-related AEs in the NSCLC indication may not be 
significantly increased using the selected ramucirumab dose of 10 mg/kg every 2 weeks, 
since the selected dose for Study JVDL is still approximately 60% lower than the 
maximum tolerated weekly dose identified in the Phase 1 dose-escalation study, 
Study JVBM (13 mg/kg weekly).

The ramucirumab exposure distribution of the 10-mg/kg every-2-week regimen 
significantly overlaps with that of the 8-mg/kg every-2-week regimen studied in 
REGARD and RAINBOW.
DLT observation is being conducted to assess the safety and tolerability of ramucirumab 
administered at 10 mg/kg every 2 weeks in combination with osimertinib administered daily at 
80 mg.
This safety assessment will examine if the higher ramucirumab dose regimen of 10 mg/kg every 
2 weeks can still maintain an acceptable safety profile in combination with osimertinib in 
NSCLC patients.  Based upon the review of the safety assessment, study modifications may be 
warranted.
Out of 12 DLT evaluable patients, only 1 patient had DLT. No SAE or Grade 4 or 5 TEAEs 
were observed for the combination of ramucirumab 10 mg/kg Q2W plus erlotinib 150 mg/day; 
no unexpected safety signals were identified.

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Abbreviations:  Cmin,ss = minimum concentration at steady state; Q = every; W = week.
Box plots depict the 5th, 25th, 50th, 75th, and 95th percentiles calculated from 
1000 simulation iterations.
Figure JVDL.2.
Predicted Cmin,ss following different dose regimens.
In summary, the dosing regimens of ramucirumab 10 or 8 mg/kg on Day 1 every 2 weeks in 
combination with osimertinib are anticipated to produce a favorable benefit-risk profile in 
patients with EGFR mutation-positive metastatic NSCLC.
5.5.2. Dose Selection for Necitumumab
The recommended dose and treatment schedules for necitumumab are 800 mg QW, 800 mg 
Q2W, or 800 mg (Days 1 and 8 of a 21-day cycle), based on safety and PK data from 2 Phase 1 
studies in heavily pretreated patients with advanced solid tumors (JFCA and JFCE).  The 
necitumumab 800-mg dose administered intravenously (I.V.) on Days 1 and 8 of each 21-day 
cycle has also been used in the recent pivotal, randomized Phase 3 trial SQUIRE in combination 
with gemcitabine/cisplatin as first-line therapy in 1093 patients with Stage IV squamous NSCLC 
(Thatcher et al. 2015).  The starting dose of necitumumab will be at Dose Level 0 at 800 mg on 
Days 1 and 8 Q3W.
Although the exposure-response analysis of SQUIRE data showed an association between drug 
exposure and efficacy, the vast majority of patients had sufficient exposure of necitumumab, as 
99.6% of patients had exposures superseding half-maximal effective concentration (82 µg/mL) 

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for OS, with the median exposure resulting in close to maximum efficacy.  Necitumumab 
disposition showed a less-than-proportional dependence on patient body weight.  Simulations 
based on population PK (PopPK) and pharmacodynamic models show that weight- or body 
surface area-based dosing would not lead to a decreased PK variability or improvement of OS.
There was no correlation detected between necitumumab PK and hepatic or renal function 
markers, and there were no differences in disposition across age, sex, or race (White vs. Asian).  
No clear relationship was observed between drug exposure and safety events.  In summary, 
PopPK/Pharmacodynamic analysis supports the administration of 800 mg necitumumab on 
Days 1 and 8 of a 21-day cycle as an appropriate dose in the target population.
5.5.3. Dose Selection for Osimertinib
Osimertinib was slowly absorbed following oral dosing with median time to reach maximum 
plasma concentration in patients and healthy volunteers ranging from 6 to 8 hours across doses.  
Osimertinib exhibited low to moderate apparent clearance and high volume of distribution in a 
low fluctuation of exposure (maximum/minimum plasma concentration [Cmax:Cmin] ratio of
approximately 1.6) with steady-state achieved by 15 days of dosing.  In NSCLC patients, the 
population estimated mean maximum steady-state concentration and the area under the plasma 
concentration-time curve at steady state (AUCss) at 80-mg dose is 501 nM and 11258 nM.h, 
respectively.
Based on PopPK analysis, dose adjustment is not required based on patient’s age, gender, body 
weight, ethnicity or smoking status.  Based on an exposure-response analysis of the pooled data 
from efficacy studies (AURA Phase 1 component, AURA extension and AURA2), there was no 
evidence of a relationship between plasma exposure (AUCss) of osimertinib and efficacy 
endpoints (probability of response or best percent change in tumor size or duration of response 
[DOR] for T790M mutation-positive patients with advanced NSCLC who have progressed on or 
after EGFR TKI therapy).  Overall, the PK profile of osimertinib supports once a day continuous 
dosing.
The AURA studies in NSCLC patients with EGFR T790M mutation-positive tumors who had 
progressed following prior therapy with an EGFR TKI agent have demonstrated that osimertinib 
80 mg QD offers benefits.  ORR was 66.1% (95% CI: 61.2, 70.7) based on blinded independent 
central review (BICR), which is substantially higher than that reported with chemotherapy in 
second- or later-lines.  The high ORR was regardless of line of therapy or other demographic or 
disease characteristics. DOR was 8.5 months (95% CI: 8.5, not calculable [NC]) based on 
investigator assessment.  The preliminary estimate of mPFS was 9.7 months (95% CI: 8.3, NC) 
based on assessments of both BICR and investigator. An improvement in patient-reported 
outcome (PRO)-reported lung cancer symptoms was supportive of the Response Evaluation 
Criteria In Solid Tumors (RECIST) efficacy data.
Osimertinib 80 mg QD has an acceptable safety profile for the intended advanced NSCLC 
population.
The 20-mg starting dose was sufficient to inhibit EGFR T790M, whereas doses equivalent to 
80 mg or more were expected to lead to more profound inhibition of tumor growth (Cross et al. 

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2014).  The current ongoing Phase 2 (AURA2) and Phase 3 (AURA3) studies employ 80-mg QD
regimen for advanced EGFR T790M-positive NSCLC patients.
In summary, PK analysis and preclinical and clinical data support 80-mg once daily regimen in 
advanced EGFR T790M-positive NSCLC patients.

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Have a diagnosis of NSCLC with at least 1 measurable lesion assessable using 
standard techniques by the Response Evaluation Criteria In Solid Tumors 
Version 1.1 (RECIST 1.1; Eisenhauer et al. 2009)
[2]
Have locally advanced or metastatic NSCLC not amenable to curative therapy
[3]
Have lung cancer with documented evidence of one of the 2 common EGFR
mutations known to be associated with EGFR TKI sensitivity (Ex19del, 
L858R)
[4]
Have disease progression immediately following first-line EGFR TKI 
treatment (with disease control as the best response to the first-line EGFR TKI 
treatment) regardless of prior chemotherapy
[5]
Have T790M-positive status using a test validated and performed locally after 
disease progression on EGFR TKI treatment
[6]
Tumor tissue from a biopsy taken after disease progression on the most recent 
EGFR TKI treatment is required.  Patients for whom newly obtained samples 
cannot be obtained (for example, inaccessible or patient safety concern) may 
submit an archived specimen only upon agreement from the Sponsor.
[7]
Have Eastern Cooperative Oncology Group Performance Status of 0 or 1 at 
the time of enrollment (Oken et al. 1982)
[8]
Have provided signed informed consent and are amenable to compliance with 
protocol schedules and testing
[9]
Have serum albumin that is ≥25 g/L at the time of enrollment
[10] Have urinary protein that is <2+ on dipstick or routine urinalysis.  If urine 
dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine 
must be collected and must demonstrate <2 g of protein in 24 hours to allow 
participation in the study.

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[11] Have adequate organ function, as defined below, with all screening labs 
performed within 7 days of treatment initiation:
System
Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
≥1.5 x 109/L
Platelets
≥100 x 109/L
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L (packed red blood cell transfusions are 
not allowed within 1 week prior to baseline hematology profile)
Renal
Creatinine OR
Measured or calculated creatinine 
clearancea (see Appendix 6)
≤1.5 x ULN OR
≥50 mL/min
Hepatic
Total bilirubin
≤1.5 x ULN
AST (SGOT) and ALT (SGPT)
≤2.5 x ULN OR
≤5 x ULN for patients with liver metastases
Coagulationb
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
INR ≤1.5 x ULN or PT ≤ 5 seconds above ULN unless patient 
is receiving anticoagulant therapy as long as INR or PT is 
within therapeutic range of intended use of anticoagulants
Partial Thromboplastin Time (PTT) or 
Activated Partial Thromboplastin Time 
(aPTT)
PTT or aPTT ≤ 5 seconds above ULN unless patient is 
receiving anticoagulant therapy as long as PTT or aPTT is 
within therapeutic range of intended use of anticoagulants
Abbreviations:  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase);
aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum 
glutamic oxaloacetic transaminase); INR = international normalized ratio; PT = prothrombin time; 
PTT = partial thromboplastin time; ULN = upper limit of normal.
a
Creatinine clearance should be calculated per institutional standard.
b
Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral 
anticoagulant or low molecular weight heparin.  If receiving warfarin, the patient must have an INR 
≤3.0 x ULN and no active bleeding (i.e., no bleeding within 14 days prior to first dose of study 
treatment) or pathological condition present that carries a high risk of bleeding (e.g., tumor involving 
major vessels or known varices).
[12] Be at least 18 years old at the time of signing informed consent
[13] Have a life expectancy of ≥3 months
[14] Have resolution, except where otherwise stated in the inclusion criteria, of all 
clinically significant toxic effects of prior systemic cancer therapy, surgery, or 
radiotherapy to Grade ≤1 by NCI CTCAE Version 4.0
[15] For male patients, are sterile (including vasectomy confirmed by 
postvasectomy semen analysis) or agree to use a highly effective method of 
contraception (2 methods preferred), and to not donate sperm starting with the 
first dose of study therapy, during the study, and for at least 6 months 
following the last dose of study therapy or country requirements, whichever is 
longer.  Refer to Appendix 1 for definition of highly effective method of 
contraception.

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[16] For female patients, are surgically sterile, postmenopausal (see Section 6.3.2
in detail), or agree to use a highly effective method of contraception (2 
methods preferred) during the study, and for 6 months following the last dose 
of study treatment or country requirements, whichever is longer.  Refer to 
Appendix 1 for definition of highly effective method of contraception.
[17] For female patients and of child-bearing potential, must have a negative serum 
or urine pregnancy test within 7 days prior to enrollment, and should not be 
breast feeding
Note:  Non-childbearing potential (by other than medical reasons) is defined 
in Section 6.3.2.
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[18] Previous treatment with an EGFR mAb (except for past treatment for 
squamous cell carcinoma of head and neck or mCRC)
[19] Previous treatment with an EGFR TKI (for example, erlotinib or gefitinib) 
within 8 days or approximately 5x half-life, whichever is longer, of the first 
dose of study treatment (If sufficient wash-out time has not occurred due to 
schedule or PK properties, an alternative appropriate wash-out time based on 
known duration and time to reversibility of drug-related AEs could be agreed 
upon by the Sponsor and the investigator.)
[20] Previous treatment with osimertinib or other third-generation EGFR TKIs
[21] Patients with symptomatic or growing brain metastases less than 4 weeks 
prior to enrollment.  Patients with asymptomatic and stable brain metastases, 
such as those who have completed radiotherapy for brain metastases at least 
4 weeks prior to receiving treatment and requiring no steroids or 
anticonvulsants for at least 2 weeks prior to receiving treatment, are eligible.

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[22] Have a serious concomitant illness or medical condition(s) including, but not 
limited to, the following:

Active infection including hepatitis B, hepatitis C, and human 
immunodeficiency virus (HIV) infection.  Screening for chronic conditions 
is not required.

Active or uncontrolled clinically serious infection

Active substance abuse disorders

History of drug-induced interstitial lung disease (ILD), ILD, or radiation 
pneumonitis requiring treatment with steroid prior to study enrollment, or 
any evidence of clinically active ILD

Known allergy or hypersensitivity reaction to any of the treatment 
components
[23] Have history of another malignancy in 3 years, EXCEPT:

adequately treated nonmelanomatous skin cancer,

curatively treated cervical carcinoma in situ,

other noninvasive carcinoma or in situ neoplasm, or

prostate cancer that is not expected to impact patient survival
[24] Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding 
episode within 12 weeks prior to enrollment.  Patients with a history of gross 
hemoptysis (defined as bright red blood of ≥1/2 teaspoon) within 2 month 
prior to enrollment are excluded.
[25] Have experienced any arterial thrombotic event or arterial thromboembolic 
event, including myocardial infarction, unstable angina (history or evidence of 
current clinically relevant coronary artery disease of current ≥Class III as 
defined by Canadian Cardiovascular Society Angina Grading Scale 
[Campeau 1976] or congestive heart failure of current ≥Class III as defined by 
the New York Heart Association), cerebrovascular accident, or transient 
ischemic attack, within 6 months prior to enrollment
[26] Have a history of deep vein thrombosis, pulmonary embolism, or any other 
significant venous thromboembolism (venous catheter thrombosis or 
superficial venous thrombosis not considered “significant”) during the
3 months prior to study enrollment. Patients with venous thromboembolism 
occurring 3 to 6 months prior to study enrollment are allowed, if being treated 
with low molecular weight heparin.
[27] Have a history of GI perforation and/or fistula within 6 months prior to 
enrollment

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[28] Have a bowel obstruction, history or presence of inflammatory enteropathy or 
extensive intestinal resection (hemicolectomy or extensive small intestine 
resection with chronic diarrhea), Crohn’s disease, ulcerative colitis, or chronic 
diarrhea
[29] Have uncontrolled hypertension, as defined in CTCAE Version 4.0, prior to 
initiating study treatment, despite antihypertensive intervention. CTCAE 
Version 4.0 defines uncontrolled hypertension as Grade >2 hypertension; 
clinically, the patient continues to experience elevated blood pressure (systolic
>160 mmHg and/or diastolic >100 mmHg) despite medications.
[30] Are receiving chronic therapy with any of the following medications within 
7 days prior to enrollment:
a.
nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, 
ibuprofen, naproxen, or similar agents)
b. other antiplatelet agents (such as clopidogrel, ticlopidine, dipyridamole, or 
anagrelide)
Aspirin use at doses up to 325 mg/day is permitted.
[31] Have had a serious or non-healing wound, ulcer, or bone fracture within
28 days prior to enrollment
[32] Have an elective or a planned major surgery during the course of the trial
[33] Have undergone major surgery within 28 days prior to enrollment, or minor 
surgical procedure such as central venous access device placement within 
7 days prior to enrollment
[34] Are currently enrolled in, or discontinued within the last 30 days from, a 
clinical trial involving an investigational product or any other type of medical 
research judged not to be scientifically or medically compatible with this 
study (except in the setting of EGFR TKI as detailed above).  Patients 
participating in surveys or observational studies are eligible to participate in 
this study.
[35] Are pregnant, or breastfeeding
[36] Have radiologically documented evidence of major blood vessel invasion or 
encasement by cancer
[37] Have radiographic evidence of pulmonary intratumor cavitation, regardless of 
tumor histology
[38] Are receiving concurrent treatment with other anticancer therapy, including 
other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, 
or targeted therapy or radiotherapy treatment to more than 30% of the bone 
marrow or with a wide field of radiation within 4 weeks prior to enrollment 
(except in the setting of EGFR TKI as detailed above).

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[39] Are currently receiving (or unable to stop use at least 1 week prior to 
receiving the first dose of osimertinib) medications or herbal supplements 
known to be potent inducers of CYP3A4 (refer to Appendix 7).
[40] Have any of the following cardiac abnormal findings:

Mean resting corrected QT interval (QTc) >470 msec obtained from 
3 electrocardiograms (ECGs), using the screening clinic ECG 
machine-derived QTc value

Any clinically important abnormalities in rhythm, conduction, or 
morphology of resting ECG; for example, complete left bundle branch 
block, third-degree heart block, or second-degree heart block

Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as heart failure, hypokalemia, congenital long QT syndrome, 
family history of long QT syndrome or unexplained sudden death under 
40 years of age in first-degree relatives, or any concomitant medication 
known to prolong the QT interval

Have a history of any of the following conditions:  presyncope or syncope 
of either unexplained or cardiovascular etiology, ventricular arrhythmia 
(including but not limited to ventricular tachycardia and ventricular 
fibrillation), or sudden cardiac arrest
[41] Have undergone chest irradiation within 2 weeks prior to study drug 
administration, have not recovered from all radiation-related toxicities, or 
requires corticosteroids.  A 2-week washout is permitted for focal palliative 
radiation to non-central nervous system disease.
[42] Have refractory nausea and vomiting, inability to swallow the formulated 
product, or previous significant bowel resection that would preclude 
absorption
[43] Have any other serious uncontrolled medical disorders or psychological 
conditions that would, in the opinion of the investigator, limit the patient’s 
ability to complete the study or sign an informed consent document
[44] Have liver cirrhosis at a level of Child-Pugh B (or worse) or liver cirrhosis 
(any degree) and a history of hepatic encephalopathy or clinical meaningful 
ascites resulting from cirrhosis
6.3.
Lifestyle Restrictions
6.3.1. Diet
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting.

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6.3.2. Contraception
Based on ramucirumab’s mechanism of action, it is likely that ramucirumab will inhibit 
angiogenesis and may potentially result in adverse effects during pregnancy and postnatal 
development.
Therefore, 1) non-pregnant, non-breast-feeding women may only be enrolled if they are willing 
to use a highly effective method of contraception or are considered to be of non-childbearing 
potential and 2) only men may be enrolled who use an effective method of contraception, or who 
are sterile (including confirmed vasectomy) and do not donate sperm (Section 6.1).
For female patients, non-childbearing potential (by other than medical reasons) is defined as any 
one of the following:

≥45 years of age and has not had menses for greater than 2 years

Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a
follicle-stimulating hormone (FSH) value in the postmenopausal range upon pretrial 
(screening) evaluation (FSH level >40 mIU/mL)

At least 6 weeks following surgical bilateral oophorectomy or tubal ligation with or 
without hysterectomy.  Documented hysterectomy or oophorectomy must be confirmed 
with medical records of the actual procedure or confirmed by an ultrasound.  Tubal 
ligation must be confirmed with medical records of the actual procedure; otherwise, the 
patient must be willing to use an adequate barrier method throughout the study, starting 
with the screening visit through 6 months after the last dose of study treatment.
Refer to Appendix 1 for definitions of effective method of contraception and highly effective 
method of contraception.
Patients should start using contraception from study Visit 1 throughout the study period up to 
6 months after the last dose of study treatment.
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  If there is any question that a 
patient will not reliably comply with the requirements for contraception, that patient should not 
be entered into the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be
re-screened, only after discussion with and permission from the Lilly clinical research physician 
(CRP).
Repeating laboratory tests during the screening period does not constitute 
re-screening. Screening laboratory tests may not be repeated more than twice in order to meet 
eligibility during the screening period.

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7.
Treatments
7.1.
Treatments Administered
Ramucirumab or necitumumab, and osimertinib will be administered per Table JVDL.6.
For the Dose-Finding Portion, the DLT observation period is for up to 2 treatment cycles for 
Arm A (4 weeks) and 1 treatment cycle for Arm B (3 weeks).
For the Dose-Expansion Portion, each patient will be treated until confirmed objective PD (see 
Section 9.1.3), unacceptable toxicity, or discontinuation for any other reason.
Across all study periods, including the continued access period (Section 7.8.1), patients will be 
treated with ramucirumab or necitumumab and/or osimertinib until confirmed PD, unacceptable 
toxicity, or discontinuation for any other reason.
Table JVDL.6.
Dose Finding Portion Treatment Regimens/ Dosing Schedule
Study Drug
Dose
Route
Timing
Ramucirumaba
Level 0: 10 mg/kg
Level -1: 8 mg/kg
I.V.
Over 60 minutes infusion Day 1 of 
each 2-week cycle
ARM A
1-hour observation 
periodb
Osimertinibc
80 mg
PO
Daily
OR
Necitumumabd
Level 0: 800 mg
Level -1: 600 mg
I.V.
Over 60 minutes infusion Days 1 and 
8 of each 3-week cycle
ARM B
1-hour observation 
periode
Osimertinibc
80 mg
PO
Daily

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Abbreviations:  IRR = infusion-related reaction; I.V. = intravenous; PO = orally.
a
Premedication is required prior to infusion of ramucirumab.  Recommended premedication agents include 
histamine H1 antagonists such as diphenhydramine hydrochloride (or equivalent).  Additional premedication 
may be provided at the investigator’s discretion.  Premedication must be provided in the setting of a prior 
Grade 1-2 IRR, as detailed in Table JVDL.8.  All premedication administered must be adequately documented in 
the electronic case report form.  
b A 1-hour observation period is required after the administration of the first and second doses of ramucirumab.  If 
there is no evidence of an IRR during the initial 2 infusions of ramucirumab, then no observation period is 
required for subsequent treatment cycles.  In the event an IRR occurs thereafter, then the 1-hour observation 
period should be reinstituted.  Refer to Section 7.7.1.1 for further instructions in detail.
c
Refer to Section 7.4.3 for further instructions on taking osimertinib.
d Prior to necitumumab infusion, consider premedication for possible skin reactions.  Preemptive treatment with 
skin moisturizers, topical steroids, doxycycline, or sunscreen may be administered as clinically appropriate to 
patients receiving necitumumab.  For additional information regarding preemptive management of skin toxicity, 
see Canadian recommendations (Melosky et al. 2009).
e
Monitor patients from the start of the infusion until at least 1 hour after the end of the infusion in an area with 
resuscitation equipment and other agents (for example, epinephrine or prednisolone equivalents) available.  Refer 
to Section 7.7.1.1 for further instructions in detail.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the site personnel

verifying that instructions are followed properly

maintaining accurate and appropriate records, including those of investigational 
product dispensing and collection

ensure appropriate supply, storage, handling, distribution, and usage of trial 
treatments in accordance with the protocol and any applicable laws and 
regulations

at the end of the study, returning all unused medication to Lilly or its designee
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the investigational products so that the situation can be assessed.
7.1.1. Packaging and Labelling
All investigational product materials will be provided by Lilly.  Clinical trial materials will be 
labeled according to the country’s regulatory requirements.  Ramucirumab and necitumumab 
vials should be stored under refrigeration at 2°C to 8°C (36°F to 46°F).  Osimertinib tablets in 
bottles should be stored at 25°C (77°F).  Excursions permitted to 15°C to 30°C (59°F to 86°F).

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7.2.
Method of Treatment Assignment
Patients meeting all inclusion/exclusion criteria will be enrolled to study regimen.  Study drug 
will be allocated to patients using an interactive web-response system (IWRS), which is 
web-based and accessible 24 hours a day.  The IWRS registration consists of assigning the 
patient a unique study identification number for all patients.
7.2.1. Selection and Timing of Doses
A cycle is defined as an interval of 14 days for Arm A/Cohort A and 21 days for Arm B.  A 
delay of a cycle due to holiday, weekend, bad weather, or other unforeseen circumstances will be 
permitted for a maximum of 3 days and not counted as a protocol deviation.
The actual doses of ramucirumab administered will be determined by measuring the patient's 
weight at the beginning of each cycle.  If the patient’s weight fluctuates by more than 10% from 
the weight used to calculate the prior dose, the dose must be recalculated.  Recalculation of the 
ramucirumab dose for weight fluctuations of <10% is permitted but not required.
Ramucirumab will be administered, over 60-minute I.V. infusion.  The maximum ramucirumab 
infusion rate is 25 mg/min.
Necitumumab will be administered, over 60-minute I.V. infusion, at a fixed dose.
Osimertinib will be taken by patients orally once a day, at a fixed dose.  If a dose of osimertinib 
is missed, the missed dose should not be made up and the next dose should be taken as 
scheduled.  For administration to patients who have difficulty swallowing solids, refer to 
osimertinib USPI or SmPC.
A patient may continue to receive ramucirumab or necitumumab in combination with osimertinib
at the assigned dose level until he or she meets 1 or more of the specified reasons for 
discontinuation (as described in Section 8).
7.2.1.1. Dose-Limiting Toxicity Observation
A 3+3 dose de-escalation design will be used to assess the safety of ramucirumab (Arm A) or 
necitumumab (Arm B) given in combination with a fixed dose of osimertinib at 80 mg daily 
(QD). Eligible patients will be enrolled into either of the 2 treatment arms. If there is a DLT, a 
forced enrollment will be applied to push new patients towards that arm until the Dose-Finding 
Portion is complete.  DLT observation period will last for 2 cycles (4 weeks) for Arm A and 
1 cycle (3 weeks) for Arm B in this portion of the study.  The following criteria will be used to 
determine the progress of the study:
Arm A - Ramucirumab and osimertinib 3+3 de-escalation design:
1) If none of the 3 DLT-evaluable patients treated at 10 mg/kg (Dose Level 0) of 
ramucirumab on Day 1 Q2W in combination with 80 mg of osimertinib QD develops a 
DLT, the study will open the Dose-Expansion Portion at Dose Level 0.

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2) If 1 of the first 3 DLT-evaluable patients develops a DLT, 3 additional patients will be 
added to Dose Level 0.  If ≤1 of 6 DLT-evaluable patients develops a DLT, the 
Dose-Expansion portion will start at Dose Level 0.
3) If ≥2 of 6 DLT-evaluable patients develop a DLT, 3 eligible subjects will be enrolled and 
treated at 8 mg/kg (Dose Level -1) of ramucirumab on Day 1 Q2W in combination with 
80 mg of osimertinib QD.
4) Similarly, if none of the 3 DLT-evaluable patients develops a DLT, the study will open 
the Dose-Expansion portion at Dose Level -1.
5) If 1 of the first 3 DLT-evaluable patients at Dose Level -1 develops a DLT, 3 additional 
patients will be added. If ≤1 of 6 DLT-evaluable patients develops a DLT, the 
Dose-Expansion portion will start at Dose Level -1.
6) If ≥2 of 6 DLT-evaluable patients in Dose Level -1 develop a DLT, Arm A of the study 
will stop.
Arm B - Necitumumab and osimertinib 3+3 de-escalation design:
1) If none of the 3 DLT-evaluable patients treated at 800 mg (Dose Level 0) of 
necitumumab on Days 1 and 8 Q3W in combination with 80 mg of osimertinib QD 
develops a DLT, the study will open the Dose-Expansion portion at Dose Level 0.
2) If 1 of the first 3 DLT-evaluable patients develops a DLT, 3 additional patients will be 
added to Dose Level 0.  If ≤1 of 6 DLT-evaluable patients develops a DLT, the 
Dose-Expansion portion will start at Dose Level 0.
3) If ≥2 of 6 DLT-evaluable patients develop a DLT, 3 eligible subjects will be enrolled and 
treated at 600 mg (Dose Level -1) of necitumumab on Days 1 and 8 Q3W in combination 
with 80 mg of osimertinib QD.
4) Similarly, if none of the 3 DLT-evaluable patients develops a DLT, the study will open 
the Dose-Expansion portion at Dose Level -1.
5) If 1 of the first 3 DLT-evaluable patients in Dose Level -1 develops a DLT, 3 additional 
patients will be added. If ≤1 of 6 DLT-evaluable patients develops a DLT, the 
Dose-Expansion portion will start at Dose Level -1.
6) If ≥2 of 6 DLT-evaluable patients in Dose Level -1 develop a DLT, Arm B of the study 
will stop.
No intrapatient dose escalation is allowed.  Patients who withdraw from the study during the 
DLT observation period for reasons other than a treatment-related toxicity may be replaced 
within the same dose level.
Ramucirumab or necitumumab in combination with osimertinib may continue at the assigned 
dose level until there is a radiographic documentation of PD, toxicity requiring cessation, 
protocol noncompliance, or withdrawal of consent.

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For each arm, if dropouts, dose interruptions, or reductions occur that result in a patient being 
nonevaluable for DLTs, additional patients will be enrolled to achieve the minimum of 
3 evaluable patients.  The need for patient replacement will be determined based on consultation 
with the investigator and Lilly CRP/clinical research scientist (CRS).
7.2.1.1.1. Definition of Dose-Limiting Toxicities
A DLT is defined as one of the following AEs reported during the DLT observation period, if 
considered to be definitely, probably, or possibly related to ramucirumab, necitumumab, and/or 
osimertinib by the investigator; and fulfills any one of the following criteria using NCI CTCAE 
Version 4.0:
1.
Any nonhematologic toxicity Grade ≥3 will be considered as DLT with the following 
exceptions:
a) Liver function abnormality:  Grade ≥3 elevation in aminotransferase (AST) or alanine 
aminotransferase (ALT) that persists for less than 7 days.  For patients with liver 
metastasis who begin treatment with Grade 2 AST or ALT, either one of the level ≥10x 
upper limit of normal (ULN) lasting for ≥7 days will be considered a DLT.
b) Renal function abnormality:  Grade ≥3 renal function test elevation that persists for 
less than 7 days
c) Skin rash: Grade 3 rash that resolves to Grade ≤2 within 14 days with appropriate 
supportive therapy
d) The following are not considered a DLT if they are transient (<7 days) and, after 
treatment, decrease to Grade 2 or lower:

Grade ≥3 hypersensitivity and injection site reactions

Grade ≥3 myalgia, fatigue, and constipation, with full supportive therapy

Grade ≥3 electrolyte imbalance, nausea, vomiting, and diarrhea
2.
Hematologic toxicity will be considered a DLT as the following:
a) Grade 4 toxicity lasting ≥7 days, or
b) Grade 3 or 4 thrombocytopenia if associated with bleeding or requires platelet 
transfusion, or
c) Febrile neutropenia
3.
Grade 5 toxicity (that is, death) if considered related to study treatment
4.
Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting, for example:
a) Any toxicity (such as confirmed ILD/pneumonitis) that is possibly related to study 
treatment that requires the withdrawal of the patient from the study during observation 
period, or
b) A delay of >14 days due to persistent Grade ≥2 treatment-related toxicities in the 
initial 2 cycles, or

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c) If a total at least 75% of the planned dose for either agent cannot be administered in the 
first 2 cycles due to toxicity
Unless determined at the DLT review meeting to initiate Dose Levels -1, no intrasubject dose 
escalation or reduction is allowed during the DLT observation period.  For the purpose of subject 
management, DLTs will lead to dose interruption during the DLT observation period.  
Depending on the AE profile, dose modifications of study drugs will be permitted after the initial 
DLT observation period.
Additional subjects will be enrolled in a cohort to achieve the minimum of 3 evaluable subjects.  
Noncompliant subjects or subjects who withdraw from the study during the DLT observation 
period for reasons other than a DLT may be replaced within the same dose level.  For the 
purpose of making decisions from a safety perspective, subjects will be considered evaluable if 
they have completed 4 weeks for Arm A or 3 weeks for Arm B of observation and have received 
at least 75% of the cohort-specified dose of study treatment. In addition, subjects with dosing 
delays in Cycle 1 of ≥2 weeks for non-DLT events will be considered not evaluable for making 
decisions and should be replaced.
After each of the 3 patients in a dose schedule completes the observation period, a safety analysis 
will occur; the data will be reviewed by study investigators and the Lilly CRP/CRS, and the 
findings documented, indicating whether each dose schedule is or is not well tolerated.  The 
results will inform the decision whether or not to move onto the Dose-Expansion portion.
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
Doses of study drugs may need to be delayed, reduced, or discontinued to manage specific AEs 
or other toxicities.
7.4.1. Ramucirumab Dose Adjustments, Delays, and Discontinuation
The ramucirumab dose may need to be delayed and/or reduced if the patient experiences an AE, 
including an adverse event of special interest (AESI) (Section 9.2.1).  Doses may be delayed to 
allow time for the patient to recover from the event.  Certain AEs require immediate and 
permanent discontinuation of study treatment (see Table JVDL.8).  If administration of 
ramucirumab is delayed for more than 4 weeks (2 cycles) after Day 1 of the most recent 
treatment cycle, the patient should be discontinued from ramucirumab treatment.  Any patient 
who requires a dose reduction will continue to receive a reduced dose until discontinuation from 
ramucirumab or discontinuation from the study.  Any patients requiring dose reduction to less 
than 6 mg/kg of ramucirumab will have ramucirumab discontinued.  Such patients may continue 
with osimertinib as a single agent.
Table JVDL.7 presents the ramucirumab dose reductions for each treatment cohort.

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Table JVDL.8 presents the criteria for dose modifications and dose discontinuations applicable if 
the patient experiences a ramucirumab AESI or other AEs at least possibly related to 
ramucirumab. Dose re-escalation for ramucirumab is not permitted.
Table JVDL.7.
Ramucirumab Dose Reductions
a
Dose Schedule 1:
(14-day Cycle)
Dose Schedule 2:
(14-day Cycle)
Recommended Dose for Expansion Cohort
8 mg/kg
on Day 1
10 mg/kg
on Day 1
First dose reduction
6 mg/kg
on Day 1
8 mg/kg
on Day 1
Second dose reduction
Not allowed
6 mg/kg
on Day 1
a
Ramucirumab dose reductions are allowed between cycles and within a given cycle.

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Table JVDL.8.
Dose-Modification Guidelines for Ramucirumab for Adverse Events at Least Possibly Related to 
Ramucirumab, including Adverse Events of Special Interest
Adverse Event
NOTE: All Specific Adverse Events Listed 
are defined as AESIs in Section 9.2.1).
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Table JVDL.7.
Treating physicians can modify or discontinue ramucirumab more conservatively than 
in the guidance below.
1.
Infusion-related reaction
1.a.
Infusion-related reaction
2
Interrupt and reduce the infusion rate by 50% for the duration of the infusion and for all 
future infusions.
Prior to all future infusions of ramucirumab, premedicate with:

an intravenous histamine H1 antagonist, such as diphenhydramine hydrochloride

dexamethasone or equivalent

acetaminophen/paracetamol
1.b.
Infusion-related reaction
3-4
Immediately and permanently discontinue ramucirumab
2.
Hypertension
2.a.
Hypertension (non-life-threatening and 
associated with symptoms)
NOTE:  Hypertension should be monitored 
prior to each ramucirumab infusion.
3

Delay ramucirumab until the hypertension is controlled with medication and is 
resolved to Grade 0-2.
o
If controlled with medication and resolved to Grade 0-2, then may resume 
ramucirumab at current dose.
o
If NOT controlled with medication and not resolved to Grade 0-2 within a 
reasonable timeframe, discontinue ramucirumab at investigator’s discretion.
2.b.
Uncontrolled hypertension, hypertensive 
crisis, or hypertensive encephalopathy
4
Immediately and permanently discontinue ramucirumab.

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Dose-Modification Guidelines for Ramucirumab for Adverse Events at least Possibly Related to Ramucirumab, including Adverse Events of Special 
Interest (continued)
Adverse Event
NOTE: All Specific Adverse Events Listed are 
defined as AESIs in Section 9.2.1).
CTCAE 
Grade
Dose-Modification Guidelines
NOTE:  Dose reductions to occur as defined in Table JVDL.7.
3.
Proteinuria
3.a.
Proteinuria = 2+ (dipstick or routine urinalysis)a

Administer ramucirumab at the current dose if clinically indicated.

Obtain 24-hour urine protein results within 3 days prior to the next ramucirumab 
dose.
o
If urine protein is <2 g/24 h, administer ramucirumab at the patient's current 
dose.
o
If urine protein is 2 g/24 h, modify the ramucirumab dose based on 24-hour 
collection.  See Proteinuria 2 g/24 h (24-hour urine collection), Line 3.c in 
this table.
3.b.
Proteinuria >2+ (dipstick or routine urinalysis)a

Delay ramucirumab until urine protein returns to <2 g/24 h.

Obtain 24-hour urine protein results within 3 days prior to the next ramucirumab 
dose.
o
If urine protein is <2 g/24 h, no further dose delay or dose reduction is 
required.
o
If urine protein remains 2 g/24 h and is not resolved within a reasonable 
timeframe, discontinue ramucirumab at investigator’s discretion.
3.c.
Proteinuria 2 g/24 h (24-hour urine collection)a

First or second occurrence:  delay ramucirumab until urine protein returns to 
<2 g/24 h.
o
If urine protein returns to <2 g/24 h, reduce ramucirumab dose.
o
If urine protein remains 2 g/24 h and is not resolved within a reasonable 
timeframe, discontinue ramucirumab at investigator’s discretion.

Third occurrence:  discontinue ramucirumab.
3.d.
Proteinuria >3 g/24 h or in the setting of nephrotic 
syndromea
Immediately and permanently discontinue ramucirumab.
4.
Arterial thromboembolic events, venous 
thromboembolic events
3 or 4
Immediately and permanently discontinue ramucirumab.
5.
Bleeding/hemorrhage
3 or 4
Immediately and permanently discontinue ramucirumab.
6.
Gastrointestinal perforation
Immediately and permanently discontinue ramucirumab.

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Adverse Event
NOTE: All Specific Adverse Events Listed are 
defined as AESIs in Section 9.2.1).
CTCAE 
Grade
Dose-Modification Guidelines
NOTE:  Dose reductions to occur as defined in Table JVDL.7.
7.
Reversible posterior leukoencephalopathy 
syndrome
Immediately and permanently discontinue ramucirumab.
8.
Congestive heart failure
3-4
Immediately and permanently discontinue ramucirumab.
9.
Fistula formation
Immediately and permanently discontinue ramucirumab.
10.
Impaired wound healing
10.a.
Prior to planned surgery
Withhold ramucirumab.
10.b
After surgery
Resume ramucirumab based on clinical judgment.
10.c.
Wound-healing complications developed during 
study treatment
Delay ramucirumab dosing until the wound is fully healed.
11.
Liver injury/liver failure
11.a.
Hepatic encephalopathy and/or hepatorenal 
syndrome resulting from liver cirrhosis
Immediately and permanently discontinue ramucirumab.
12
Hypothyroidism
2-4
Therapy with ramucirumab can be continued while treatment for the thyroid disorder 
is instituted.
13
Other adverse events considered at least possibly 
related to ramucirumabb
13.a
Non-life threatening and reversible
3
May delay ramucirumab until resolved to Grade 0-1.

If resolved to Grade 0-1, may reduce ramucirumab dose.

If NOT resolved to Grade 0-1 within a reasonable timeframe, discontinue 
ramucirumab at investigator’s discretion.
13.b
Adverse Event
4
Permanently discontinue treatment immediately, with the exception of Grade 4 fever 
or Grade 4 laboratory abnormality, in which case:

First occurrence:  Delay ramucirumab until resolved to Grade 0-1.
o
If resolved to Grade 0-1, may resume ramucirumab original dose at the 
discretion of the investigator.
o
If NOT resolved to Grade 0-1 within a reasonable timeframe, discontinue 
ramucirumab at investigator’s discretion.

Second occurrence:  Delay ramucirumab until resolved to Grade 0-1.
o
If resolved to Grade 0-1, reduce ramucirumab dose.
o
If NOT resolved to Grade 0-1 within a reasonable timeframe, discontinue 
ramucirumab at investigator’s discretion.

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Dose-Modification Guidelines for Ramucirumab for Adverse Events at least Possibly Related to Ramucirumab, including Adverse Events of Special 
Interest (concluded)
Abbreviations:  AESI = adverse event of special interest; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.
a
Perform urinalysis within 3 days prior to each infusion of ramucirumab.  If 24-hour urine collection is also performed, the results of 24-hour urine collection 
should be used for clinical decision-making.
b Patients who enter the study with symptoms or laboratory values equivalent to NCI-CTCAE Version 4.0 Grade 1-2 adverse events should not necessarily 
have dose delays or reductions related to the persistence or mild worsening of those symptoms or laboratory values.  Grade 2 toxicities which represent 
clinically significant worsening of symptoms from baseline, ramucirumab dose may be delayed at the discretion of the investigator.  If the toxicity is resolved 
to Grade 0-1, then reduce ramucirumab dose.  If the toxicity is not resolved to Grade 0-1, then discontinue ramucirumab.

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7.4.2. Necitumumab Dose Adjustments, Delays, and Discontinuation
Prior to each administration of necitumumab, all toxicities associated with necitumumab must 
have resolved to Grade ≤2 (except for alopecia and skin toxicity) or baseline.  Pretreatment 
laboratory data may not be older than 72 hours (Day 1 of each cycle) or 24 hours (Day 8 of each 
cycle).
If the criteria are not met at the time of a planned treatment, the following general rules for the 
management of treatment delays apply:

In the case of reversible Grade 3-4 necitumumab-related toxicity, administration 
of necitumumab will be at the reduced dose or interrupted, but osimertinib will 
continue according to the planned schedule.

If administration of necitumumab is delayed for more than 6 weeks (2 cycles) 
after Day 1 of the most recent treatment cycle, the patient should be discontinued 
from necitumumab treatment.
The following are general dose-modification guidelines for toxicity associated with 
necitumumab.  Please see Sections 7.7.1.1 and 7.7.1.3 for specific information on the 
management of necitumumab-related hypersensitivity/ infusion-related reactions (IRRs), skin 
reactions, conjunctivitis, hypomagnesemia, and thromboembolic events.
For patients starting at necitumumab 600 mg on Days 1 and 8, one dose reduction is permitted.  
Patients who cannot tolerate necitumumab 400 mg should discontinue necitumumab; such 
patients may continue with osimertinib as a single agent.
For patients starting at dose level 800 mg on Days 1 and 8, 2 dose reductions are allowed 
following reversible CTCAE Grade ≥3 AEs that require delay of necitumumab treatment for up 
to 6 weeks following Day 1 of the most recent treatment cycle, unless DLT criteria are met.  In 
this setting, necitumumab may be re-administered at a reduced dose (600 mg) if necessary only if 
AE is resolved to Grade ≤2.  A second dose reduction is permitted for this level of event 
(Grade ≥3).  Necitumumab must be discontinued if further dose reduction is required beyond 
400 mg on Days 1 and 8 Q3W.  The patient may continue to receive osimertinib as a single 
agent.
Necitumumab dose adjustments are allowed both within a cycle and between cycles.
Necitumumab may be held up to 6 weeks (2 cycles) from Day 1 of the most recent treatment 
cycle to permit sufficient time for recovery from the toxicity.  If a dose delay occurs, the 
investigator may resume necitumumab dosing at the same dose level for the remainder of the 
study or at reduced dose (assuming resolution to at least Grade 1 for nonhematologic and at least 
Grade 2 for hematologic toxicity).  If the patient experiences the same toxicity with the same or 
greater severity (CTCAE grade) requiring a dose delay within a cycle or at start of the next cycle, 
the patient must be dose reduced and not re-challenged a second time at the prior dose level.
If a patient experiences CTCAE Grade ≥3 hematologic toxicity possibly related to necitumumab, 
unless DLT criteria are met, then dosing must be delayed (until the toxicity resolves to either 

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baseline or at least Grade 2) and the dose of necitumumab must be reduced by 1 dose level (see 
below).
If a patient experiences CTCAE Grade ≥3 nonhematologic toxicity possibly related to 
necitumumab, unless DLT criteria are met, then dosing must be delayed (until the toxicity 
resolves to either baseline or at least Grade 1) and the dose of necitumumab must be reduced by 
1 dose level (see below).
For patients requiring dose reduction(s), any re-escalation to a prior dose level is permitted only 
after consultation with the Lilly CRP.  After re-escalation, subsequent dose adjustments should 
be based on the dose of necitumumab that the patient is currently receiving.  Following a dose 
reduction, the dose of necitumumab may be re-escalated to the pre-reduction dose, provided that 
at least 2 administrations of the reduced dose were given, and only after consultation with the 
Lilly CRP.
Table JVDL.9 presents the necitumumab dose reductions.
Table JVDL.9.
Dose Adjustments of Necitumumab
Dose Adjustment Level
I.V. Dose
Frequency
0
800 mg
Days 1 and 8 Q3W
-1
600 mg
Days 1 and 8 Q3W
-2
400 mg
Days 1 and 8 Q3W
Abbreviations:  I.V. = intravenous; Q3W = every 3 weeks.
Events that necessitate more than 2 dose reductions warrant discontinuation from necitumumab 
treatment.  Patients who enter the study with symptoms or laboratory values equivalent to NCI 
CTCAE Version 4.0 Grade 1-2 AEs should not have dose reductions related to the persistence or 
mild worsening (for example, from Grade 1 to Grade 2) of those symptoms or laboratory values.
In the event of alterations of necitumumab therapy due to a necitumumab-related toxicity, 
osimertinib need not be altered, and the planned osimertinib schedule should be maintained.  
Similarly, necitumumab therapy should not be delayed for osimertinib-related toxicities.
7.4.3. Osimertinib Dose Adjustments, Delays, and Discontinuation
Patients receiving ramucirumab or necitumumab plus osimertinib can have the osimertinib dose 
reduced if the toxicity is specifically attributable to osimertinib at the discretion of the 
investigator.  Patients may continue treatment with ramucirumab or necitumumab if they are 
discontinued from osimertinib.  Dose re-escalation for osimertinib is not permitted.
Patients should be treated following the recommendations, warnings, and precautions given for 
osimertinib.
Table JVDL.10 shows the dose-modification criteria and guidelines for management of common 
osimertinib toxicities.

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Table JVDL.10.
Recommended Dose Modifications for Osimertinib
Target Organ
Adverse Reactiona
Dose Modification
Pulmonary
Interstitial lung disease 
(ILD)/Pneumonitis
Permanently discontinue osimertinib.
Cardiac
QTc interval greater than 500 msec 
on at least 2 separate ECGs
Withhold osimertinib until QTc interval is 
less than 481 msec or recovery to baseline 
if baseline QTc is greater than or equal to 
481 msec, then resume at 40-mg dose.
QTc interval prolongation with 
signs/symptoms of life threatening 
arrhythmia
Permanently discontinue osimertinib.
Asymptomatic, absolute decrease in 
LVEF of 10% from baseline and 
below 50%
Withhold osimertinib for up to 4 weeks.
• If improved to baseline LVEF, resume.
• If not improved to baseline, permanently 
discontinue.
Symptomatic congestive heart 
failure
Permanently discontinue osimertinib.
Other
Grade 3 or higher adverse reaction
Withhold osimertinib for up to 3 weeks.
If improvement to Grade 0-2 within 
3 weeks
Osimertinib may be restarted at the same 
dose (80 mg) or a lower dose (40 mg).
If no improvement within 3 weeks
Permanently discontinue osimertinib.
Abbreviations:  ECGs = electrocardiograms; LVEF = left ventricular ejection fraction; QTc = QT interval corrected 
for heart rate.
a
Adverse reactions graded by the National Cancer Institute-Common Terminology Criteria for Adverse Events 
version 4.0 (NCI CTCAE v4.0).
7.4.4. Dose Delays for Reasons Not Related to Study Treatment
Dosing interruptions of any study drug are also permitted for reasons not related to study 
treatment (for example, elective surgery, unrelated medical events, patient vacation, and/or 
holidays).
Patients should resume the delayed study drug(s) within 4 weeks for ramucirumab and 6 weeks 
for necitumumab of the scheduled interruption, with every effort made to start on Day 1 of the 
next dosing schedule, unless otherwise discussed with the Sponsor.  If a dose of osimertinib is 
missed, the patient should not make up for the missed dose and should take the next dose at the 
regular time.  The reason for interruption should be documented on the case report form (CRF).
7.5.
Preparation/Handling/Storage/Accountability
Refer to the respective IBs for detailed information about preparation, handling, and storage of 
ramucirumab, necitumumab, and osimertinib.
7.6.
Treatment Compliance
Ramucirumab and necitumumab will be administered only at the investigational sites by the 
authorized study personnel.  As a result, treatment compliance is ensured.

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Patient compliance with osimertinib will be assessed at each visit.  Compliance will be assessed 
by direct questioning, review of diary, and counting returned tablets.  Deviations from the 
prescribed dosage regimen should be recorded in the CRF.
A patient will be considered significantly noncompliant if he or she missed 4 or more 
consecutive doses of osimertinib in a visit interval, or took <70% or >130% amount of expected 
study drug in a visit interval during the study.  A patient will also be considered significantly 
noncompliant if he or she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication.
Patients who are not evaluable for pharmacokinetics, but who complete 1 cycle of therapy, may 
be replaced upon consultation with the investigator(s) and the Lilly CRP/CRS to ensure adequate 
PK data, unless accrual to that cohort has stopped due to a DLT.
7.7.
Concomitant Therapy
A list of restricted and excluded concomitant therapies and exceptions is provided in 
Appendix 7.  All premedication, supportive care, and concomitant medication must be reported 
on the CRF at each visit.
7.7.1. Supportive Care
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  For the 3 study drugs, specific AEs have been identified based on past data for 
special monitoring and, when necessary, supportive care.  For ramucirumab and necitumumab, 
these are referred to as AESI.
7.7.1.1.
Infusion-Related Reactions - Ramucirumab and Necitumumab
IRRs have been identified as events of interest for both ramucirumab and necitumumab.  In the 
event of an IRR, blood samples will be collected for PK and immunogenicity analysis for 
ramucirumab and necitumumab, respectively, at the following time points:  (i) as close as 
possible to the onset of the IRR, (ii) at the resolution of the IRR, and (iii) 30 days following the 
IRR.
IRRs may occur during or following ramucirumab or necitumumab administration.  Patients 
should be closely monitored for signs and symptoms indicative of an IRR from the initiation of 
the infusion in an area where resuscitation equipment and other agents (such as epinephrine and 
corticosteroids) are readily available.
Signs and symptoms usually develop during or shortly after infusion and generally resolve 
within 24 hours.  Symptoms of IRRs include rigors/tremors, back pain/spasms, chest pain and/or 
tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.  In severe cases, 
symptoms include bronchospasm, supraventricular tachycardia, and hypotension.
7.7.1.1.1. Infusion-Related Reactions - Ramucirumab
Table JVDL.8 presents ramucirumab dose modification for patients who experience an IRR 
associated with ramucirumab.

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Patients must be closely monitored for a 1-hour observation period following the ramucirumab 
infusions for the first 2 infusions.  If the patient shows no evidence of an IRR with the first 2 
infusions of each study drug, no observation period is required for subsequent infusions.  In the 
event an IRR occurs thereafter, the 1-hour observation should be reinstituted.
For the first 2 ramucirumab infusions, measure blood pressure and pulse at the following time 
points:  (i) within 15 minutes prior to the infusion, (ii) after completion of the infusion, and 
(iii) at the end of the 1-hour post-infusion observation period.  For all subsequent infusions of 
ramucirumab, measure blood pressure and pulse prior to the infusion.  Measure other vital signs 
as clinically indicated.
7.7.1.1.2. Infusion-Related Reactions - Necitumumab
Hypersensitivity/IRRs were reported with necitumumab.  The onset of events usually occurred 
after the first or second administration of necitumumab.  Monitor patients closely for any 
potential adverse effects from the start of the infusion until at least 1 hour after the end of the 
infusion in an area with resuscitation equipment and other agents (for example, epinephrine or 
prednisolone equivalents) available.
Table JVDL.11 provides general treatment recommendations for hypersensitivity/IRRs to 
necitumumab. 

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Table JVDL.11.
Necitumumab Infusion-Related Reaction Treatment Guidelines
Grade 
of 
Reaction
Management Recommendations
First Occurrence
Second Occurrence
1

Decrease infusion rate by 50% for the duration of 
the infusion, and monitor patient for worsening of 
condition.a

For all subsequent infusions, premedicate with 
diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent); additional premedication may be 
administered at the investigator’s discretion.

Decrease infusion rate by 50% for the duration of 
the infusion, and monitor patient for worsening of 
condition.a

Administer dexamethasone 10 mg I.V. (or 
equivalent).

For all subsequent infusions, premedicate with 
diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent), acetaminophen 650 mg orally (or 
equivalent), and dexamethasone 10 mg I.V. (or 
equivalent); additional premedication may be 
administered at the investigator’s discretion.
2

Stop the infusion, and resume the infusion when the 
infusion reaction has resolved to ≤Grade 1; 
decrease infusion rate by 50% when the infusion 
resumes.a

Monitor patient for worsening of condition.

If necessary, administer diphenhydramine 
hydrochloride 50 mg I.V. (or equivalent), 
acetaminophen 650 mg orally for fever, and 
oxygen.

For all subsequent infusions, premedicate with 
diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent); additional premedication may be 
administered at the investigator’s discretion.

Stop the infusion, and resume the infusion when 
the infusion reaction has resolved to ≤ Grade 1; 
decrease infusion rate by 50% when the infusion 
resumes.a

Administer dexamethasone 10 mg I.V. (or 
equivalent).

Monitor patient for worsening of condition.

If necessary, administer diphenhydramine 
hydrochloride 50 mg I.V. (or equivalent), 
acetaminophen 650 mg orally for fever, and 
oxygen.

For all subsequent infusions, premedicate with 
diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent), acetaminophen 650 mg orally (or 
equivalent), and dexamethasone 10 mg I.V. (or 
equivalent); additional premedication may be 
administered at the investigator’s discretion.
3-4

Stop the infusion and disconnect the infusion tubing 
from the patient.

Administer diphenhydramine hydrochloride 50 mg 
I.V. (or equivalent), dexamethasone 10 mg I.V. (or 
equivalent), bronchodilators for bronchospasm, 
epinephrine, and other medications / treatments as 
medically indicated.

Hospital admission may be indicated.

Permanently discontinue necitumumab.
N/A
Abbreviations:  IRRs = infusion-related reactions; I.V. = intravenously; N/A = not applicable.
a Once the infusion rate has been reduced for a Grade 1 or 2 hypersensitivity/IRRs, it is recommended that the 
lower infusion rate be utilized for all subsequent infusions.  The infusion duration should not exceed 2 hours.

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7.7.1.2.
Supportive Care for Ramucirumab
7.7.1.2.1. Supportive Care by Adverse Event of Special Interest
7.7.1.2.1.1.
Hypertension
An increased incidence of severe hypertension (CTCAE Grade 3) has been reported in patients 
receiving ramucirumab compared with placebo.  In most cases, hypertension was controlled 
using standard antihypertensive treatment.  Preexisting hypertension should be controlled before 
starting ramucirumab treatment.
Monitoring of blood pressure is required during, and should occur prior to, ramucirumab therapy.  
Every attempt should be made to control blood pressure to systolic <140 mmHg and diastolic 
<90 mmHg prior to starting treatment with ramucirumab.  Routine clinical and laboratory 
monitoring is required in patients who again develop hypertension or experience a deterioration 
in previous hypertension.
7.7.1.2.1.2.
Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGFR2 pathway, 
including ramucirumab.  In ramucirumab clinical trials, the majority of events were Grade 1 or 2.  
Monitoring for the development or worsening of proteinuria during ramucirumab therapy is 
required.  Discontinue ramucirumab if the patient experiences proteinuria >3 g/24 hours or 
nephrotic syndrome.
7.7.1.2.1.3.
Thromboembolic Events
7.7.1.2.1.3.1.
Arterial Thromboembolic Events
Serious, sometimes fatal arterial thromboembolic events (ATEs), including myocardial 
infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, have been reported in 
clinical trials.
7.7.1.2.1.3.2.
Venous Thromboembolic Events
Venous thromboembolic events (VTEs) are associated with cancer; however, the incidence of 
VTEs likely varies depending on the type of cancer, stage, and intensity of imaging.  
Additionally, VTEs have been associated with some antiangiogenic therapy, although the 
incidence varies depending on the type of therapy, use of concomitant chemotherapy agents, and 
specific disease state.  VTEs have been reported from clinical studies investigating ramucirumab, 
particularly in the context of metastatic disease or in regions adjacent to implanted venous access 
devices.
7.7.1.2.1.4.
Bleeding/Hemorrhage
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding.  Severe GI hemorrhages, including fatal events, have been reported in patients with 
gastric-GEJ cancer treated with ramucirumab in combination with paclitaxel.
Serious hemorrhagic AEs have been reported from clinical studies investigating ramucirumab.  
Hemorrhagic complications are associated with some malignancies (that is, variceal bleeding 

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from portal hypertension in hepatocellular carcinoma, lower GI hemorrhage from bowel 
metastases in ovarian carcinoma), although the rate of these complications varies considerably.  
As detailed in the ramucirumab IB, the incidences of hemorrhagic events to date, significant 
background incidence of bleeding in some malignancies, and use of concomitant antiplatelet 
therapy in some of the reported cases preclude any definitive association between bleeding and 
ramucirumab, although ongoing surveillance and identification (and exclusion) of patients with 
high bleeding risk remain essential and are detailed in the inclusion/exclusion criteria.
7.7.1.2.1.5.
Gastrointestinal Perforation
An infrequent incidence of GI perforations has been associated with some antiangiogenic 
therapeutic agents, most specifically in the context of colorectal cancer (treated with combination 
regimens, including anti-VEGF antibodies and cytotoxic chemotherapy) and in advanced ovarian 
cancer.  These events may be associated with extensive abdominal/peritoneal disease burden.  
Gastrointestinal perforation has been reported from clinical studies investigating ramucirumab.  
The incidences of these events to date and presence of significant comorbidities and risk factors 
preclude any definitive association with ramucirumab, although ongoing surveillance remains 
essential.  More information about GI perforation may be found in the IB.
7.7.1.2.1.6.
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical and radiologic 
syndrome typically consisting of reversible cortical neurological dysfunction and brain-imaging 
findings of subcortical edema involving the posterior circulation, particularly the occipital lobes 
(Hinchey et al. 1996).  The symptoms of RPLS most often include generalized seizures, 
headache, delirium, and cortical blindness, although these may vary significantly and 
occasionally include focal neurological deficits (Hinchey et al. 1996; Garg 2001; Lee et al. 
2008).  Magnetic resonance imaging (MRI) represents the most reliable method for diagnosis 
(Lee et al. 2008).  Clinical symptoms and MRI abnormalities usually recover within days to 
weeks with proper management, although permanent neurologic dysfunction has been reported 
(Hinchey et al. 1996; Tajima et al. 1999; Garg 2001; Lee et al. 2008).
Across the clinical program to date, 2 cases of RPLS have been reported:  One case occurred in 
each arm of the recently completed double-blind, randomized, placebo-controlled Phase 3 
Study RAISE evaluating ramucirumab in combination with FOLFIRI versus FOLFIRI in 
combination with placebo for patients with metastatic colorectal cancer.
RPLS should be identified and treated promptly in order to minimize potential for permanent 
neurological damage.  Treatment encompasses careful control of blood pressure, withdrawal of 
potentially causative medication, and administration of anticonvulsant agents to those 
experiencing seizures (Stott et al. 2005).
7.7.1.2.1.7.
Congestive Heart Failure
An increased risk of congestive heart failure (CHF) has been associated with some 
antiangiogenic therapeutic agents, particularly in patients with metastatic breast cancer 
previously treated with anthracyclines.  A small number of CHF events (including fatal) were 

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also reported in patients who had received ramucirumab after prior treatment with anthracyclines 
in the Phase 2 and Phase 3 studies.
Patients with risk factors should be closely monitored for signs and symptoms of CHF.
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease, such as preexisting coronary artery disease or CHF.  Ramucirumab should be 
discontinued in the event of any Grade 3 or 4 events consistent with CHF.
7.7.1.2.1.8.
Fistula Formation
Because fistula formation has been associated with antiangiogenic agents, patients may be at 
increased risk for the development of fistula when treated with ramucirumab.  Some fistulas can 
be resolved with surgical procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and Cleck 
2009).
7.7.1.2.1.9.
Surgery and Impaired Wound Healing
Because ramucirumab is an antiangiogenic therapy, it may have the potential to adversely affect 
wound healing.  Ramucirumab did not impair wound healing in a study conducted in animals; 
however, the impact of ramucirumab on serious or nonhealing wounds has not been evaluated in 
humans.
7.7.1.2.1.10. Liver Failure and Other Significant Liver Injury
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  Patients with 1) cirrhosis at a level of Child-Pugh 
Class B (or worse) or 2) cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis should not be enrolled in clinical trials with 
ramucirumab.  “Clinically meaningful ascites” is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.
7.7.1.2.2. Supportive Care Agents for Ramucirumab - Guidelines
Supportive care measures may include but are not limited to antiemetic agents, opiate and 
nonopiate analgesic agents, appetite stimulants, and granulocyte and erythroid growth factors.  
Guidelines regarding the use of specific supportive care agents are presented below.
7.7.1.2.2.1.
Antiemetic Agents
Although emesis is not an expected side effect of ramucirumab, the use of antiemetic agents is 
permitted at the discretion of the investigator.  Acceptable antiemetic agents include 5-HT3
receptor antagonists (for example, ondansetron), dopamine receptor antagonists (for example, 
metoclopramide), corticosteroids (for example, dexamethasone), and others.
7.7.1.2.2.2.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.  Opiate and 
nonopiate analgesic agents are permitted (including acetaminophen/paracetamol); however, use 
of NSAIDs and/or aspirin is restricted (Appendix 7).

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7.7.1.2.2.3.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.  Examples 
include megestrol acetate, dronabinol, and others.
7.7.1.2.2.4.
Granulocyte-Colony Stimulating Factors
The as-needed use of granulocyte-colony stimulating factors is permitted at the discretion of the 
investigator based on American Society of Clinical Oncology (ASCO) guidelines (Smith et al. 
2006) (Appendix 7).
7.7.1.2.2.5.
Erythroid Growth Factors
The as-needed use of erythroid-stimulating factors (for example, erythropoietin) is permitted at 
the discretion of the investigator based on ASCO guidelines (Rizzo et al. 2008) (Appendix 7).
7.7.1.2.2.6.
Other Supportive Care Agents
The use of benzodiazepines, antidepressants, laxatives, and other agents that may be helpful in 
controlling disease-related symptoms are also permitted and encouraged, except as prohibited in 
Appendix 7.
7.7.1.3.
Supportive Care for Necitumumab by Adverse Event of Special Interest
7.7.1.3.1. Skin Reactions
Reactive treatment recommendations for skin reaction, based on the Canadian recommendations 
presented by Melosky et al. (2009), are summarized in Table JVDL.12.
Skin rash (any grade) should be treated as per Table JVDL.12.  If a patient experiences a Grade 1 
or 2 acne-like rash, necitumumab treatment should continue without dose modification or delay.  
Dose delays and or modifications for necitumumab are to be considered in case of skin reactions 
of Grade 3 or that are considered intolerable.  If a patient experiences Grade 4 skin reactions, 
treatment with necitumumab should be permanently discontinued.

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Table JVDL.12.
Managing Skin Reactions
Grade of 
Reaction
Recommendations for Management
1

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.
2

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

If clinically appropriate in the opinion of the investigator, administer oral minocycline or 
doxycycline 100 mg twice daily (or equivalent), for a minimum of 4 weeks and continuing for as 
long as rash is symptomatic.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.
3

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

Administer oral minocycline or doxycycline 100 mg twice daily (or equivalent), for a minimum of 
4 weeks and continuing for as long as rash is symptomatic.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.

Necitumumab administration will be temporarily withheld until symptoms resolve to Grade ≤2, 
but not for longer than a maximum of 6 weeks following Day 1 of the most recent treatment cycle.

Following improvement to Grade ≤2, necitumumab may be re-administered, with a dose reduction 
of 50% but not below 400 mg.  This dose may be increased to 75% of the original dose after a 
minimum of 1 treatment cycle (3 weeks), if symptoms do not recur.  If symptoms do not recur for 
another treatment cycle, the dose may be re-escalated to the initial dose.

If reactions do not resolve to Grade ≤2 after 6 weeks (that is, after withholding 2 consecutive 
doses of necitumumab), or if reactions recur or become intolerable at 50% of the original dose, 
necitumumab treatment should be permanently discontinued.

Patients who experience Grade 3 skin induration / fibrosis will be immediately discontinued from 
necitumumab.
4

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

Administer oral minocycline or doxycycline 100 mg twice daily (or equivalent), for a minimum of 
4 weeks and continuing for as long as rash is symptomatic.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.

Necitumumab administration must be immediately and permanently discontinued.
A dermatology referral may be indicated for skin reactions that do not improve following 
1-2 weeks of treatment, reactions that are severely symptomatic (for example, necrosis, 
blistering, or petechial or purpuric lesions), reactions of NCI CTCAE Grade ≥3, or reactions with 
an uncharacteristic appearance.
As with all concomitant medications/procedures, any actions taken to ameliorate skin toxicity 
will be documented in the concomitant medication module of the electronic CRF (eCRF).

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7.7.1.3.2. Conjunctivitis
For patients with treatment-related conjunctivitis <Grade 3, the investigator is advised to initiate 
symptomatic treatment and follow up observation of the event.  If the severity increases to 
Grade ≥3, or symptoms persists for >10 days after symptomatic treatment, the investigator is 
advised to refer the patient to an ophthalmologist for further evaluation and treatment.
7.7.1.3.3. Electrolyte Abnormalities
Consistent with observations with other EGFR mAbs, hypomagnesemia has been very 
commonly reported in patients treated with necitumumab in combination with cisplatin-based 
regimens.  Hypomagnesemia is considered a class effect for EGFR mAbs.  Monitor patients for 
hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia prior to each 
administration of necitumumab and after completion of necitumumab, until within normal limits.  
Prompt repletion is recommended, as appropriate.
7.7.1.3.4. Thromboembolic Events
In the Phase 3 Study JFCC, there was an increase in VTEs and ATEs in the investigational arm 
(necitumumab in combination with gemcitabine and cisplatin) compared to the active control 
arm (gemcitabine and cisplatin).  The relative risk of VTEs or ATEs was approximately 3-fold 
higher in patients with a reported history of VTEs or ATEs.
In Study JFCB (INSPIRE), which investigated necitumumab in combination with pemetrexed 
and cisplatin (PC+N) in patients with nonsquamous NSCLC, patients experienced an increased 
rate of serious thromboembolic events (including fatal events) in the PC+N Arm as compared to 
pemetrexed and cisplatin (PC) alone.  Furthermore, the addition of necitumumab did not improve 
the efficacy outcome over PC alone in advanced nonsquamous NSCLC.  
Administration of necitumumab in combination with pemetrexed and cisplatin is not 
recommended.
Discontinuation of necitumumab in patients who experience a VTE or ATE should be considered 
after a thorough benefit-risk assessment for the individual patient.
7.7.1.3.5. Pneumonia and Sepsis
During the conduct of Study JFCL (JFCL; Phase 2 study to investigate carboplatin and soluble 
paclitaxel with or without necitumumab in patients with squamous NSCLC), following the non-
blinded review of SAE cases that included reports related to pneumonia and sepsis, an imbalance 
in the number of SAEs, including fatal cases, for the necitumumab group compared with the 
paclitaxel-carboplatin group was found.
The early occurrence of a number of these cases may have indicated an issue regarding the 
enrollment of the appropriate patients.  The sponsor had therefore provided clarification and 
reinforcement of the inclusion/exclusion criteria, requesting the investigator’s particular attention 
with regard to infections and conditions predisposing to infections ongoing at the time of 
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additional reports were received, notably of cases reporting pneumonia and septic complications 
with concurrent neutropenia.
The review of the data from the Phase 3 study of necitumumab in combination with gemcitabine 
and cisplatin (JFCC; SQUIRE) did not show any evidence of an increased risk of serious lung 
infections associated with necitumumab in this combination.
Special attention should be given to patients with clinical evidence of concomitant infectious 
conditions including early signs of active infections.  Treatment of any infection should be 
initiated according to local standards.
7.7.1.3.6. Cardiorespiratory Disorders
An increased frequency of cardiorespiratory arrest or sudden death was observed with 
necitumumab. Cardiorespiratory arrest or sudden death was reported in the pivotal Study JFCC 
(SQUIRE) in 2.8% (15/538) of patients treated with necitumumab plus gemcitabine and cisplatin 
compared to 0.6% (3/541) of patients treated with chemotherapy alone.  Twelve of the 15 
patients died within 30 days of the last dose of necitumumab and had comorbid conditions, 
including history of chronic obstructive pulmonary disease (n=7), hypertension (n=5), 
hypomagnesemia (n=4), and coronary artery disease (n=3).  Eleven of the 12 patients had an 
unwitnessed death.
7.7.1.4.
Supportive Care for Osimertinib by Adverse Event of Special Interest
7.7.1.4.1. Diarrhea
After 1 month treatment with osimertinib, there is an approximate 20% chance of an AE of 
diarrhea at any point in time.  Where treatment was required, the most frequently used class of 
medication administered were antipropulsives (for example, loperamide).
Apply the following supportive care guidance for diarrhea:
Uncomplicated CTCAE v4.0 Grade ≤2 diarrhea:

Dietetic measures:
•
Stop all lactose-containing products.
•
Drink 8 to 10 large glasses of clear liquids per day.
•
Eat frequent small meals.
•
Recommend low-fat regimen enriched with rice, bananas, and apple sauce.

Pharmacological treatment:
•
Administer loperamide:  initial dose 4 mg, followed by 2 mg every 4 hours of after 
every unformed stool.
•
Grade 1 intermittent diarrhea may not require treatment.
•
Consider continuation of loperamide until diarrhea-free for 12 hours.
•
Consider electrolyte replacement, as appropriate.

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CTCAE v4.0 Grade ≥3 or any grade with complications (dehydration, fever, and/or 
Grade ≥3 neutropenia):

Dietetic measures:
•
As per Grade ≤2 diarrhea

Pharmacological treatment:
•
As per Grade ≤2 diarrhea
•
If dehydration is severe, administer octreotide and use intravenous fluids as 
appropriate.
•
Consider prophylactic antibiotics, especially if diarrhea is persistent beyond 24 hours 
or there is fever or Grade 3-4 neutropenia.
•
Consider electrolyte replacement, as appropriate, and consider more frequent 
measurement of electrolytes until AE resolves.
7.7.1.4.2. Skin Reactions
Rash Treatment Guidance:
CTCAE v4.0 Grade 1:
•
Emollient cream application, and/or
•
Topical steroid moderate strength bid, and/or
•
Topical antibiotic bid
CTCAE v4.0 Grade 2:
•
Treatment same as Grade 1
•
Consider using oral antibiotic for 6 weeks.
CTCAE v4.0 Grade ≥3:
•
Topical steroid moderate strength bid, and
•
Oral antibiotic for 6 weeks (switch to broad spectrum/gram negative cover if infection 
suspected [yellow crusts, purulent discharge, painful skin/nares])
•
Consider skin swab for bacterial culture.
Dry Skin / Xerosis Treatment Guidance:
CTCAE v4.0 Grade 1:
•
Face/Hands/Feet: over-the-counter moisturizing cream or ointment bid
•
Body:  ammonium lactate 12% cream bid or salicylic acid 6% cream bid
CTCAE v4.0 Grade 2:
•
Treatment same as Grade 1

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CTCAE v4.0 Grade ≥3:
•
Treatment same as Grade 1/2, plus
•
Eczematous areas of body: topical steroid moderate strength bid
Pruritus Treatment Guidance:
CTCAE v4.0 Grade 1:
•
Topical steroid moderate strength bid or topical antipruritic bid
CTCAE v4.0 Grade 2:
•
Topical steroid moderate strength bid or topical antipruritic bid
•
Oral antihistamine
CTCAE v4.0 Grade ≥3:
•
Oral antihistamine
•
GABA agonist (gabapentin 300 mg or pregabalin 50-75 mg every 8 hours)
Paronychia Treatment Guidance:
CTCAE v4.0 Grade 1:
•
Topical antibiotic bid and vinegar soaks#
CTCAE v4.0 Grade 2:
•
Topical antibiotic bid and vinegar soaks#
•
Topical silver nitrate weekly
CTCAE v4.0 Grade ≥3:
•
Topical antibiotic bid and vinegar soaks#
•
Topical silver nitrate weekly
•
Consider nail avulsion / removal
# Soaking fingers or toes in a 1:1 solution of white vinegar in water for 15 minutes every day
7.7.1.4.3. QTc
Patients with QT interval corrected by Fridericia formula (QTcF) prolongation to >500 msec 
should have study treatment interrupted and regular ECGs performed until resolution to 
<481 msec or recovery to baseline if baseline QTcF is >481 msec and then restarted at a reduced 
dose of 40 mg. If the toxicity does not resolve to ≤Grade 1 within 21 days, the patient will be 
permanently withdrawn from osimertinib.
7.7.1.4.4. Interstitial Lung Disease
If new or worsening pulmonary symptoms (for example, dyspnea) or radiological abnormality 
suggestive of ILD is observed, an interruption in osimertinib dosing is recommended, and the 

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Lilly study team should be informed.  A questionnaire regarding the results of the full diagnostic 
workup (including high-resolution computed tomography [HRCT], blood and sputum culture, 
and hematological parameters) will be sent to investigators.  It is strongly recommended to 
perform a full diagnostic workup to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  In the 
presence of confirmatory HRCT scans where other causes of respiratory symptoms have been 
excluded, a diagnosis of ILD should be considered and osimertinib permanently discontinued.
In the absence of a diagnosis of ILD, osimertinib may be restarted following consultation with 
the Lilly CRP.
Patients with a diagnosis of ILD will not be permitted to restart osimertinib.
7.8.
Treatment after Study Completion
The study completion will occur approximately 2 years after last patient enrolled, or when 
adequate number of events are observed for survival outcome estimation, whichever comes first.  
Investigators will continue to follow Schedule of Activities (Section 2) for all patients until 
notified by Lilly that study completion has occurred.
7.8.1. Continued Access Period
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks.  The continued 
access period begins after study completion and ends at end of trial (Figure JVDL.3).
Continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
The patient’s continued access to study treatment will end when a criterion for discontinuation is 
met (Section 8).  Continued access follow-up will begin the day after the patient and the 
investigator agree to discontinue study treatment and lasts approximately 30 (±7) days.  
Follow-up procedures will be performed as shown in the Continued Access Schedule of 
Activities (Table JVDL.4).

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a
Lilly will notify sites when the continued access period begins and ends.
b
Approximately 2 years after last patient enrolled, or when adequate number of 
events are observed for survival outcome estimation, whichever comes first.
c
End of trial occurs at the last visit or last scheduled procedure for the last 
patient.
Figure JVDL.3.
Continued access diagram.
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.  
Study Treatment Period
Study Completionb
Patient and investigator 
agree to discontinue  
study treatment
Study treatment
Continued access 
follow-up
(approximately 30 days)
Continued Access Perioda
End of Trialc

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment in the following circumstances:

The patient is enrolled in any other clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication, discontinuation 
from the study treatment occurs prior to introduction of the new agent.

The investigator decides that the patient should be discontinued from study treatment.

The patient requests that the patient be withdrawn from study treatment.

The patient is significantly noncompliant with study procedures and/or treatment.

disease progression
Patients who are discontinued from study treatment will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CRP to allow the 
inadvertently enrolled patient to continue in the study with or without study drug(s).
8.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice.

The patient becomes pregnant during the study.  See Section 9.2.3 regarding regulatory 
reporting requirements on fetal outcome and breast-feeding.

The investigator decides that the patient should be discontinued from the study.

The patient requests to be discontinued from the study.

The patient’s designee (for example, parents, legal guardian, or caregiver) requests that 
the patient be discontinued from the study.
Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Section 2).
8.3.
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.  Study site personnel are expected to make 

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diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.

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9.
Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study.
Appendix 3 provides a list of the laboratory tests that will be performed for this study.
Appendix 4 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2).
9.1.1. Efficacy Assessments at Baseline and during Study Treatment
RECIST 1.1 (Eisenhauer et al. 2009) will be applied as the primary measure for assessment of 
tumor response and date of disease progression.  Local tumor imaging (investigator assessment 
with site radiological reading) will be used.
Tumor imaging should be performed by computed tomography (CT), which is preferred for the 
majority of patients, as the more commonly used modality.  Magnetic resonance imaging (MRI) 
should only be used when CT is contraindicated or for imaging in the brain.  The same imaging 
technique should be used for a patient throughout the trial.  CT scan or MRI of chest and upper 
abdomen including both adrenal glands are required, with pelvic imaging performed if clinically 
indicated.
The subsections below describe in detail the tumor imaging and assessment measures at baseline 
and during study treatment.
9.1.1.1.
Baseline Tumor Imaging
Initial tumor imaging at screening must be performed within 21 days prior to the date of 
enrollment (assignment to treatment) or within 28 days of the first dose of study treatment.  The 
site study team must review screening images to confirm the patient has measurable disease per 
RECIST 1.1.
A contrast CT scan or MRI of the brain will be performed at baseline prior to enrollment for all 
patients (per Exclusion Criterion [21] regarding brain metastases), and thereafter every 6 weeks 
(±7 days) despite any treatment delays, if a patient had brain metastases at study entry or if 
clinically indicated. Scans performed as part of routine clinical management are acceptable for 
use as initial tumor imaging if they are of diagnostic quality and performed within the 
protocol-required time frame as described above.

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9.1.1.2.
Tumor Imaging during Study Treatment
During study treatment, tumor response will be assessed every 6 weeks (± 7 days) by 
investigator, with confirmatory assessment obtained at the next routine scheduled imaging 
time point (that is, after 6 weeks ± 7 days), despite any treatment delays.  After 24 weeks, tumor 
assessment will be conducted every 12 weeks (± 7 days). The start of treatment will be 
considered Cycle 1 Day 1 (C1D1) or the day that the first dose of any study treatment is 
administered.
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor-imaging 
assessment not less than 4 weeks from the date the response was first documented.  The tumor 
imaging for confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response or at the next scheduled scan (that is, 6 weeks ± 7 days later), whichever is 
clinically indicated.
Continue to perform imaging until whichever of the following occurs first:

disease progression confirmed by the second radiographic exam

the start of new anticancer treatment

withdrawal of consent

death

end of trial
9.1.2. Efficacy Assessments during Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted per the Schedule of 
Activities (Section 2).
Tumor assessments may continue for patients who discontinue from the study treatment for 
reasons other than disease progression every 6 to 12 weeks depending on standard of care.
9.1.3. Efficacy Measures
The objective response rate (ORR) is the proportion of enrolled patients who have received 
any amount of either study drug, have at least 1 postbaseline tumor image, and achieve a best 
overall response of complete response (CR) or partial response (PR).
Duration of response (DOR) is defined only for responders (patients with a confirmed CR or 
PR).  It is measured from the date of first evidence of a confirmed CR or PR to the date of 
objective progression or the date of death due to any cause, whichever is earlier.  If a responder 
is not known to have died or have objective progression as of the data inclusion cutoff date, DOR 
will be censored at the date of the last complete objective progression-free disease assessment.
Disease Control Rate (DCR) is defined as the proportion of enrolled patients who have a best 
overall response of CR, PR, or stable disease.
Progression-free survival (PFS) is defined as the time from the date of first study treatment 
until the date of the first observed radiographically documented PD or death due to any cause, 
whichever is earlier.  The censoring is taken in the following order:

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-
if a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the enrollment date, regardless of whether or not objectively determined 
disease progression or death has been observed for the patient; otherwise,
-
if a patient is not known to have died or have objective progression as of the data 
inclusion cutoff date for the analysis, the PFS time will be censored at the last complete 
objective progression-free disease assessment date.
ORR, DOR, DCR, and PFS will be assessed based on RECIST 1.1 (Eisenhauer et al. 2009).
Overall survival (OS), including 1- and 2- year survival rates, is determined from the date of 
first study treatment until death due to any cause.  If the patient was alive at the data inclusion 
cutoff date for the analysis (or was lost to follow-up), OS will be censored on the last date the 
patient was known to be alive.
9.1.4. Appropriateness of Assessments
The measures used in this study are consistent with those used in most conventional oncology 
trials.
9.2.
Adverse Events
The investigator will use CTCAE Version 4.0 (NCI 2009) to assign AE terms and severity 
grades.
Investigators are responsible for:

monitoring the safety of patients in this study and for alerting Lilly or its designee to any 
event that seems unusual, even if this event may be considered an unanticipated benefit 
to the patient

the appropriate medical care of patients during the study

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study treatment or the study, or that caused 
the patient to discontinue study drug(s) before completing the study.  The patient should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or 
is reasonably explained.  Frequency of follow-up evaluation is left to the discretion of 
the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via CRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, study site personnel 
will record via CRF any change in the preexisting conditions and any new conditions as AEs.  
Investigators should record their assessment of the potential relatedness of each AE to study 
procedure or study treatment via CRF.

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The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies. A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuations that result 
from AEs to Lilly or its designee via CRF, clarifying, if possible, the circumstances leading to 
the dose modification or discontinuation of treatment.
9.2.1. Adverse Events of Special Interest
9.2.1.1.
Infusion-Related Reactions - Ramucirumab and Necitumumab
Any treatment-related IRRs are defined according to the CTCAE Version 4.0 definition (General 
Disorders and Administration Site Conditions).  Symptoms occurring during or following 
infusion of investigational therapy may also be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome (Immune System Disorders).  In the 
setting of symptoms occurring during or following infusion of investigational therapy, 
investigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.
9.2.1.2.
Adverse Events of Special Interest - Ramucirumab
Section 7.7.1.2.1 describes supportive care measures for each ramucirumab AESI.  
Table JVDL.8 presents the dose-modification guidelines for ramucirumab AESIs.  Contact the 
Lilly CRP if questions arise concerning AESIs.
9.2.1.3.
Adverse Events of Special Interest - Necitumumab
Section 7.7.1.3 describes supportive care for necitumumab AESIs.  Table JVDL.11 provides 
general treatment recommendations for hypersensitivity/IRRs to necitumumab.  Contact the Lilly 
CRP if questions arise concerning AESIs.
9.2.1.4.
Adverse Events of Special Interest – Osimertinib
Section 7.7.1.4 describes supportive care for osimertinib AESIs.  Contact the Lilly CRP if 
questions arise concerning AESIs.
9.2.2. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

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
considered significant by the investigator for any other reason:  important medical events 
that may not result in death, be life-threatening, or require hospitalization may be 
considered serious, based upon appropriate medical judgment.
Although all AEs after signing the ICF are recorded in the CRF, SAE reporting begins after the 
patient has signed the ICF and has received study treatment.  However, if an SAE occurs after 
signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedure.
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly-approved method.  If alerts are issued via telephone, they are 
to be immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported.  However, to fulfill regulatory requirements any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment.
9.2.3. Pregnancy
Cases of pregnancy that occur during maternal or paternal exposures to investigational products 
(ramucirumab, necitumumab, and osimertinib) should be reported within 24 hours.  Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
congenital abnormality, fetal death, intrauterine death, miscarriage and stillbirth, or other 
disabling or life-threatening complication to the mother or newborn must be reported as AEs.  
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  The following additional measures will be taken in the case of pregnancy:

A patient who becomes pregnant will be immediately removed from the study.

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
It is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a patient (spontaneously reported to them) that occurs during the trial or 
within 120 days of completing the trial or 30 days following cessation of treatment if the 
patient initiates new anticancer therapy, whichever is earlier.

All patients who become pregnant must be contacted by the site at least monthly and the 
patient’s status documented to the completion/termination of the pregnancy; the 
investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.
9.2.4. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and associated 
detailed guidances.
9.2.5. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or drug delivery system so that the 
situation can be assessed.
9.3.
Treatment of Overdose
Refer to the ramucirumab, necitumumab, and osimertinib IBs.
9.4.
Safety
9.4.1. Other Safety Measures
For each patient, ECGs, vital signs, laboratory tests, or other tests should be collected as shown 
in the Schedule of Activities (Section 2).
9.4.1.1.
Electrocardiograms
For each patient, 12-lead digital ECGs will be collected according to the Schedule of Activities
(Section 2) as triplicate ECGs at baseline and single ECGs in subsequent cycles.  Patients must 
be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection.

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Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high-quality records.
Electrocardiograms will be interpreted by the investigator or qualified designee at the site as 
soon after the time of ECG collection as possible, and ideally while the patient is still present, to 
determine whether the patient meets entry criteria and for immediate patient management, should 
any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/ QTcF interval from baseline, or 
other clinically significant quantitative or qualitative change from baseline, is present, the 
investigator will assess the patient for symptoms (for example, palpitations, near syncope, or 
syncope) and to determine if the patient can continue in the study.  The investigator or qualified 
designee is responsible for determining if any change in patient management is needed and must 
document his/her review of the ECG printed at the time of evaluation.
The investigator (or qualified designee) must document his/her review of the ECG printed at the 
time of evaluation.  Local ECG findings at baseline and end of treatment, and any on study 
clinically significant abnormal findings, will be reported into the eCRF and any alert reports.
9.4.2. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP 
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review:

trends in safety data

laboratory analytes (Appendix 3)

adverse events, including ramucirumab and necitumumab AESI (Section 9.2.1).

If a patient experiences elevated ALT 5× ULN and elevated total bilirubin 2× ULN, 
clinical and laboratory monitoring should be initiated by the investigator.

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests.  See Appendix 5.
Safety data will be reviewed during the study. A safety review committee (SRC) consisting of 
the Lilly CRP, Global Patient Safety physician, statistician, the primary investigator, and ad hoc 
SRC members as needed will be responsible for review of safety data.
9.5.
Pharmacokinetics
Pharmacokinetic samples will be collected as shown in Appendix 4.
Blood samples will be drawn for all patients for the assessment of ramucirumab and 
necitumumab concentrations in serum (also known as bioanalytical samples).  Sampling times 

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were selected to coincide with expected Cmax and Cmin and with consideration to draw minimum 
volume of blood from patients and ensuring that the patients do not to need to make an extra visit 
to provide these samples.
Instructions for the collection and handling of bioanalytical blood samples will be provided by 
the Sponsor.  The actual start and end date and time of ramucirumab and necitumumab infusion 
administration must be recorded on the eCRF.  The actual date and time that each bioanalytical 
blood sample was drawn must be recorded on the laboratory accession page after the sample is 
drawn.
Ramucirumab and necitumumab concentrations in bioanalytical serum samples will be measured 
using a validated assay methodology in a laboratory designated by the Sponsor.
Bioanalytical samples collected to measure ramucirumab and necitumumab concentration will be 
retained for a maximum of 1 year following the last patient visit for the study.
9.6.
Pharmacodynamics
Pharmacodynamics has been included in Section 9.8.
9.7.
Pharmacogenomics
9.7.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in 
Appendix 4, where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to study treatment
and to investigate genetic variants thought to play a role in NSCLC.  Assessment of variable 
response may include evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number. These samples and any data generated can 
be linked back to the patient only by the study site personnel.  Samples will be retained for a 
maximum of 15 years after the last patient visit for the study, or for a shorter period if local 
regulations and/or ethical review boards (ERBs) impose shorter time limits, at a facility selected 
by the sponsor.  This retention period enables use of new technologies, response to questions 
from regulatory agencies, and investigation of variable response that may not be observed until 
later in drug development or when the drugs become commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing technologies include whole genome and exome
sequencing, genome-wide association studies, candidate gene studies, and epigenetic analyses.  
Regardless of the technology utilized, data generated will be used only for the specific research 
scope described in this section.

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9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety), and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including 
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular 
elements.
As part of Lilly’s ongoing efforts to understand the relationship between cancer, genetics, and 
response to therapy, this study will analyze biomarkers relevant to study treatment, angiogenesis, 
immune functioning, and/or NSCLC and/or for related research methods or validation of 
diagnostic tools or assays.
Samples for biomarker research will be collected as specified in Appendix 4, where local 
regulations allow. It is possible that biomarker data for patients in the study have already been 
generated from samples that were collected and analyzed prior to enrolling in this trial. This 
may include data generated from genetic analyses. If available, these data may be requested 
from medical records for use in the research described in Sections 9.8.1 and 9.8.2.
9.8.1. Samples for Non-pharmacogenetic Biomarker Research
Plasma samples for nonpharmacogenetic biomarker research will be collected as specified in
Appendix 4, where local regulations allow.
Samples will be examined for biomarkers related to NSCLC, variable response to study 
treatment, the mechanism of action of ramucirumab (for Cohort A), the EGFR pathway, immune 
functioning, and/or for research-related methods or validating diagnostic tools or assays.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility 
selected by the sponsor.  This retention period enables use of new technologies, response to 
questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in drug development or when the drugs become commercially available.
9.8.2. Tumor Tissue Samples
Tumor tissue will be examined for biomarkers related to NSCLC, ramucirumab, necitumumab, 
the EGFR pathway, immune functioning, and/or research-related methods or validating 
diagnostic tools or assay.
Collection of the following tumor tissue sample(s) is required for all patients in order to 
participate in this study:
Formalin-fixed paraffin-embedded tumor tissue obtained from a biopsy taken after disease 
progression on the most recent EGFR TKI treatment from the primary tumor or metastatic site 

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should be provided as a block or unstained slides.  Due diligence should be used to make sure 
that tumor sample (not a normal adjacent or a tumor margin sample) is provided.  Pathology 
report accompanying archival tissue may also be requested. The report must be coded with the 
patient number. Personal identifiers, including the patient’s name and initials, must be removed 
from the institutional pathology report prior to submission.  Archival blocks will be sectioned 
and returned to the study site. Slides and tissue samples collected on-study will not be returned.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility 
selected by the Sponsor.  This retention period enables use of new technologies, response to 
questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in drug development or when the drugs become commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  However, existing technologies, including mutation profiling, copy number 
variability, gene expression, and/or immunohistochemistry, may be performed on these tissue 
samples to assess potential associations with these biomarkers and clinical outcomes.
In addition to the required tumor tissue and biomarker samples discussed in Sections 9.8.1 and 
9.8.2, patients may be asked to undergo optional collection of an additional biopsy specimen and 
blood sample after treatment with study drug(s) has been initiated, including potentially after 
disease progression.  Such additional biopsies should be performed only if they do not create 
undue risk to the patient.  If these additional samples are requested, they will be used to further 
investigate molecular features that may explain treatment response and resistance mechanisms.
9.8.3. Immunogenicity Assessments
Immunogenicity samples will be collected at baseline for all patients and when an IRR occurs.  
The immunogenicity assessments will be performed only for those patients who experienced an 
IRR.
Blood samples for immunogenicity testing will be collected as shown in Appendix 4 to 
determine antibody production against ramucirumab (for Arm A and Cohort A) or necitumumab 
(for Arm B).  Immunogenicity will be assessed by validated immunogenicity assays designed to 
detect anti-ramucirumab and anti-necitumumab antibodies in the presence of ramucirumab (for 
Arm A and Cohort A) and necitumumab (for Arm B), respectively.  Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of ramucirumab (for Arm 
A and Cohort A) or necitumumab (for Arm B).
Samples will be retained for a maximum of 15 years after last the patient visit for the study, or 
for a shorter period if regulations and ERBs impose shorter time limits, at a facility selected by 
the sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
ramucirumab or necitumumab.
9.9.
Health Economics
Not applicable.

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10. Statistical Considerations
10.1. Sample Size Determination
The primary objective for the Dose-Finding Portion and the Dose-Expansion Portion is to 
evaluate safety and tolerability. The sample size of the Dose-Expansion Portion is selected to 
allow adequate assessment of safety at the recommended doses for ramucirumab in combination 
with osimertinib.
The following sample sizes apply to each portion of the study:
Dose-Finding Portion: up to 12 DLT-evaluable patients each for Arms A and B
Dose-Expansion Portion: 22 patients for Cohort A 
During the Dose-Expansion Portion, 22 patients in Cohort A will be treated, to provide a 
preliminary assessment of tumor response and an assessment of safety. All patients enrolled in 
the Dose-Finding Portion (Arm A) will also be included for all planned analyses. The null 
hypothesis is based on the assumption that the ORR is no greater than 60% and the target 
treatment effect (alternative response rate) of the combination treatment on ORR is greater than 
70% and 75%, respectively. Based on these assumptions, a sample size of n=25 provides 
statistical power of approximately 58% and 78%, respectively, with a 1-sided 0.20 significance 
level.
10.2. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly.
For the Dose-Finding Portion, a 3+3 dose de-escalation design will be used to assess the safety 
of ramucirumab or necitumumab in combination with osimertinib. Additional patients will be 
enrolled in a dosing schedule to achieve the minimum of 3 evaluable patients for each arm, if 
dropouts or dose interruptions or reductions occur that result in a patient being nonevaluable for 
DLTs. Data will be reviewed by dose schedule group (3 patients) for each arm.
For the Dose-Expansion Portion, final analysis will occur upon the completion of the study.  
Primary analysis will be conducted approximately 6 months after last patient receives initial 
dose.  All patients enrolled in the Dose-Finding Portion (Arm A) and the Dose-Expansion 
Portion (Cohort A) will be included for all planned analyses. Patients enrolled in Arm B of the
Dose-Finding Portion will be analyzed separately.
Descriptive statistics will be derived where appropriate. The rate of DLTs will be summarized
by arm; dose exposure for each study drug will be calculated.
Pharmacodynamics/ Biomarkers
Pharmacodynamic and tailoring biomarker analyses will be based on the subset of patients from 
the above cohorts from whom a valid assay result (according to laboratory guideline) has been 
obtained.
General

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Additional details may be provided in a separate statistical analysis plan (SAP) for the study.  
Any change to the data analysis methods described in the protocol will require an amendment
ONLY if it changes a principal feature of the protocol.  Additional exploratory analyses of the 
data will be conducted as deemed appropriate.
10.3. Statistical Analyses
10.3.1. Efficacy Analyses
ORR and DCR (according to RECIST 1.1), and the corresponding confidence intervals, will be 
provided for Arm A and Cohort A. Patients enrolled in Arm B of the Dose-Finding Portion will 
be analyzed separately.  Time-to-event variables, such as time to response, DOR, PFS, and OS,
will be estimated by Kaplan-Meier (1958) methodology. Presentations of efficacy may include 
patients enrolled in the Dose-Finding Portion with the same treatment schedule.
10.3.2. Safety Analyses
All patients who receive at least 1 dose of ramucirumab, necitumumab, or osimertinib will be 
evaluated for safety and toxicity.  Adverse event terms and severity grades will be assigned by 
the investigator using CTCAE Version 4.0.
Safety analyses will include summaries of the following:

DLTs:  the number of patients who experienced any DLTs during DLT observation 
period will be summarized by dose schedule in the Dose-Finding Portion for each arm.

AEs, including severity and possible relationship to study drug

AEs by Medical Dictionary for Regulatory Activities® System Organ Class (SOC) by 
decreasing frequency of Preferred Term within SOC

Laboratory and nonlaboratory AEs by CTCAE term and maximum CTCAE grade 
(regardless of causality and at least possibly related to study treatment)
10.3.3. Other Analyses
10.3.3.1. Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, as defined in the SAP, or 
discontinuing (overall and by reason for discontinuation).  A summary of all important protocol 
deviations will be provided.
10.3.3.2. Patient Characteristics
Patient characteristics which will be summarized by:

Patient demographics will be reported using descriptive statistics. Demographic data are 
collected and reported to demonstrate that the study population represents the target 
patient population considered for regulatory approval.

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
Baseline disease characteristics will be summarized by presenting frequency counts and 
percentages (for example, for pathological diagnosis [histological or cytological] and 
disease stage).

Disease-related therapies will include prior anticancer treatments and prior radiotherapies 
(such as type of therapy, regimen, and prior surgery).
Other patient characteristics will be summarized as deemed appropriate.
10.3.3.3. Concomitant Therapy
A summary of prior and concomitant medications by treatment arm will be reported.
10.3.3.4. Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation anticancer therapies will 
be provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
class and/or name.
10.3.3.5. Treatment Compliance
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated patients by treatment arm.
10.3.3.6. Pharmacokinetic Analyses
Serum Cmin and concentrations at 1 hour post end of infusion (approximately Cmax) for 
ramucirumab and necitumumab will be summarized by descriptive statistics.
10.3.3.7. Immunogenicity Analyses
Immunogenicity samples will be collected at baseline for all patients and when an IRR occurs.  
The immunogenicity analyses will be performed only for those patients who experienced an IRR.
Immunogenicity (anti-ramucirumab and anti-necitumumab antibody) incidence will be tabulated
for those individuals who experience an IRR, and correlation to ramucirumab and necitumumab 
drug level, activity, and safety will be assessed, as appropriate, respectively.  The measures that 
will be analyzed include the presence of baseline antidrug antibodies (ADA), treatment-emergent 
ADA, neutralizing ADA, and incidence of ADA related to IRRs.
10.3.3.8. Biomarker Analysis
Biomarkers may be summarized and assessed for correlations with clinical outcomes.
10.3.4. Interim Analysis
For the Dose-Finding Portion, safety and PK data will be reviewed on an arm-by-arm basis 
during the study. The purpose of these data reviews is to evaluate the safety and tolerability for 
each dose schedule and determine if a DLT has been observed. The investigators and the Lilly 
study team will evaluate the totality of data to determine whether or not to move into the 
Dose-Expansion Portion.

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Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, 
Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, 
Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, 
Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, 
Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish 
Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and 
Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line 
treatment for European patients with advanced EGFR mutation-positive non-small-cell lung 
cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol.
2012;13(3):239-246.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, 
Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, 
Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in 
patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol.
2013;31(27):3327-3334.
Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, 
Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, 
Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with 
advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): 
an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-1244.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, 
Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, 
Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of 
Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N 
Engl J Med. 2005;353(2):123-132.
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, 
Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF. Clinical 
and biological features associated with epidermal growth factor receptor gene mutations in 
lung cancers. J Natl Cancer Inst. 2005;97(5):339-346.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, 
Cantor SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, 
Schwartzberg L, Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, 
Wolff AC. Update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205.

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Stahel RA, Dafni U, Gautschi O, Felip E, Curioni-Fontecedro A, Peters S, Massutí B, 
Cardenal F, Aix SP, Früh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, 
Carcereny E, Sanchez Ronco M, Molina MA, Rosell R. A phase II trial of erlotinib (E) and 
bevacizumab (B) in patients with advanced non-small-cell lung cancer (NSCLC) with 
activating epidermal growth factor receptor (EGFR) mutations with and without T790M 
mutation. The Spanish Lung Cancer Group (SLCG) and the European Thoracic Oncology 
Platform (ETOP) BELIEF trial. European Cancer Congress 2015. Abstract number: 3BA.
Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a 
misnomer reviewed. Intern Med J. 2005;35(2):83-90.
Tagrisso (osimertinib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 
2015.
Tajima Y, Isonishi K, Kashiwaba T, Tashiro K. Two similar cases of encephalopathy, possibly a 
reversible posterior leukoencephalopathy syndrome: serial findings of magnetic resonance 
imaging, SPECT and angiography. Intern Med. 1999;38(1):54-58.
Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, 
Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, 
Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators.
Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-
line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an 
open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763-774.
Wheler JJ, Tsimberidou AM, Falchook GS, Zinner RG, Hong DS, Fok JY, Fu S, Piha-Paul SA, 
Naing A, Kurzrock R. Combining erlotinib and cetuximab is associated with activity in 
patients with non-small cell lung cancer (including squamous cell carcinomas) and wild-type 
EGFR or resistant mutations. Mol Cancer Ther. 2013;12(10):2167-2175.
Yoshimura N, Okishio K, Mitsuoka S, Kimura T, Kawaguchi T, Kobayashi M, Hirashima T, 
Daga H, Takeda K, Hirata K, Kudoh S. Prospective assessment of continuation of erlotinib or 
gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition 
of pemetrexed. J Thorac Oncol. 2013;8(1):96-101.
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, 
Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, 
Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with 
advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a 
multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742.

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Appendix 1. Abbreviations and Definitions
Term
Definition
ADA
antidrug antibody
AE
Adverse event:  any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product.
AESI
adverse event of special interest 
ALT
alanine aminotransferase 
ANC
absolute neutrophil count 
aPTT
activated partial thromboplastin time 
ASCO
American Society of Clinical Oncology 
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
AUCss
area under the plasma concentration-time curve at steady state
BCRP
breast cancer resistance protein
β-hCG
beta human chorionic gonadotropin 
BICR
blinded independent central review 
C1D1
Cycle 1 Day 1
CHF
congestive heart failure
CI
confidence interval
Cmax
maximum concentration
Cmin
minimum concentration
Cmin,ss
minimum concentration at steady state
CR
complete response
CRF
case report form 

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CRP
Clinical research physician:  Individual responsible for the medical conduct of the 
study.  Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer.
CRS
clinical research scientist
CSR
clinical study report 
CT
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CYP
cytochrome P450
DCR
disease control rate
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
effective method of 
contraception
male condom with spermicide, female condom with spermicide, diaphragm with 
spermicide, cervical sponge, or cervical cap with spermicide.
Also see the definition of highly effective method of contraception.
EGFR
epidermal growth factor receptor
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
EU
European Union
FOLFIRI
irinotecan, 5-fluorouracil, and folic acid
FSH
follicle-stimulating hormone
GCP
good clinical practice

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GEJ
gastroesophageal junction 
GI
gastrointestinal 
highly effective 
method of 
contraception
combined oral contraceptive pill and mini-pill, NuvaRing®, implantable contraceptives, 
injectable contraceptives (such as Depo-Provera®), intrauterine device (such as 
Mirena® and ParaGard®), contraceptive patch for women <90 Kg (<198 pounds), total 
abstinence, or vasectomy.
Also see the definition of effective method of contraception.
HIV
human immunodeficiency virus
HR
hazard ratio
HRCT
high-resolution computed tomography
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IgG
immunoglobulin G
ILD
interstitial lung disease
INR
International Normalized Ratio
interim analysis
An interim analysis is an analysis of clinical trial data conducted before the final 
reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRR
infusion-related reaction
I.V.
intravenous 
IWRS
interactive web-response system
mAb
monoclonal antibody
mCRC
metastatic colorectal cancer
mPFS
median progression-free survival
MRI
magnetic resonance imaging

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MTD
maximal tolerated dose
MUGA
Multiple-gated acquisition
NC
not calculable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute 
NSAIDs
nonsteroidal anti-inflammatory agents
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease 
PFS
progression-free survival
PI
package insert
PK
Pharmacokinetics
PopPK
population pharmacokinetics
PR
partial response
PRO
patient-reported outcome
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
QD
once daily
QTc
corrected QT interval
QTcF
QT interval corrected by Fridericia formula
randomize
the process of assigning patients to an experimental group on a random basis
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.

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re-screen
to screen a patient who was previously declared a screen failure for the same study
RNA
ribonucleic acid
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event
SAP
Statistical Analysis Plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SRC
safety review committee
SUSARs
suspected unexpected serious adverse reactions
T3
triiodothyronine
T4
thyroxine
TEAE
Treatment-emergent adverse event:   an untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TKI
tyrosine kinase inhibitor
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor
VEGFR2
vascular endothelial growth factor receptor 2
VTE
venous thromboembolic event

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Appendix 2. Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any study procedures and prior to the administration of study treatment.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial.
Ethical Review
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on GCP.
The investigator must give assurance that the ERB was properly constituted and convened as 
required by ICH guidelines and other applicable laws and regulations.  
The study site’s ERBs should be provided with the following:

the current IB and updates during the course of the study

the ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 

applicable ICH GCP Guidelines

applicable laws and regulations.
Some obligations of Lilly may be assigned to a third-party organization.  
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data.

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Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
Protocol Signatures
Lilly’s responsible medical officer will approve the protocol, confirming that, to the best of his 
or her knowledge, the protocol accurately describes the planned design and conduct of the study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final clinical study report 
for this study, indicating agreement that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study. 
The investigator with the most enrolled patients will serve as the CSR coordinating investigator.  
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.
The Lilly responsible medical officer and statistician will approve the final CSR for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide Lilly, 

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applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into Lilly-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 3. Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology – Local lab
Clinical Chemistry – Local lab and Central laba
Erythrocyte (RBC) 
Hemoglobin (HGB)
Serum Concentrations of:
Hematocrit (HCT)
Alkaline phosphatase
Platelet (PLT)
Alanine aminotransferase (ALT)
Leukocytes (WBC)
Aspartate aminotransferase (AST)
Absolute Neutrophil Count
Lactate dehydrogenase (LDH)
Lymphocytes
Creatine kinase (CK)
Monocytes
Eosinophils
Basophils
Creatinine 
Uric acid 
Calcium
Glucose 
Thyroid Function Tests – Central lab
Albumin
Thyroid stimulating hormone (TSH)
Phosphorus
Total triiodothyronine (T3)
Potassium
Free thyroxine (T4)
Sodium
Magnesium
Total bilirubin
Urinalysis – Local lab
Routine dipstick measurements, and if clinically 
indicated, microscopic analysis.
Proteinb
Blood
Glucose
Direct bilirubin (if total bilirubin is elevated above 
the upper limit of normal)
Total protein
Blood urea nitrogen (BUN)
Chloride
Specific gravity
Coagulation Test – Local lab
Prothrombin time (PT) or International normalized 
ratio (INR) 
Partial thromboplastin time (PTT) or activated PTT 
(aPTT)
Pregnancy Testc – Local lab
Urine or Serum
β-human chorionic gonadotropin (β-hCG)
Abbreviations:  RBC = red blood cell; WBC = white blood cell.
a
Central chemistry laboratories will be required to determine patient eligibility at baseline; local chemistry 
laboratory testing will not be permitted for a determination of patient eligibility. Local chemistry laboratory 
results may be used for on-study dosing decisions; if so, chemistry testing must also still be performed by the 
central laboratory. These central chemistry laboratory results will be used for subsequent safety analyses.
b If urine dipstick or routine analysis indicates proteinuria ≥2+, a 24 hour urine collection (to assess protein) must 
be obtained.
c
Minimum sensitivity 25 IU/L or equivalent units of β-human chorionic gonadotropin (β-hCG), for women of 
childbearing potential (WOCBP).  If urine pregnancy results cannot be confirmed as negative, a serum pregnancy 
test will be required.

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Appendix 4. Sampling Schedule for Pharmacokinetics, 
Immunogenicity, Biomarkers, and Pharmacogenetics
It is essential that the exact infusion start and stop times (actual clock readings), as well as 
infusion parameters (such as, type of infusion pump, flow rate settings) are recorded.  The exact 
time of collection of each venous blood sample will be based on the clock used to record 
infusion times.  It is essential that the pharmacokinetic blood samples not be withdrawn from the 
same site as the drug infusion.

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Sampling Schedule for Pharmacokinetics, Immunogenicity, Biomarkers, and 
Pharmacogenetics – Ramucirumab Arm and Cohort
Visit/Cycle Day
Sample Time
PKa
(Serum)
IGa
(Serum)
Biomarker
(Plasma)
PGf
(Whole Blood)
Day -14 to Day 1 
of Cycle 1
Predoseb
X
X
X
X
Day 1 of Cycle 1
1 h post end of ramucirumab 
infusionc
X
Day 1 of Cycle 2
Predosed
X
Day 1 of Cycle 4
Predosed
X
Day 1 of Cycle 5
Predosed
X
Day 1 of Cycle 7
Predosed
X
X
Day 1 of Cycle 13
Predosed
X
Short-term 30-day 
Safety Follow-Up 
Period
Anytimee
X
Note: It is essential that the dosing days, dosing times, draw dates and draw times are accurately recorded.
Abbreviations:  IG = immunogenicity; PG = pharmacogenetic(s); PK = pharmacokinetic(s).
a
In the event of an infusion-related reaction, a blood sample will be collected for both PK and immunogenicity 
analysis as close to the onset of the reaction as possible, at the resolution of the event, and 30 days following the 
event.
b Prior to the first infusion (baseline; may be obtained within 14 days prior to the initial infusion of 
ramucirumab/placebo on Day 1 Cycle 1).
c
Collection window: within 1 to 1.5 hours after the end of ramucirumab infusion.
d Collection window: within 3 hours prior to ramucirumab infusion.
e
When applicable, plasma should be collected as close as possible to the time of disease progression during the 
study treatment period.  If for any reason the post progression sample cannot be collected at the time of 
progression, this should be done during the 30-day follow-up period.  The post progression sample should be 
collected before the initiation of any new anticancer therapy.
f
Mandatory whole blood sample will be used for pharmacogenetic analysis.  It is highly recommended to draw the 
whole blood sample prior to the first dose.  However, it can be collected later during the study if necessary.

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Sampling Schedule for Pharmacokinetics, Immunogenicity, Biomarkers, and 
Pharmacogenetics – Necitumumab Arm
Visit/Cycle Day
Sample Time
PKa
(Serum)
IGa
(Serum)
Biomarker
(Plasma)
PGf
(Whole Blood)
Day -14 to Day 1 
of Cycle 1
Predoseb
X
X
X
X
Day 1 of Cycle 1
1 h post end of necitumumab
infusiond
X
Day 1 of Cycle 3
Predosec
X
1 h post end of necitumumab 
infusiond
X
Day 1 of Cycle 5
Predosec
X
X
Day 1 of Cycle 7
Predosec
X
Day 1 of Cycle 9
Predosec
X
Short-term 30-day 
Safety Follow-Up 
Period
Anytimee
X
Note:  It is essential that the dosing days, dosing times, draw dates and draw times are accurately recorded.
Abbreviations:  IG = immunogenicity; PG = pharmacogenetic(s); PK = pharmacokinetic(s).
a
In the event of an infusion-related reaction, a blood sample will be collected for both PK analysis and 
immunogenicity as close to the onset of the reaction as possible, at the resolution of the event, and 30 days 
following the event.
b Prior to the first infusion (baseline; may be obtained within 14 days prior to the initial infusion of necitumumab 
on Day 1 Cycle 1).
c
Prior to necitumumab infusion.
d 1 hour ±10 minutes post end of necitumumab infusion.
e
When applicable, plasma should be collected as close as possible to the time of disease progression during the 
study treatment period.  If for any reason the post progression sample cannot be collected at the time of 
progression, this should be done during the 30-day follow-up period.  The post progression sample should be 
collected before the initiation of any new anticancer therapy.
f
Mandatory whole blood sample will be used for pharmacogenetic analysis.  It is highly recommended to draw the 
whole blood sample prior to the first dose.  However, it can be collected later during the study if necessary.

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Appendix 5. Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa, b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
GGT
CPK
Anti-Smooth Muscle Antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = Gamma-glutamyl transferase; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 6. Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.
For serum creatinine concentration in 
mg/dL:
CrCl =
(mL/min) 
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(mL/min)
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a
Age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault 1976.

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Appendix 7. Protocol JVDL Restricted and Prohibited 
Concomitant Therapy
The table below describes medications, treatments, and drug classes restricted or prohibited, with 
exceptions and conditions for use during the study treatment period (there are no prohibited 
therapies during the follow- up period).  Patients who, in the assessment by the investigator, 
require the use of any of the prohibited treatments for clinical management should be removed 
from the trial.  Patients may receive other supportive therapy or vaccinations that the investigator 
deems to be medically necessary.
In addition, there are potential interactions between osimertinib and either CYP3A4 inducers or 
CYP3A4 inhibitors.  Drugs that induce CYP3A4, such as carbamazepine, fosphenytoin, 
oxcarbazepine, pentobarbital, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. 
John’s wort, may reduce the effects of osimertinib through increased osimertinib metabolism and 
decreased plasma concentrations.  Therefore, avoid strong CYP3A4 inducers if possible.  For 
strong CYP3A4 inhibitors, avoid concurrent administration if possible; however, if no alternative 
exists, the patient should be closely monitored for signs of toxicity.

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Therapy
As 
Needed
Chronic 
Use
Exceptions or Conditions for Use
Anti-platelet therapy
yes
no
Chronic use of aspirin up to 325 mg/day is permitted.
Anticoagulation therapy
no
Yes, with 
restrictions
At enrollment, patients on full-dose anticoagulation must be on 
a stable dose (minimum duration 14 days) of oral anticoagulant 
or low molecular weight heparin or similar agent.  If on 
warfarin, the patient must have an INR ≤3 and no active 
bleeding or pathological condition present that carries a high 
risk of bleeding (e.g., tumor involving major vessels or known 
varices).
Anti-cancer biological 
therapy
no
no
Chemotherapy
no
no
Colony-stimulating 
factors
yes
no
Follow local guidelines.
Erythroid growth factors
yes
no
Follow local guidelines.
Experimental medicines 
or investigational 
agents
no
no
Other than ramucirumab, necitumumab, or osimertinib
Glucocorticoids
no
no
Systemic glucocorticoids are permitted to modulate symptoms 
from an event of clinical interest of suspected immunologic 
etiology.  The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor.
Note:  Inhaled steroids are allowed for management of asthma.
Immunotherapy 
no
no
Other than inhaled steroids and vaccinations 
NSAIDs
yes
no
Chronic use of aspirin up to 325 mg/day is permitted.
In addition, in certain medical situations, NSAIDs may be the 
best treatment option (for example, for pain management). 
Increased risk of bleeding should be considered by the treating 
physician and the patient. 
Radiation therapy
no
no
Localized radiation therapy to a symptomatic, solitary lesion or 
to the brain may be allowed after consultation with the Sponsor.
BCRP
Yes
Yes
Monitor for AEs (including CK) of the BCRP substrate (e.g., 
rosuvastatin, sulfasalazine) and signs of changed tolerability of 
osimertinib, unless otherwise instructed in its approved labeling, 
when coadministered with osimertinib.
If the patient experiences any potentially relevant AEs 
suggestive of muscle toxicity including unexplained muscle 
pain, tenderness, or weakness, particularly if accompanied by 
malaise or fever, rosuvastatin must be stopped and any 
appropriate further management should be taken.
Abbreviations:  BCRP = breast cancer resistance protein; INR = international normalized ratio; NSAIDs = 
nonsteroidal anti-inflammatory drugs.

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Appendix 8. Protocol Amendment I4T-MC-JVDLc 
Summary An Open-Label, Multicenter, Phase 1 Study 
with Expansion Cohorts of Ramucirumab or 
Necitumumab in Combination with Osimertinib in 
Patients with Advanced T790M-Positive EGFR-Mutant 
Non-Small Cell Lung Cancer after Progression on 
First-Line EGFR TKI Therapy
Overview
Protocol I4T-MC-JVDL, An Open-Label, Multicenter, Phase 1 Study with Expansion Cohorts of 
Ramucirumab or Necitumumab in Combination with Osimertinib in Patients with Advanced 
T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer after Progression on First-Line 
EGFR TKI Therapy, has been amended.  The new protocol is indicated by amendment (c) and 
will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Study completion was redefined as occurring approximately 2 years after last patient 
enrolled, or when adequate number of events are observed for survival outcome estimation, 
whichever comes first.  

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Section 1. Synopsis
Length of Study Portion
The duration of the Dose-Expansion Portion (excluding the Continued Access Period) from first 
patient enrolled to the completion of the study is approximately 2.5 2 years.  The completion of the 
study is defined as 1 year after last patient enrolled, or when 18 of the 22 (80%) patients in Cohort A in 
the Dose-Expansion Portion have confirmed progressive disease, unacceptable toxicity, or 
discontinuation for any other reason, adequate number of events are observed for survival outcome 
estimation, whichever comes first.
Section 5.3. Study Completion and End of Trial Definition
There will be a database lock to report the primary data analyses approximately 6 months after 
last patient receives initial dose in the Dose-Expansion Portion of the study.
The completion of the study (Study Completion) is defined as 1 year approximately 2 years after 
last patient enrolled, or when 18 of the 22 (80%) patients in Cohort A in the Dose-Expansion 
Portion have confirmed PD, unacceptable toxicity, or discontinuation for any other reason 
adequate number of events are observed for survival outcome estimation, whichever comes first.  
Section 7.8. Treatment after Study Completion
The study completion will occur 1 year approximately 2 years after last patient enrolled, or when 
18 of the 22 (80%) patients in Cohort A in the Dose-Expansion Portion have confirmed PD, 
unacceptable toxicity, or discontinuation for any other reason adequate number of events are 
observed for survival outcome estimation, whichever comes first. Investigators will continue to
follow Schedule of Activities (Section 2) for all patients until notified by Lilly that study
completion has occurred.
7.8.1.
Continued Access Period
Figure JVDL.3
Continued access diagram.
b
One year Approximately 2 years after last patient enrolled, or when 18 of the 22 
(80%) patients in Cohort A in the Dose-Expansion Portion have confirmed progressive 
disease, unacceptable toxicity, or discontinuation for any other reason adequate number 
of events are observed for survival outcome estimation, whichever comes first.

Leo Document ID = 62c44003-1388-46b3-9002-fc9b01d4f568
Approver: 
Approval Date & Time: 28-Mar-2018 14:05:35 GMT
Signature meaning: Approved
PPD