An Open-Label, Multicenter, Phase 1b Study With an Expansion Cohort to Evaluate Safety and Efficacy of the Combination of Necitumumab With Pembrolizumab in Patients With Stage IV Non-Small Cell Lung Cancer
Phase: PHASE1
Conditions: Stage IV Non-Small Cell Lung Cancer
Sponsor: Eli Lilly and Company

Protocol I4X-MC-JFCQ(d) 
 
An Open-Label, Multicenter, Phase 1b Study with an Expansion Cohort to Evaluate Safety and 
Efficacy of the Combination of Necitumumab with Pembrolizumab in Patients with Stage IV 
Non-Small Cell Lung Cancer 
 
NCT02451930 
Approval Date: 17-Sep-2018 

I 4 X-M C -J F C Q( d ) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 0 1 2 2 1 1
1.
Pr ot o c ol I 4 X -M C -J F C Q ( d)
A n O p e n -L a b el , M ulti c e nt er, P h a s e 1 b St u d y wit h a n 
E x p a n si o n C o h ort t o E v al u at e S af et y  a n d Effi c a c y of t h e 
C o m bi n ati o n of N e cit u m u m a b wit h P e m br oli z u m a b i n 
P ati e nt s wit h St a g e I V N o n -S m all C ell L u n g C a n c er
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
n e cit u m u m a b ( L Y 3 0 1 2 2 1 1) or p e m br oli z u m a b ( M K 3 4 7 5), u n l es s s u c h p er s o n s ar e b o u n d 
b y  a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.  T hi s 
d o c u m e nt a n d it s a s s o ci at e d att a c h m e nt s ar e s u bj e ct t o U nit e d St at e s Fr e e d o m of 
I nfor m ati o n A ct E x e m pti o n 4.
N e cit u m u m a b ( L Y 3 0 1 2 2 1 1) , P e m br oli zu m a b ( M K 3 4 7 5)
T hi s i s a n o p e n -l a b el, m ulti c e nt er, P h a s e 1 b st u d y wit h a n e x p a n si o n c o h ort i n p ati e nt s wit h 
St a g e I V n o n -s m all c ell l u n g c a n c er ( N S C L C) . T h e  st u d y c o n si st s of 3 p art s ( P art A , P a rt 
B, a n d P art C ).  P art A i s a si n gl e -ar m, o p e n -l a b el, d o s e-e s c al ati o n st u d y t o d et er mi n e t h e 
r ec o m m e n d e d d o s e of  n e cit u m u m a b i n c o m bi n ati o n wit h p e m br oli z u m a b. P a rt B i s a n
o p e n -l a b el st u d y t o e v al u at e t h e ef fi c a c y a n d s af et y of n e cit u m u m a b i n c o m bi n ati o n wit h 
p e m br oli z u m a b.   P a rt C i s a n o pe n -l a b el st u d y t o e v al u at e t h e s af et y of n e cit u m u m a b at t h e 
r ec o m m e n d e d d o s e fr o m P art A i n c o m bi n ati o n wit h p e m br oli z u m a b i n J a p a n e s e p ati e nt s.
A p pr o v al D at e: 1 7- S e p- 2 0 1 8 G M T
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a, U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 2 7 M a y 2 0 1 5 .
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 0 3 M ar c h 2 0 1 6 .
A m e n d m e nt ( b ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 1 1 J ul y 2 0 1 6 .
A m e n d m e nt ( c ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 0 6 O ct o b er 2 0 1 6.
A m e n d m e nt ( d) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w.

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2.
Synopsis
Study Rationale
Necitumumab (IMC-11F8; LY3012211; Portrazza®) is a recombinant human monoclonal 
antibody (mAb) of the immunoglobulin G, subclass 1 (IgG1) that blocks the ligand-binding site 
of the epidermal growth factor receptor (EGFR).  EGFR is detectable in approximately 85% to 
90% of patients with advanced, metastatic non-small cell lung cancer (NSCLC).  Necitumumab 
has shown signals of antitumor activity in 2 Phase 1 trials when administered as monotherapy in 
heavily pretreated patients including but not limited to patients with NSCLC.  Portrazza has 
recently been approved in the US and EU for the treatment of adult patients with metastatic 
squamous NSCLC in combination with gemcitabine and cisplatin.
Pembrolizumab (MK-3475, Keytruda®) is a humanized IgG4 mAb directed against programmed 
death-1 (PD-1) T-cell co-receptor, thus blocking its interaction with ligands, PD-L1 and PD-L2.  
Pembrolizumab is approved for treatment of melanoma in several countries; in the US and EU it 
is approved for the treatment of advanced (unresectable or metastatic) melanoma in adults.  
Pembrolizumab has also been approved for treatment of NSCLC in several countries; in the US 
it is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 
as determined by an FDA-approved test and who have disease progression on or after platinum-
containing chemotherapy.
The rationale for combining both agents is based on clinical single-agent data that show activity 
of EGFR-directed mAbs and pembrolizumab in NSCLC, and preclinical data suggesting that the 
antitumor activity of EGFR antibodies can be attributed, at least in part, to various immune 
effector mechanisms.
The individual toxicity profiles of necitumumab and pembrolizumab suggest that no overlapping 
Grade ≥3 toxicity is expected; skin rash Grade 1-2 has been seen with both agents, hence some 
overlap is expected.
Different modes of action, preclinical data, and the clinical efficacy of necitumumab as well as 
other EGFR mAbs and pembrolizumab in NSCLC provide a rationale for the investigation of 
necitumumab in combination with pembrolizumab in patients with Stage IV NSCLC.
The purpose of this Phase 1b study with an expansion cohort is to explore the safety and 
preliminary efficacy of necitumumab plus pembrolizumab in patients with Stage IV NSCLC who 
have progressed after 1 platinum-based chemotherapy regimen.

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Clinical Protocol Synopsis:  Study I4X-MC-JFCQ
Name of Investigational Products:  Necitumumab (LY3012211); Pembrolizumab (MK-3475)
Title of Study:  An Open-Label, Multicenter, Phase 1b Study with an Expansion Cohort to Evaluate Safety and 
Efficacy of the Combination of Necitumumab with Pembrolizumab in Patients with Stage IV Non-Small Cell Lung 
Cancer
Number of Planned Patients:
Part A
   Enrolled: 3 to 12
Part B (Expansion Cohort)
   Enrolled: 54
Part C (Japanese patients)
   Enrolled: 6 to 12
Phase of Development:  1b
Length of Study:  approximately 22 months
Planned first patient visit:  15-Aug-2015
Planned last patient visit:  21-Jun-2017
Planned interim analyses:  first 15 evaluable patients in Part B portion of the study who have completed 2 cycles of 
study treatment (or otherwise discontinued study treatment) will be analyzed for safety.  Interim efficacy analyses 
may be performed as needed to aid in the planning of future trials. Patients with squamous and nonsquamous 
NSCLC, from Part A, who received the recommended necitumumab dose for Part B will be included in the interim 
analyses.
Objectives:  
The primary objectives of the study are:
Part A: to determine the dose-limiting toxicity (DLT) of necitumumab at doses of 600 mg and 800 mg on Days 1 
and 8 when combined with pembrolizumab 200 mg on Day 1 every 3 weeks (Q3W), in patients with Stage IV
NSCLC as measured by the number of patients with a DLT in Cycle 1.
Part B: to evaluate the efficacy of necitumumab in combination with pembrolizumab in terms of overall response
rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in patients with Stage IV
NSCLC.
Part C: to determine the DLT of necitumumab at the recommended dose from Part A in combination with 
pembrolizumab in Japanese patients with Stage IV NSCLC as measured by the number of patients with a DLT in 
Cycle 1.
The secondary objectives of the study are:
Part A and Part C:

to investigate the safety profile as assessed by clinical and laboratory significant events of necitumumab in 
combination with pembrolizumab 

to determine the ORR by RECIST 1.1

to determine the pharmacokinetics (PK) of necitumumab in presence of pembrolizumab

to determine the immunogenicity of necitumumab in presence of pembrolizumab
Part B: to demonstrate the feasibility of necitumumab at the recommended dose in combination with 
pembrolizumab by:

investigating the safety profile as assessed by clinical and laboratory significant events

determining disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and 
overall survival (OS) by RECIST 1.1.

determining PK of necitumumab in presence of pembrolizumab

determining the immunogenicity of necitumumab in presence of pembrolizumab
The exploratory objective is to further evaluate as follows:

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Parts A, B, and C:  to investigate relationship between immune- and EGFR-pathway-related biomarkers and 
treatment outcomes.
Part B: to assess immune-related (ir)ORR, irDCR, irDOR, and irPFS by adapted RECIST 1.1 (immune-related 
RECIST [irRECIST]).

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Study Design: This is an open-label, multicenter Phase 1b study with an expansion cohort to investigate 
necitumumab in combination with pembrolizumab in approximately 78 patients with Stage IV NSCLC (American 
Joint Committee on Cancer Staging Manual, 7th edition).  The study consists of 3 parts:

Part A:  Dose-escalation part with increasing doses of necitumumab (600 mg or 800 mg on Days 1 and 8 
Q3W) to determine a recommended dose range for necitumumab that may be safely administered in 
combination with a fixed regimen of pembrolizumab 200 mg Day 1 Q3W in patients with Stage IV 
NSCLC.

Part B (expansion cohort):  Dose confirmation of necitumumab in combination with a fixed regimen of 
pembrolizumab 200 mg on Day 1 Q3W and exploration of clinical antitumor activity in patients with 
Stage IV NSCLC.

Part C:  DLT confirmation using the recommended dose from Part A for necitumumab in combination 
with a fixed regimen of pembrolizumab 200 mg on Day 1 Q3W in Japanese patients with Stage IV 
NSCLC.
Approximately 54 patients will be enrolled in Part B: approximately 27 patients with squamous histology and 
approximately 27 patients with nonsquamous histology.
Patients will be treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or 
withdrawal of consent.  Patients who are on study therapy at study completion may continue to receive study 
therapy in the continued access period until they meet the discontinuation criteria. Part A and Part B of this study 
will be considered complete approximately 6 months after the last patient in Part B has been enrolled, and Part C of 
this study will be considered complete approximately after all the patients in Part C have completed 8 cycles or 
discontinued early.
Diagnosis and Main Criteria for Inclusions and Exclusions:
Key inclusion/exclusion criteria at the time of enrollment

The patient has histologically or cytologically confirmed NSCLC. 
Part A: NSCLC Stage IV (any histological type)
Part B: NSCLC Stage IV (squamous and nonsquamous)
Part C:  NSCLC Stage IV in Japanese patients (squamous and nonsquamous)

The patient must have progressed after 1 platinum-based chemotherapy regimen for Stage IV NSCLC.  
Prior vascular endothelial growth factor (VEGF)/VEGF receptor-targeting agents and 
neoadjuvant/adjuvant therapies are permitted.  Prior treatment with EGFR-tyrosine kinase inhibitor and 
anaplastic lymphoma kinase (ALK) inhibitors is mandatory in patients with NSCLC whose tumor has 
EGFR-activating mutations or ALK translocations, respectively.

Measurable disease at the time of study entry as defined by RECIST 1.1.

The patient has an evaluable tumor tissue, an archived formaldehyde fixed-paraffin embedded (FFPE)
block or at a minimum 15 slides (freshly cut slides should be submitted to the central laboratory), is 
available for biomarker analyses, or if not available, patient is willing to undergo a tumor biopsy of an 
extra-central nervous system lesion (core or excisional biopsy).

The patient has resolution to Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤1 of all 
clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy (with the exception of 
alopecia).

Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1.

The patient has no brain metastases that are symptomatic.
Test Product, Dosage, and Mode of Administration:  

Necitumumab is a sterile, preservative-free, intravenous infusion supplied in 50-mL vials containing 
16 mg/mL (800 mg/50 mL) of product, and administered over 60 minutes at a dose of 600 mg or 800 mg on 
Days 1 and 8 of each 21-day cycle.

Pembrolizumab drug product is available in 2 dosage forms intended for intravenous administration:  a 
lyophilized powder, 50 mg/vial, ready to be reconstituted with sterile water for injection prior to use, and a 
liquid, 100 mg/vial, both in Type I glass vials intended for single use only. Pembrolizumab is administered 
over 30 minutes (-5 min/+ 10 min) at a dose of 200 mg on Day 1 of each 21-day cycle.

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Reference Therapy, Dose, and Mode of Administration:  
Not Applicable
Planned Duration of Treatment:  
Baseline period:  up to 21 days
Treatment period: 21 days treatment cycle 
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  begins the day after short-term follow-up is completed and continues 
until the patient’s death or overall study completion
Study completion: Part A and Part B of this study will be considered complete approximately 6 months after the 
last patient in Part B has been enrolled, and Part C of this study will be considered complete approximately after all 
the patients in Part C have completed 8 cycles or discontinued early.
Continued Access Period:  Patients who are on study therapy at study completion may continue to receive study 
therapy in the continued access period until they meet the discontinuation criteria.
Criteria for Evaluation:  
Efficacy: 
Objective Response Rate (ORR) is defined as the proportion of patients achieving a best overall response of 
partial response (PR) or complete response (CR).
Disease Control Rate (DCR) is defined as the proportion of patients achieving a best overall response of stable 
disease (SD), PR, or CR.
Progression-Free Survival (PFS) is defined as the time from the date of first dose of any study drug until the date 
of radiographically documented PD or death due to any cause, whichever is earlier.
Overall Survival (OS) is defined as the time from the date of first dose of any study drug to the date of death from 
any cause.
Safety:
Part A and Part C:  DLTs, serious adverse events (SAEs), adverse events (AEs), vital sign measurements, 
laboratory analyses, and electrocardiograms (ECGs)
Part B: SAEs, AEs, vital sign measurements, laboratory analyses, and ECGs
Pharmacokinetics:
Serum concentrations of necitumumab prior to infusion (minimum concentration [Cmin]) and at end of the 
necitumumab infusion (approximately maximum concentrations for necitumumab).
Bioanalytical:
Serum concentrations of necitumumab will be measured using validated enzyme-linked immunosorbent assays.
Immunogenicity:
Serum anti-necitumumab antibody titer levels will be determined.
Translational research:
A tumor tissue block or tumor tissue slides will be collected to correlate biomarker results with clinical outcomes
related to the EGFR pathway, innate and adaptive immunity, and/or other biomarkers associated with the disease 
pathobiology and therapeutic molecules.
Blood samples will be collected for exploratory biomarker analyses.

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Statistical Methods:  
Efficacy:  The primary Part B outcome variable in this study will be the ORR.  The Part B statistical null 
hypothesis states that the true ORR is 20%, whereas the research hypothesis states that the true ORR is 35%.  If the 
research hypothesis is true, there is an 83% chance of rejecting the null hypothesis.  If the null hypothesis is true, 
then there is at most a 10% chance of rejecting the null hypothesis.  Therefore, the sample size of 54 evaluable 
patients in Part B has a nominal one-sided alpha level of 0.10, with statistical power of 83%.
Safety:  Safety analyses will be performed for all patients enrolled in the study who receive any amount of study
drug (necitumumab or pembrolizumab).  Numbers and rates of AEs will be reported by National Cancer Institute 
CTCAE terms. Laboratory and nonlaboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grades, including the total for maximum Grade 3 and above. These summaries will be provided for events 
deemed by the investigator to be related to study treatment, and repeated for events regardless of study drug 
causality. Adverse events will be summarized by Medical Dictionary for Regulatory Activities System Organ 
Class (MedDRA™SOC), by decreasing frequency of Preferred Term within SOC.  Other safety parameters will be 
summarized as appropriate.
An interim safety analysis will be performed after the first 15 evaluable patients in the Part B portion of the trial 
have completed 2 cycles of study treatment (or otherwise discontinued study treatment).  Patients with squamous 
and nonsquamous NSCLC from Part A who received the recommended necitumumab dose for Part B will be 
included in the interim analyses.  The interim safety analysis will be conducted to permit evaluation of safety data 
by the sponsor.
Interim efficacy analyses may be performed as needed to aid in the planning of future trials. There is no plan to 
stop the study for positive efficacy, the type-1 error for final primary analysis will not be affected and hence is not 
adjusted.
Immunogenicity:  Incidence of anti-necitumumab antibodies will be tabulated.
Pharmacokinetics:  Summary statistics of necitumumab data will be presented graphically as well as in tabulated 
form.  Additional exploratory analyses using population PK approach may be performed if warranted by data.
Translational research:  Translational research will be performed to analyze relevant biomarkers and to correlate 
them with clinical outcome.

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3.
Table of Contents
An Open-Label, Multicenter, Phase 1b Study with an 
Expansion Cohort to Evaluate Safety and Efficacy of the 
Combination of Necitumumab with Pembrolizumab in 
Patients with Stage IV Non-Small Cell Lung Cancer
Section
Page
1.
Protocol I4X-MC-JFCQ(d) An Open-Label, Multicenter, Phase 1b 
Study with an Expansion Cohort to Evaluate Safety and Efficacy of 
the Combination of Necitumumab with Pembrolizumab in Patients 
with Stage IV Non-Small Cell Lung Cancer........................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................8
4.
Abbreviations and Definitions...........................................................................................15
5.
Introduction ......................................................................................................................21
5.1.
Non-Small Cell Lung Cancer .......................................................................................21
5.2.
Necitumumab...............................................................................................................22
5.2.1.
Rationale for Necitumumab Dose Selection .........................................................24
5.3.
Pembrolizumab ............................................................................................................24
5.3.1.
Rationale for Pembrolizumab Dose Selection.......................................................25
5.4.
Study Rationale............................................................................................................26
6.
Objectives.........................................................................................................................28
6.1.
Primary Objective ........................................................................................................28
6.2.
Secondary Objectives...................................................................................................28
6.3.
Exploratory Objectives.................................................................................................28
7.
Study Population...............................................................................................................29
7.1.
Inclusion Criteria..........................................................................................................29
7.2.
Exclusion Criteria ........................................................................................................31
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................33
7.3.
Discontinuation............................................................................................................34
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................34
7.3.2.
Discontinuation of Study Therapy........................................................................34
7.3.3.
Discontinuation from the Study............................................................................35
7.3.4.
Patients who are Lost to Follow-Up .....................................................................35
7.3.5.
Discontinuation of Study Sites .............................................................................36
7.3.6.
Discontinuation of the Study................................................................................36
8.
Investigational Plan...........................................................................................................37

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8.1.
Summary of Study Design............................................................................................37
8.1.1.
Study Completion and End of Trial......................................................................41
8.1.2.
Continued Access Period......................................................................................42
8.2.
Discussion of Design and Control ................................................................................43
9.
Treatment..........................................................................................................................45
9.1.
Treatments Administered .............................................................................................45
9.2.
Materials and Supplies .................................................................................................46
9.3.
Method of Assignment to Treatment ............................................................................47
9.4.
Selection and Timing of Doses.....................................................................................47
9.4.1.
Special Treatment Considerations ........................................................................47
9.4.1.1.
Dose-Limiting Toxicity (Parts A and C) .........................................................47
9.4.1.2.
Dose Adjustments and Delays ........................................................................48
9.4.1.2.1.
Pembrolizumab.........................................................................................48
9.4.1.2.1.1.
Pembrolizumab Dose Modifications....................................................48
9.4.1.2.2.
Necitumumab ...........................................................................................51
9.4.1.2.2.1.
Necitumumab Dose Modifications ......................................................51
9.4.1.3.
Treatment Guidelines and Dose Modifications for 
Specific Adverse Events.................................................................................53
9.4.1.3.1.
Hypersensitivity and Infusion-Related Reactions ......................................53
9.4.1.3.1.1.
Management of Infusion Reactions for 
Necitumumab......................................................................................53
9.4.1.3.1.2.
Management of Infusion Reactions for 
Pembrolizumab...................................................................................55
9.4.1.3.2.
Skin Reactions..........................................................................................56
9.4.1.3.2.1.
Reactive Treatment .............................................................................56
9.4.1.3.3.
Conjunctivitis ...........................................................................................58
9.4.1.3.4.
Electrolyte Abnormalities .........................................................................58
9.4.1.3.5.
Thromboembolic Events...........................................................................58
9.4.1.3.6.
Pneumonia and Sepsis...............................................................................58
9.4.1.3.7.
Cardiorespiratory Disorders......................................................................59
9.4.2.
Supportive Care Guidelines for Pembrolizumab...................................................59
9.4.2.1.
Immune-Mediated Pneumonitis ......................................................................59
9.4.2.2.
Type 1 Diabetes Mellitus (if new onset, including 
diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA) or T1DM or Grade 3-4 
Hyperglycemia ...............................................................................................60
9.4.2.3.
Immune-Mediated Hypophysitis.....................................................................60
9.4.2.4.
Immune-Mediated Hyperthyroidism or Hypothyroidism.................................60

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9.4.2.5.
Hepatic Injury.................................................................................................61
9.4.2.6.
Renal Failure or Immune-Mediated Nephritis .................................................61
9.5.
Blinding .......................................................................................................................61
9.6.
Concomitant Therapy...................................................................................................61
9.6.1.
Supportive Care ...................................................................................................62
9.6.2.
Colony-Stimulating Factors and Erythropoiesis-Stimulating 
Agents..................................................................................................................62
9.6.3.
Therapy for Diarrhea/Colitis ................................................................................63
9.6.4.
Antiemetic Therapy..............................................................................................63
9.6.5.
Analgesic Agents .................................................................................................63
9.6.6.
Bisphosphonates and RANK-L Targeted Agents..................................................63
9.6.7.
Therapy for Febrile Neutropenia ..........................................................................64
9.7.
Treatment Compliance .................................................................................................64
10.
Efficacy, Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements.....................................................................................65
10.1. Efficacy Measures........................................................................................................65
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................65
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................66
10.1.3.
Primary Efficacy Measure (Part B only)...............................................................66
10.1.3.1.
Tumor Imaging and RECIST Assessment.......................................................66
10.1.3.1.1.
Initial Tumor Imaging...............................................................................66
10.1.3.1.2.
On Study Tumor Imaging .........................................................................66
10.1.3.2.
Tumor Response Assessment..........................................................................67
10.1.4.
Secondary Efficacy Measures...............................................................................67
10.1.5.
Exploratory Efficacy Measures ............................................................................67
10.1.5.1.
Adapted RECIST 1.1 (irRECIST)...................................................................67
10.1.6.
Resource Utilization.............................................................................................70
10.2. Safety Evaluations........................................................................................................70
10.2.1.
Adverse Events ....................................................................................................71
10.2.1.1.
Serious Adverse Events ..................................................................................72
10.2.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................73
10.2.1.3.
Events of Clinical Interest - Pembrolizumab...................................................73
10.2.2.
Other Safety Measures .........................................................................................74
10.2.2.1.
Electrocardiograms.........................................................................................74
10.2.3.
Safety Monitoring ................................................................................................74
10.2.4.
Complaint Handling.............................................................................................75
10.3. Sample Collection and Testing.....................................................................................75

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10.3.1.
Samples for Study Qualification and Health Monitoring.......................................75
10.3.2.
Samples for Pharmacogenetics and Translational Research ..................................76
10.3.2.1.
Whole Blood Sample for Genetic Research ....................................................76
10.3.2.2.
Tumor Tissue Collection ................................................................................77
10.3.2.3.
Plasma and Whole Blood Samples for Biomarker 
Research.........................................................................................................78
10.3.3.
Samples for Immunogenicity Research.................................................................78
10.3.4.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................78
10.4. Appropriateness of Measurements................................................................................79
11.
Data Quality Assurance.....................................................................................................80
11.1. Data Capture System....................................................................................................80
12.
Sample Size and Statistical Methods .................................................................................81
12.1. Determination of Sample Size ......................................................................................81
12.2. Statistical and Analytical Plans.....................................................................................81
12.2.1.
General Considerations ........................................................................................81
12.2.2.
Patient Disposition...............................................................................................82
12.2.3.
Patient Characteristics..........................................................................................82
12.2.4.
Concomitant Therapy...........................................................................................82
12.2.4.1.
Postdiscontinuation Therapy...........................................................................82
12.2.5.
Treatment Compliance .........................................................................................82
12.2.6.
Primary Outcome and Methodology.....................................................................82
12.2.7.
Analyses of Efficacy ............................................................................................82
12.2.7.1.
Exploratory Outcome and Methodology .........................................................83
12.2.8.
Pharmacokinetic and Immunogenicity Analyses...................................................83
12.2.9.
Translational Research Analyses..........................................................................84
12.2.10. Safety Analyses....................................................................................................84
12.2.11. Subgroup Analyses ..............................................................................................85
12.2.12. Interim Analyses..................................................................................................85
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................86
13.1. Informed Consent.........................................................................................................86
13.2. Ethical Review.............................................................................................................86
13.3. Regulatory Considerations ...........................................................................................86
13.3.1.
Investigator Information.......................................................................................87
13.3.2.
Protocol Signatures ..............................................................................................87
13.3.3.
Final Report Signature .........................................................................................87
14.
References ........................................................................................................................88

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List of Tables
Table
Page
Table JFCQ.9.1.
Treatment Regimens/Dosing Schedule ...................................................45
Table JFCQ.9.2.
Dose Modification Guides for Pembrolizumab Drug-Related 
Adverse Events.......................................................................................50
Table JFCQ.9.3.
Dose Adjustments of Necitumumab........................................................52
Table JFCQ.9.4.
Necitumumab Infusion-Related Reaction Treatment Guidelines .............54
Table JFCQ.9.5.
Pembrolizumab Infusion-Related Reaction Treatment Guidelines...........55
Table JFCQ.9.6.
Managing Skin Reactions .......................................................................57
Table JFCQ.10.1.
General Guidance for Decision Making on Repeated Radiologic 
Assessment in Patients with Initial PD based on Clinical Status..............69
Table JFCQ.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........71

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List of Figures
Figure
Page
Figure JFCQ.8.1.
Illustration of study design......................................................................38
Figure JFCQ.8.2.
Study period and continued access diagram. ...........................................42

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JFCQ Study Schedule...............................................................92
Attachment 2.
Protocol JFCQ Clinical Laboratory Tests..............................................101
Attachment 3.
Protocol JFCQ ECOG Performance Status Performance Status.............102
Attachment 4.
Protocol JFCQ Creatinine Clearance Formula.......................................103
Attachment 5.
Protocol JFCQ RECIST Criteria 1.1 .....................................................104
Attachment 6.
Protocol JFCQ Pharmacokinetic, Immunogenicity, and Blood-
Based Markers Sampling Schedule.......................................................111
Attachment 7.
Protocol Amendment I4X-MC-JFCQ(d) Summary An Open-Label, 
Multicenter, Phase 1b Study with an Expansion Cohort to Evaluate 
Safety and Efficacy of the Combination of Necitumumab with 
Pembrolizumab in Patients with Stage IV Non-Small Cell Lung 
Cancer..................................................................................................114

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4.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug(s) antibodies
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.
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
Assent
Agreement from an individual who is not legally capable of providing consent, but who 
can understand the circumstances and risks involved in participating in a study 
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
Audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BCG
Bacillus Calmette-Guérin
CI
confidence interval
CK
creatine kinase
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.
companion diagnostic
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product
Complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.

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continued access 
period
The period between study completion and end of trial during which patients on study 
treatment who continue to experience clinical benefit and no undue risks may continue 
to receive study treatment until one of the criteria for discontinuation is met. 
CR
complete response
CRF/eCRF
case report form/electronic case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
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.
CrCl
creatinine clearance
CSF
colony-stimulating factor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DILI
drug-induced liver injury
DKA
diabetic ketoacidosis
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECI
Event of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
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

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ERB/IRB
ethical review board/institutional review board
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical trial are protected.
ESAs
erythropoiesis-stimulating agents
EU
European Union
FFPE
formaldehyde fixed-paraffin embedded
GC
gemcitabine/cisplatin
GC+N
gemcitabine/cisplatin plus necitumumab
GCP
good clinical practice
H0
null hypothesis
Ha
alternative hypothesis
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IgG1
immunoglobulin G, subclass 1
IHC
immunohistochemistry
ILD
interstitial lung disease
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical trial data, that is conducted before the final 
reporting database is created/locked.

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investigational 
product (IP) 
[hereon referred to as 
study treatment]
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.  Investigational product (IP) includes a product 
with a marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from the 
authorized form,
2.
used for an unauthorized indication, or 
3.
used to gain further information about the authorized form.
In this study, the IPs are necitumumab (LY3012211; IMC-11F8) and pembrolizumab
(MK-3475).
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
irCR
immune-related complete response
irPD
immune-related progressive disease
irPR
immune-related partial response
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
IRR
infusion-related reaction
irSD
immune-related stable disease
I.V.
intravenous(ly)
IWRS
interactive web-response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mOS
median overall survival
mPFS
median progression-free survival
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSAIDs
non-steroidal anti-inflammatory drugs

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NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PC
pemetrexed–cisplatin
PC+N
necitumumab plus pemetrexed–cisplatin
PD
progressive disease
PD-1
programmed death-1
PD-L
programmed death-1 ligand
PFS
progression-free survival
PI
package insert
PK
pharmacokinetic(s)
PopPK
population pharmacokinetics
PR
partial response
PT
prothrombin time
PTT/aPTT
partial thromboplastin time/activated partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
RANK-L
receptor activator of nuclear factor kappa-B ligand
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.
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
Statistical Analysis Plan

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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.  In this study,
screening involves invasive or diagnostic procedures and/or tests (for example, blood 
draws).  For this type of screening, informed consent for these screening procedures 
and/or tests shall be obtained.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SmPC
Summary of Product Characteristics
SOC
System Organ Class
Study completion
Part A and Part B of this study will be considered complete approximately 6 months 
after the last patient in Part B has been enrolled, and Part C of this study will be 
considered complete approximately after all the patients in Part C have completed 8 
cycles or discontinued early.
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
TKI
tyrosine kinase inhibitor
ULN
upper limits of normal
US
United States
USPI
United States package insert
VEGF
vascular endothelial growth factor
VEGFR2
vascular endothelial growth factor receptor 2
VTE
venous thromboembolic event

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5.
Introduction
5.1.
Non-Small Cell Lung Cancer
Lung cancer is the most common cancer worldwide, with an estimated 1.6 million new cases per 
year, and the leading cause of cancer-related mortality with 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.  
Patients with localized disease have a 5-year survival rate of approximately 55%; however, 
5-year survival drops significantly for patients with regional (26.1%) or distant (3.9%) disease at
diagnosis (Howlader et al. 2014).
Current standard first-line chemotherapy for patients with Stage IV NSCLC and a good 
performance status consists of a platinum-based doublet, using either cisplatin or carboplatin in 
combination with pemetrexed (only for nonsquamous NSCLC), taxanes, vinorelbine, or 
gemcitabine. The combination of a platinum-doublet with the anti-vascular endothelial growth 
factor (VEGF) antibody bevacizumab is a treatment option for nonsquamous patients only. 
Induction chemotherapy may be followed by maintenance therapy, administered either as switch 
or continuation maintenance. Second-line treatment options after failure of first-line 
chemotherapy with or without maintenance treatment consist of monotherapy with either 
docetaxel, erlotinib, or pemetrexed depending on type of prior treatment. Lately, an anti-
vascular endothelial growth factor receptor 2 (VEGFR2) antibody, ramucirumab, in combination 
with docetaxel was approved in the United States (US) and European Union (EU) for the second-
line treatment of metastatic NSCLC, including squamous and nonsquamous histologies 
(Cyramza Summary of Product Characteristics [SmPC]/US package insert [USPI]). Recently, 
monoclonal antibodies (mAbs) directed against programmed death-1 (PD-1) T-cell co-receptor, 
nivolumab and pembrolizumab, have been approved in the US for the treatment of patients with 
metastatic NSCLC with progression on or after platinum-based chemotherapy, whereby 
pembrolizumab was approved for the treatment of those NSCLC patients whose tumors express 
PD-L1 as determined by an FDA-approved test (Opdivo USPI, Keytruda USPI). In the EU 
nivolumab is approved for the treatment of adult patients with locally advanced or metastatic 
NSCLC after prior chemotherapy (Opdivo SmPC).  Pembrolizumab has also been approved for 
treatment of patients with NSCLC in EU (Keytruda SmPC). For patients with tumors harboring 
epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-activating mutations, 
monotherapy with an EGFR-TKI is used upfront, followed by osimertinib (Tagrisso USPI) in 
patients with EGFR T790M mutation-positive cancer or a platinum-based doublet as second-line
treatment, or as second- or third-line treatment if not used previously. For patients with 
anaplastic lymphoma kinase (ALK)-gene arrangement, treatment should include monotherapy 
with an ALK inhibitor (Heigener and Reck 2014).
More recently, necitumumab has been approved in the US and EU for first-line treatment of 
patients with metastatic squamous NSCLC (Portrazza SmPC/USPI).

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Despite the advancement of systemic treatments for patients with Stage IV NSCLC, the available 
therapeutic options remain limited and the prognosis of the patients is poor, resulting in a 
continued medical need for new treatment options.
5.2.
Necitumumab
Necitumumab (LY3012211) is a recombinant human mAb of the immunoglobulin (Ig) G1 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.
EGFR is expressed in a variety of tumors, including colorectal, head and neck, breast, and 
NSCLC (Salomon et al. 1995).  In patients with advanced and metastatic NSCLC, EGFR is 
detectable in approximately 85% to 90% of patients (Fontanini et al. 1995; Pirker et al. 2009).  
Pharmacologic inhibition of EGFR signaling through competitive inhibition of ligand binding 
has been shown to play a role in the treatment of several cancers, leading to registration of 
necitumumab in squamous NSCLC and 2 other anti-EGFR mAbs in a number of other 
indications (Necitumumab/Portrazza PI/SmPC, Cetuximab/Erbitux PI/SmPC, 
Panitumumab/Vectibix PI/SmPC).  Moreover, another randomized Phase 3 trial, conducted with 
cetuximab, showed evidence that the addition of an EGFR mAb to a platinum-based doublet can 
significantly increase survival in patients with advanced NSCLC (Pirker et al. 2009).
The necitumumab Phase 1 program included 2 single-agent dose-escalation Phase 1 trials in 
Western (I4X-IE-JFCE [JFCE]) and Japanese (I4X-IE-JFCA [JFCA]) patients with advanced 
solid tumors or for which no standard therapy was available.
Study JFCE included 60 patients and investigated necitumumab intravenous (I.V.) once a week 
(Arm A, n=29) or once every 2 weeks (Arm B, n=31) at sequential absolute dose levels from 
100 mg to 1000 mg.  No dose-limiting toxicities (DLTs) were observed in Arm A, which 
included 9 patients treated at 1000 mg.  Grade 3 headache was the major DLT, occurring in 2 of 
9 patients in the 1000-mg dose cohort of Arm B. Because of the timely relationship to the first 
dose of necitumumab, these were considered to be dose-related and the dose level of 800 mg was 
defined as the maximum tolerated dose (MTD) for both schedules.  Grade ≥3 adverse events 
(AEs) considered at least possibly related to necitumumab affected 10.3% (n = 3) of patients in 
Arm A and 22.6% (n = 7) of patients in Arm B. Overall, the most common related Grade ≥3 
AEs were fatigue (4 patients; 2 patients each in Arm A and Arm B); headache (2 patients in Arm 
B), and acne (2 patients, 1 patient each in Arm A and Arm B); others included anemia, diarrhea, 
nausea, vomiting, hypokalemia, and decreased blood magnesium (1 patient each, all in Arm B). 
No Grade 5 necitumumab-related AEs were observed in this study.
In Study JFCA, 15 patients were enrolled and treated (Cohort 1: 600 mg necitumumab on Days 
1 and 8 of a 3-week cycle, n = 3; Cohort 2: 800 mg every 2 weeks, n = 6; and Cohort 3: 800 mg 
on Days 1 and 8 of a 3-week cycle, n = 6).  No DLTs were observed in this study during the first 
3-week cycle for any cohort.  The most common treatment-emergent AEs (TEAEs) regardless of 
grade or relationship to study therapy were headache (n = 11; 73.3%), dry skin (n = 10; 66.7%), 

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pruritus (n = 9; 60.0%), and rash (n = 8; 53.3%).  One patient in Cohort 2 experienced 2 related 
Grade 3 TEAEs of dry skin and rash; all other related events observed in the study were Grade 
≤2.
Signals of antitumor activity of necitumumab monotherapy were observed in both studies with 
heavily pretreated patients.  For Study JFCE, in total 2 partial response (PR) and 16 stable 
disease (SD; 1 PR, 8 SD for each treatment arm) were observed (disease control rate [DCR] 
Arm A 31%, Arm B 29%).  For Study JFCA, SD was seen within all cohorts in a total of 
10 patients (DCR 66.7%), including 1 patient with squamous NSCLC and 1 patient with 
nonsquamous NSCLC.
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 
patients with Stage IV squamous NSCLC (Thatcher et al. 2015).  The study met its primary 
objective, demonstrating a statistically significant improvement in overall survival (OS) in the 
GC+N Arm compared with the GC Arm (hazard ratio [HR] = 0.84; p=0.012).  This was 
supported by a statistically significant improvement in progression-free survival (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 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. 2013).  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 frequency of 
study drug related deaths was 4.9% and 2.9% for PC+N and PC, respectively.
Based on these data, the combination of necitumumab plus pemetrexed-cisplatin is not being 
considered for further development.  Of note, no safety signal with regard to thromboembolic 

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events, including fatal events, has been identified for necitumumab in completed clinical trials 
when administered as monotherapy or in combination with mFOLFOX-6 (5-FU/FA and 
oxaliplatin) chemotherapy.
The randomized Phase 2 trial, I4X-MC-JFCL (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. Study I4X-JE-JFCM is a Phase 1b/2 study in Japanese patients with Stage IV 
squamous NSCLC that compares necitumumab plus gemcitabine-cisplatin versus gemcitabine-
cisplatin alone.  The trial is monitored by an IDMC and continues as planned.
For more details regarding the necitumumab development program, reference is made to the 
Investigator’s Brochure (IB).
5.2.1. Rationale for Necitumumab Dose Selection
The recommended dose and treatment schedules for necitumumab are 800 mg (weekly), 800 mg 
(once every 2 weeks), or 800 mg (Days 1 and 8 of a 21-day cycle), based on safety and 
pharmacokinetics (PK) data from 2 Phase 1 studies in heavily pretreated patients with advanced 
solid tumors (JFCA and JFCE). The necitumumab 800-mg dose administered 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 -1 of the MTD (600 mg on Days 1 and 8 every 3 weeks [Q3W]).  Since this is the 
first time these 2 mAbs are combined in a clinical setting, the recommended, biologically active 
dose of pembrolizumab was selected and it was chosen to use a DLT-driven design to escalate 
necitumumab to MTD.
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) 
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.
5.3.
Pembrolizumab
Pembrolizumab [Keytruda (US)], a humanized monoclonal antibody against the programmed 
death receptor-1 (PD-1) protein, has been developed by Merck & Co. for the treatment of 
patients with cancer. Pembrolizumab is approved for treatment of patients with melanoma in 

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several countries; in the US and EU it is approved for the treatment of patients with advanced 
(unresectable or metastatic) melanoma in adults.  Pembrolizumab has also been approved for 
treatment of patients with NSCLC in several countries; in the US it is indicated for the treatment 
of patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-
approved test and who have disease progression on or after platinum-containing chemotherapy. 
Patients with NSCLC and EGFR or ALK genomic tumor aberrations should also have disease 
progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy trials in 
subjects with non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial 
cancer, gastric cancer, triple negative breast cancer and Hodgkin’s Lymphoma as determined by 
response rate.  Ongoing clinical trials are being conducted in these tumor types as well as a 
number of other advanced solid tumor indications and hematologic malignancies.  For study 
details please refer to the IB.
5.3.1. Rationale for Pembrolizumab Dose Selection
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W. The dose 
recently approved in the US and several other countries for treatment of melanoma subjects is 2 
mg/kg Q3W. Information on the rationale for selecting 200 mg Q3W is summarized below.
In Keynote-001, an open-label Phase 1 clinical trial, conducted to evaluate the safety, 
tolerability, PK and pharmacodynamics, and anti-tumor activity of pembrolizumab when 
administered as monotherapy. The dose escalation portion of this trial evaluated 3 dose levels, 1 
mg/kg, 3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose expansion cohorts 
evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid tumors. All dose 
levels were well tolerated and no DLTs were observed. This first-in-human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels. No MTD has been identified. In addition, 2 randomized cohort 
evaluations of melanoma patients receiving pembrolizumab at a dose of 2 mg/kg versus 10 
mg/kg Q3W have been completed, and 1 randomized cohort evaluating 10 mg/kg Q3W versus 
10 mg/kg Q2W has also been completed. The clinical efficacy and safety data demonstrate a 
lack of clinically important differences in efficacy response or safety profile across doses.
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W. Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in patients 
with melanoma in the range of doses between 2 mg/kg and 10 mg/kg. Exposures for 200 mg 
Q3W are expected to lie within this range and will be close to those obtained with 2 mg/kg Q3W 
dose.  
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed. The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have a low clearance and a 
limited volume of distribution. The distribution of exposures from the 200 mg fixed dose are 
predicted to considerably overlap those obtained with the 2 mg/kg dose and importantly will 

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maintain individual patient exposures within the exposure range established in melanoma as 
associated with maximal clinical response. Pharmacokinetic properties of pembrolizumab, and 
specifically the weight-dependency in clearance and volume of distribution are consistent with 
no meaningful advantage to weight-based dosing relative to fixed dosing.
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a direct 
interaction with tumor cells, rendering it independent of the specific tumor type. In addition, 
available PK results in patients with melanoma, NSCLC, and other tumor types support a lack of 
meaningful difference in pharmacokinetic exposures obtained at tested doses among tumor 
types. Thus the 200 mg Q3W fixed-dose regimen is considered an appropriate fixed dose for 
other tumor indications as well.
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.  The existing data suggest 200 mg 
Q3W as the appropriate dose for pembrolizumab.  
5.4.
Study Rationale
The purpose of this study is to explore the efficacy and safety of necitumumab plus 
pembrolizumab in patients with Stage IV NSCLC who have progressed after 1 platinum-based 
chemotherapy regimen.
Necitumumab (LY3012211) is a recombinant human mAb of IgG1 class, which targets EGFR.  
Necitumumab demonstrates a high affinity to its target and blocks ligand-induced receptor 
phosphorylation and downstream signaling.  EGFR is detectable in approximately 85% to 90% 
of patients with NSCLC (Fontanini et al. 1995; Pirker et al. 2009).  Pharmacologic inhibition of 
EGFR signaling through competitive inhibition of ligand binding has been shown to play a role 
in the treatment of several cancers, and EGFR mAbs are approved in various tumor indications 
(Erbitux PI/SmPC, Vectibix PI/SmPC).  Necitumumab (PORTRAZZA®) is indicated, in 
combination with gemcitabine and cisplatin, for the treatment of adult patients with metastatic 
squamous NSCLC (Portrazza USPI/SmPC). The necitumumab SQUIRE trial showed 
statistically significant improvements in OS and PFS, with an overall favorable benefit-risk 
profile.  In addition, a recent meta-analysis investigating the addition of an EGFR mAb to 
platinum-based first-line therapy demonstrated a significantly improved OS and PFS in patients 
with advanced NSCLC (Pujol et al. 2014).
Pembrolizumab (MK-3475, Keytruda®) is a humanized IgG4 mAb directed against PD-1 T-cell 
co-receptor, thus blocking its interaction with ligands, PD-L1 and PD-L2.  KEYTRUDA is 
indicated for the treatment of: (a) patients with unresectable or metastatic melanoma
(KEYTRUDA USPI/SmPC); (b) in the US, also for patients with metastatic NSCLC whose 
tumors express PD-L1 as determined by an FDA-approved test and who have disease 
progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK 
genomic tumor aberrations should have disease progression on FDA-approved therapy for these 

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aberrations prior to receiving KEYTRUDA (Keytruda USPI). Pembrolizumab is also 
investigated as a single agent or in combination with chemotherapy or immunotherapy in the 
treatment of Stage IV NSCLC.  So far, pooled efficacy and safety results from several ongoing 
single-agent Phase 1 trials with expansion cohorts in NSCLC were reported.  Antitumor activity 
was similar in squamous and nonsquamous NSCLC.  Treatment-naïve patients responded better 
than experienced on ORR, mPFS, and mOS (Garon et al. 2015).  The analysis was also 
performed in relation to the biomarker using IHC assay for PD-L1 expression, identifying 
patients with strongly positive, weak, or negative PD-L1 expression.  PFS and OS were longer in 
patients with PD-L1 strong-positive versus PD-L1 weak-positive/ negative tumors (Garon et al. 
2015).
The rationale for combining both agents is based on clinical single-agent data that show activity 
of EGFR-directed mAbs and pembrolizumab in NSCLC, and preclinical data suggesting that the 
antitumor activity of EGFR antibodies can be attributed, at least in part, to various immune 
effector mechanisms:

EGFR signaling results in the loss of chemokine expression that mediates tumor evasion 
in cutaneous squamous cell carcinoma (Pivarcsi et al. 2007) and was found to positively 
regulate PD-L1 expression in lung cancer cells (Akbay et al. 2013).

EGFR ligand (amphiregulin) enhances function of regulatory T cells mediated by the 
EGFR (Zaiss et al. 2013).

EGFR IgG1 antibody triggers activation of natural killer and dendritic cells followed by 
development of tumor antigen-specific T-cell immunity (Srivastava et al. 2013).

Human natural killer cells increase CD137 expression when exposed to colon and H&N 
cancer cells treated with EGFR IgG1 antibody.

The increase in CD137-expressing NK cells is directly correlated to an increase in 
EGFR-specific CD8+ T cells (Kohrt et al. 2014).  
Hence, combination of PD-1 and EGFR blockade may be a promising therapeutic strategy to 
extend the duration of treatment response and delay development of resistance.
The individual toxicity profiles of necitumumab and pembrolizumab suggest that no overlapping 
Grade ≥3 toxicity is expected; skin rash Grade 1-2 has been seen with both agents, hence some 
overlap is expected.
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of necitumumab may be found in the necitumumab IB and Portrazza PI.  Information on AEs 
expected to be related to the study drug may be found in Section 7 (Development Core Safety 
Information) of the IB.  Information on serious adverse events (SAEs) expected in the study 
population independent of drug exposure and that will be assessed by the sponsor in aggregate, 
periodically during the course of the study, may be found in Section 6 (Effects in Humans) of the 
IB.
More detailed information about the known and expected benefits and risks of pembrolizumab 
may be found in the Keytruda USPI and pembrolizumab IB.

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6.
Objectives
6.1.
Primary Objective
This study is divided into 3 parts:
Part A: to investigate safety and tolerability of pembrolizumab 200 mg Q3W when combined 
with necitumumab administered at the doses of 600 mg and 800 mg on Days 1 and 8 of 21-day 
cycles in patients with Stage IV NSCLC (all histologies) as measured by number of patients with 
a DLT during Cycle 1
Part B: to evaluate the efficacy of necitumumab in combination with pembrolizumab in terms 
of ORR by RECIST 1.1 in patients with Stage IV NSCLC of squamous and nonsquamous 
histology
Part C: to investigate safety and tolerability of pembrolizumab 200 mg Q3W when combined 
with necitumumab administered at the recommended dose from Part A in Japanese patients with 
Stage IV NSCLC of squamous and nonsquamous histology as measured by number of patients 
with a DLT during Cycle 1
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:
Part A and Part C:

to investigate the safety profile as assessed by significant clinical and laboratory events of 
necitumumab in combination with pembrolizumab

to determine the ORR (by RECIST 1.1)

to determine PK of necitumumab in presence of pembrolizumab

to determine the immunogenicity of necitumumab in presence of pembrolizumab
Part B:
To demonstrate the feasibility of combining necitumumab with pembrolizumab at the 
recommended doses by:

investigating the safety profile as assessed by clinical and laboratory significant events

determining disease control rate (DCR), duration of response (DOR), and PFS by 
RECIST 1.1, and OS

determining PK of necitumumab in the presence of pembrolizumab

determining the immunogenicity of necitumumab in the presence of pembrolizumab
6.3.
Exploratory Objectives

to investigate biomarkers and correlate these markers to clinical outcome

to assess immune-related (ir)ORR, irDCR, irDOR, and irPFS by adapted RECIST 1.1
(immune-related RECIST [irRECIST])

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7.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened. Individuals may be re-screened once. At the time of re-screening, the individual 
must sign a new informed consent form (ICF) and will be assigned a new identification number.
Central laboratory testing is required for assessment of eligibility.  Note that repeating laboratory 
tests during the 21-day screening period does not constitute rescreening.  Laboratory tests may 
not be repeated more than once in order to meet eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
The patient has histologically or cytologically confirmed NSCLC.

Part A: NSCLC Stage IV (any histological type)

Part B: NSCLC Stage IV (squamous and nonsquamous)

Part C:  NSCLC Stage IV in Japanese patients (squamous and 
nonsquamous)

[2]
The patient has Stage IV NSCLC (American Joint Committee on Cancer 
Staging Manual, [AJCC] 7th Edition [Edge et al. 2010]) at the time of study 
entry.
[3]
The patient has measurable disease at the time of study entry as defined by 
RECIST 1.1 (Eisenhauer et al. 2009). Tumor lesions situated in a previously 
irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
[4]
The patient must have progressed after 1 platinum-based chemotherapy 
regimen for Stage IV NSCLC.  Prior therapy with VEGF/VEGFR targeting 
agents is permitted. Prior neoadjuvant/adjuvant therapy is permitted.  Prior 
treatment with EGFR-TKI and ALK inhibitors is mandatory in patients with 
NSCLC whose tumor has EGFR-activating mutations or ALK translocations, 
respectively.
[5]
The patient has an evaluable tumor tissue, an archived formaldehyde fixed-
paraffin embedded (FFPE) block or at a minimum 15 slides (freshly cut slides 
should be submitted to the central laboratory), is available for biomarker 
analyses, or if not available, patient is willing to undergo a tumor biopsy of an 
extra-central nervous system (CNS) lesion (core or excisional biopsy). See 
Section 10.3.2 for further details.

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[6]
The patient has given written informed consent/assent prior to any 
study-specific procedures.  Written consent may also be provided by a legal 
representative. 
[7]
The patient is 18 years or older if required by local law or regulations.
[8]
The patient has resolution to Grade ≤1 by the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
Version 4.0, of all clinically significant toxic effects of prior chemotherapy, 
surgery, radiotherapy (with the exception of alopecia).
[9]
The patient has an Eastern Cooperative Oncology Group performance status 
(ECOG PS) score of 0-1 (see Attachment 3).
[10] The patient has adequate organ function prior to treatment initiation, 
including:

hematologic:  absolute neutrophil count 1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 9 g/dL. Transfusion of blood products 
(including platelets or red blood cells) or administration of colony 
stimulating factors (including G-CSF, GM-CSF or recombinant 
erythropoietin) within 4 weeks prior to study Day 1 Cycle 1 are not allowed.

hepatic:  bilirubin 1.5 × the upper limit of normal (ULN), alkaline 
phosphatase, alanine aminotransferase (ALT), and aspartate transaminase 
(AST) 3.0 times ULN.  For patients with hepatic metastases, ALT and 
AST equaling ≤5.0 times ULN are acceptable.

renal:  serum creatinine 1.2 x ULN or calculated creatinine clearance 
(CrCl) >50 mL/min (per the Cockcroft-Gault formula as defined in 
Attachment 4) for patients with creatinine levels >1.2 institutional ULN

Serum albumin level >25 g/L

Coagulation parameters:  international normalized ratio (INR) ≤1.5, or 
prothrombin time (PT), partial thromboplastin time (PTT), or activated 
partial thromboplastin time (aPTT) ≤5 seconds above ULN unless patient is 
receiving anticoagulant therapy as long as INR, PT, PTT, or aPTT is within 
therapeutic range of intended use of anticoagulants
[11] The patient is a man who is sterile (including vasectomy confirmed by 
post-vasectomy semen analysis) or abstains from heterosexual activity or 
agrees to use an adequate method of contraception 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; OR

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[12] The patient is a woman of child-bearing potential who tests negative for 
pregnancy within 72 hours prior to receiving first dose of study medication 
based on a serum pregnancy test and agrees to use 2 methods of birth control
or abstain from heterosexual activity during the study and for 6 months 
following the last dose of the study drug(s) or country requirements, 
whichever is longer; or be of non-child bearing potential.  Non-childbearing 
potential is defined as (by other than medical reasons):

≥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 value in the postmenopausal range upon pretrial 
(screening) evaluation, or

post hysterectomy, oophorectomy or tubal ligation.  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 
2 adequate barrier methods throughout the study, starting with the screening visit 
through 6 months after the last dose of study therapy.
[13] The patient has an estimated life expectancy of at least 12 weeks.
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] The patient is currently enrolled in a clinical trial involving an investigational 
product (IP; hereon referred to as study treatment) or non-approved use of a 
drug or device (other than the study treatment/device used in this study), or 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
[15] Has had a prior anti-cancer mAb within 4 weeks prior to study Day 1 or who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier. Note:  Subjects with ≤ Grade 2 
neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may 
qualify for the study. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-
PD-L2 agent is not allowed.
[16] The patient has a diagnosis of immunodeficiency or is receiving systemic 
steroid therapy or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the sponsor.
[17] The patient has undergone major surgery in the 30 days prior to study 
enrollment or, if earlier, they have not recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.

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[18] The patient has undergone chest irradiation within 2 weeks prior to Day 1 
Cycle 1 study drugs administration, has not recovered from all radiation-
related toxicities, requires corticosteroids, or has had radiation pneumonitis.  
A 2-week washout is required for focal palliative radiation to non-CNS 
disease.
[19] The patient has brain metastases that are symptomatic. The patients who have 
completed radiotherapy for brain metastases at least 4 weeks prior to receiving 
treatment, who are now non symptomatic and are not using steroids or 
anticonvulsants for at least 7 days prior to receiving treatment, are eligible.
Patients with asymptomatic brain metastases without need for treatment with 
steroids and who have not been treated with radiotherapy are eligible. This 
exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.
[20] The patient has a history of arterial thromboembolic event (ATE) or venous 
thromboembolic event (VTE) within 3 months prior to study enrollment. 
Patients with history of VTE beyond 3 months prior to study enrollment can 
be enrolled if they are appropriately treated with anticoagulation therapy 
according to the local standard.
[21] The patient has a history or evidence of 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.
[22] The patient has experienced myocardial infarction within 6 months prior to 
study enrollment.
[23] The patient has active infection requiring systemic therapy, including active 
tuberculosis or known history of infection with the human immunodeficiency 
virus (HIV 1/2 antibodies), or hepatitis B (e.g., HBsAg reactive) and/or C 
virus (e.g., HCV RNA [qualitative] is detected).
[24] The patient has a history of significant neurological or psychiatric disorders, 
including dementia, seizures, or bipolar disorder, potentially precluding 
protocol compliance.
[25] The patient has 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.
[26] The patient has 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.

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[27] The patient has a known allergy / history of hypersensitivity reaction to any of 
the treatment components, including any ingredient used in the formulation of 
necitumumab or pembrolizumab, or any other contraindication to one of the 
administered treatments.
[28] The patient is pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening 
visit through 6 months after the last dose of trial treatment.
[29] The patient has a known history of drug abuse that, in the opinion of the 
investigator, may have an impact on the safety of the patient and/or limit the 
patient’s ability to complete the study or adhere to any protocol procedure.
[30] The patient has a concurrent active malignancy and is receiving concurrent 
treatment with other anticancer therapy, including other chemotherapy, 
immunotherapy, hormonal therapy, chemo-embolization, targeted therapy, or 
an investigational agent. Previous history of malignancy other than NSCLC is 
permitted, provided that he/she has been free of disease for ≥3 years, with the 
exception of adequately treated basal or squamous cell carcinoma of the skin, 
preinvasive carcinoma of the cervix, in situ carcinoma of the breast, or low-
grade prostate cancer with no plan for treatment intervention.
[31] The patient has a history of an interstitial lung disease (ILD) or (non-
infectious) pneumonitis that required steroids or current pneumonitis.
[32] The patient has an active autoimmune disease or a documented history of 
autoimmune disease, or a syndrome that requires systemic steroids or 
immunosuppressive agents. Patients with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule.  Patients that require 
intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study. Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.
[33] The patient has received a live vaccine within 30 days prior to the first dose of 
trial treatment.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, 
H1N1 flu, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine.
Seasonal flu vaccines that do not contain live virus are permitted.
[34] The patient is or has an immediate family member (for example, spouse, 
parent/legal guardian, sibling, or child) who is investigational site or sponsor 
staff directly involved with this trial, unless prospective institutional review 
board (IRB) approval (by chair or designee) is given allowing exception to 
this criterion for a specific patient.
7.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria [14] and [15] eliminate drugs that cannot be mapped to a standard drug 
dictionary, or for which little data are known to analyze the potential relationship of AEs or drug 

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interactions.  Exclusion Criteria [14] through [26] and [28] through [34] ensure that previous or 
currently required treatments or conditions do not complicate on-study treatment and/or analysis 
of data.  Exclusion Criterion [27] excludes patients who may be at elevated risk of toxicity based 
on the known safety profile of necitumumab and pembrolizumab.
7.3.
Discontinuation
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
All enrolled patients who discontinue, regardless of whether or not they received study 
treatment, will have procedures performed as shown in the Study Schedule (Attachment 1).
Patients who are discontinued from study treatment early will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without study drug.  Inadvertently enrolled patients 
may be maintained in the study and on study treatment when the Lilly CRP agrees with the 
investigator that it is medically appropriate for that patient. The patient may not continue in the 
study with or without study drug if the Lilly CRP does not agree with the investigator’s 
determination it is medically appropriate for the patient 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.
7.3.2. Discontinuation of Study Therapy
Patients will be discontinued from the study treatment in the following circumstances: 

Enrollment in any other clinical trial involving a study drug or enrollment in 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 study therapy occurs prior to introduction of the new agent.

Investigator/Physician Decision
o
The investigator/physician decides that the patient should be withdrawn from the 
study due to an intercurrent illness or change in the patient’s condition that 
renders the patient unsuitable for further treatment in the opinion of the 
investigator.

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o
Any study therapy-related event that is deemed life-threatening, regardless of 
grade, warrants discontinuation of that therapy and/or discontinuation from all 
therapy if appropriate in the opinion of the investigator.
o
If the patient has progressive disease (PD, confirmed by irRECIST or 
unconfirmed but with clinically worsening/deterioration [Section 10.1.5.1 and 
Table JFCQ.10.1]).
o
Any event(s) which would require a given study therapy to be modified by more 
than 2 dose reductions or to be held for more than 6 weeks following Day 1 of the 
most recent cycle warrants discontinuation of that therapy.
o
The patient becomes pregnant during treatment.

Patient Decision
o
The patient or patient’s designee (for example, parents or legal guardian) requests 
to be withdrawn from the study or study treatment.

Sponsor Decision
o
The sponsor stops the study or stops the patient’s participation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practices (GCP).

The patient is significantly noncompliant with study procedures and/or treatment.

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient).

A Grade 3 to 4 IRR, and potentially other drug-related AEs, as specified in Section 9.4.1
below.

Patients, who experience complete response (CR), that have been treated for at least 
24 weeks from Cycle 1 Day 1with pembrolizumab and necitumumab or pembrolizumab 
alone and had at least 2 treatments with pembrolizumab with or without necitumumab 
beyond the date when the initial CR was declared can discontinue treatment.
7.3.3. Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

the investigator decides that the patient should be discontinued from the 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 occurs prior to introduction of the new agent

the patient or the patient’s designee requests that the patient be withdrawn from the study

Lilly stops the study or stops the patient’s participation in the study for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP
Patients who are discontinued from study participation will not be followed for PD or survival.
7.3.4. Patients who are 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. Site personnel, or an independent third 

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party, will attempt to collect the vital status (that is, alive or dead) for all patients who are lost to 
follow-up, including patients who do not receive study treatment within legal and ethical 
boundaries.  Site personnel, or an independent third party, may search public sources for vital 
status information.  If the patient's vital status is determined, the vital status will be documented 
and the patient will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.
7.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.

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8.
Investigational Plan
8.1.
Summary of Study Design
Study I4X-MC-JFCQ is an open-label, multicenter Phase 1b study with an expansion cohort to 
investigate necitumumab in combination with pembrolizumab in approximately 78 patients with 
Stage IV NSCLC (AJCC Staging Manual, 7th edition).
The study consists of 3 parts:

Part A:  Dose-escalation part with increasing doses of necitumumab (initially 600 mg
and then 800 mg on Days 1 and 8 Q3W) to determine a recommended dose for
necitumumab that may be safely administered in combination with a fixed regimen of 
pembrolizumab 200 mg on Day 1 Q3W in patients with Stage IV NSCLC.

Part B (Expansion Cohort):  Dose confirmation of necitumumab in combination with a 
fixed regimen of pembrolizumab 200 mg on Day 1 Q3W and exploration of clinical
antitumor activity in patients with Stage IV NSCLC.

Part C (Japanese patients):  DLT confirmation using the recommended dose from Part 
A for necitumumab in combination with a fixed regimen of pembrolizumab 200 mg on 
Day 1 Q3W in Japanese patients with Stage IV NSCLC.  
In Part B, approximately 54 patients will be enrolled with an approximately even split between 
squamous and nonsquamous histology.
Figure JFCQ.8.1 illustrates the study design.

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* Part C will first enroll 6 patients. If 2 out of 6 patients experience DLTs, the sponsor will examine the safety data 
and consult with an external committee as needed.  The sponsor will decide if the dose is intolerable, or if additional 
patients will be enrolled to the same dose level (or lower dose level) for further investigation.  If additional patients 
are needed, 6 additional Japanese patients will be enrolled (to maximum of 12 Japanese patients in Part C).
Abbreviations: D = day; DLT = dose-limiting toxicity; MTD = maximum tolerated dose; n = number of patients; 
Q3W = every 21 days.
Figure JFCQ.8.1.
Illustration of study design.
Part A is a single-arm, dose-escalation study to determine the recommended dose for the 
expansion cohort (Part B) and Japanese patients (Part C).
Part A:
Cohort 1

Pembrolizumab, administered I.V. over 30 minutes (−5 min/+10 min) at an absolute
dose of 200 mg on Day 1, followed by

Necitumumab, administered I.V. over 60 minutes at a dose of 600 mg on Days 1 and 8, 
Q3W
Cohort 2
Cohort 1 (n 3-6)
Pembrolizumab  200 mg
D1 Q3W
Necitumumab     600 mg
D1 and 8 Q3W
Cohort 2 (n 6)
Pembrolizumab  200 mg
D1 Q3W
Necitumumab     800 mg
D1 and 8 Q3W
Add 3 patients
STUDY 
DISCONTINUATION
1 DLT
MTD cohort 1 dose
≥2 DLT/6pts
≤1 DLT
1 DLT/6pts
0 DLT
Pembrolizumab
200 mg D1 Q3W
Necitumumab
Dose from Part A D1 and 8 Q3W
Part B
(n = 54)
Part A (n = 3-12)
≥2 DLT/6pts
Part C (Japanese)
(n = 6-12*)
Pembrolizumab
200 mg D1 Q3W
Necitumumab
Dose from Part A D1 and 8 Q3W

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
Pembrolizumab, administered I.V. over 30 minutes (−5 min/+10 min) at an absolute
dose of 200 mg on Day 1, followed by

Necitumumab, administered I.V. over 60 minutes at a dose of 800 mg on Days 1 and 8, 
Q3W
Note:  At the time of approval of the JFCQ(c) protocol amendment, all patients who are still on 
the study will be administered necitumumab I.V. infusion over 60 minutes.
A maximum of 12 evaluable patients with Stage IV NSCLC will be enrolled in Part A.  Any 
patient who is discontinued from the study before completing Cycle 1 will be excluded from the 
DLT population, unless a DLT was observed.  Patients who do not complete Cycle 1 for reason 
other than DLT will be replaced.
If 1 of 3 patients in cohort 1 experiences a DLT during Cycle 1, 3 additional patients will be 
enrolled in the cohort.  If ≥2 of 6 patients experience a DLT in Cohort 1, the study must be 
discontinued.
Cohort 2 will enroll 6 patients.  If ≤1 of the 6 patients develops a DLT, Cohort 2 dose will be the 
recommended Phase 2 dose.  If ≥2 of the 6 patients experience a DLT in Cohort 2, then the dose 
in Cohort 1 will be the MTD.
Dose escalation within a cohort will not be permitted. Patients assigned to a cohort dose level 
will remain at that level throughout the study.  Patients who withdraw from the study during the 
DLT period for reasons other than a treatment-related toxicity may be replaced within the same 
dose level.
Necitumumab plus pembrolizumab may be continued at the assigned dose level until disease 
progression, the development of unacceptable toxicity or withdrawal of consent by the patient, or 
sponsor/investigator decision.
Part B:
Part B will enroll approximately 54 patients.  It is a single-arm study to evaluate efficacy and 
safety of necitumumab in combination with pembrolizumab in patients with Stage IV 
squamous or nonsquamous NSCLC (Figure JFCQ.8.1).  Patients will be treated with 
pembrolizumab 200 mg on Day 1 Q3W and the dose of necitumumab identified from Part A 
of the study on Days 1 and Day 8 Q3W.
Provided there is an acceptable safety profile in Part A of this study, Part B will be initiated, 
which will include an interim safety analysis after the first 15 evaluable patients have completed 
2 cycles of study treatment (or otherwise discontinued study treatment).  Patients with squamous 
and nonsquamous NSCLC from Part A who received the recommended necitumumab dose for 
Part B will be included in the safety interim analysis.  
The final analysis for all outcomes for Part B will be performed approximately 6 months after 
completing enrollment of the study population.

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A treatment cycle will be defined as 21 days.  Study therapy, consisting of necitumumab plus 
pembrolizumab, will continue until there is a radiographic documentation of PD, toxicity 
requiring cessation, protocol noncompliance, or withdrawal of consent. Discontinuation of 
treatment may be considered for patients who have attained a confirmed CR that have been 
treated for at least 24 weeks from Cycle 1 Day 1 with pembrolizumab and necitumumab or 
pembrolizumab alone and had at least 2 treatments with pembrolizumab with or without 
necitumumab beyond the date when the initial CR was declared.  
Part C:
Part C will only enroll patients from Japan.  It is a single-arm study to evaluate safety and 
tolerability of necitumumab at the recommended dose identified from Part A of the study on 
Days 1 and Day 8 Q3W in combination with pembrolizumab 200 mg on Day 1 Q3W in 
Japanese patients with stage IV NSCLC (Figure JFCQ.8.1).  
Part C will first enroll 6 patients.  If 2 out of 6 patients experience DLTs, the sponsor will 
examine the safety data and consult with an external committee as needed. The sponsor will 
decide if the dose is intolerable, or if additional patients will be enrolled to the same dose 
level (or lower dose level) for further investigation.  If additional patients are needed, 6 
additional Japanese patients will be enrolled (to maximum of 12 Japanese patients in Part C).  
Terms used to describe the periods during the trial are defined below:

Baseline:  begins when the ICF is signed and ends at the first study treatment (or at 
discontinuation, if no treatment is given).

Study Period:  begins at the first study treatment and ends at study completion. The 
study period does not include the continued access period.
o
Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue study 
treatment.  The date of this agreement is to be reported on the case report form 
(CRF) as the Date of Discontinuation from study treatment.

Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.
Short-term 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.
Long-term follow-up begins the day after short-term follow-up is completed and 
continues until the patient’s death or overall study completion.

Continued Access Period:  begins after study completion and ends at the end of trial.  
During the continued access period, patients on study treatment who continue to 
experience clinical benefit and no undue risks may continue to receive study treatment 
until one of the criteria for discontinuation is met.  The continued access period includes 
continued access follow-up.

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o
Continued access follow-up:  begins the 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.
8.1.1. Study Completion and End of Trial
Part A and Part B of this study will be considered complete (that is, the scientific evaluation will 
be complete [study completion]) approximately 6 months after the last patient in Part B of the 
study has been enrolled, and Part C of this study will be considered complete approximately after 
all the patients in Part C have completed 8 cycles or discontinued early.  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.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up.

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a Lilly will notify sites when continued access period begins and ends.
b Part A and Part B of this study will be considered complete approximately 6 months 
after the last patient in Part B has been enrolled, and Part C of this study will be 
considered complete approximately after all the patients in Part C have completed 8 
cycles or discontinued early.
Figure JFCQ.8.2.
Study period and continued access diagram.
8.1.2. Continued Access Period
The continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs.  Patients receiving study treatment and experiencing 
ongoing clinical benefit and no undue risks may continue to receive study treatment in the 
continued access period until one of the criteria for discontinuation is met (Section 7.3).  Lilly
will notify investigators when the continued access period begins.
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.
End of 
Trial
Study 
Completion
Patients on 
Treatment
Patient on Study Treatment
Study Period
Continued 
Access Perioda
Patient on 
Study 
Treatment
Short-Term 
Follow-Up 
Long-Term 
Follow-Up
Patient 
Discontinues 
Study 
Treatment
Continued 
Access 
Period 
Follow-Up
Final Analysis 
(all outcome)b
Last visit/
scheduled 
procedure for 
last patient
Patient 
Discontinues 
Study 
Treatment

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Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
During the continued access period, all AEs, SAEs, and study drug exposure will be reported on 
the CRF.  Serious adverse events will also be reported to Lilly Global Patient Safety (see 
Section 10.2.1).  In the event that an SAE occurs, Lilly may request additional information (such 
as local laboratory results, concomitant medications, and hospitalizations) in order to evaluate 
the reported SAE. Blood samples for PK and immunogenicity analysis for necitumumab will be 
collected in the event of an IRR and during the continued access follow-up.
During the continued access period, the sponsor will collect only the data shown in 
Attachment 1.  It is recommended that routine monitoring, using an assessment schedule similar 
to that outlined in Attachment 1 (including radiographic evaluation of disease), be continued as 
necessary to confirm patient eligibility to continue on treatment.  However, the results of all 
these assessments may not be routinely collected by the sponsor, and all nonmandatory 
assessments (that is, all assessments not explicitly described in Attachment 1) may be performed 
locally rather than centrally.
8.2.
Discussion of Design and Control
In this open-label, Phase 1b study with an expansion cohort, the selected fixed-dose of 
pembrolizumab of 200 mg on Day 1 Q3W is an experimental dose but the differences in 
exposure for a 200-mg fixed-dose regimen relative to a 2-mg/kg Q3W body weight-based 
regimen registered currently for melanoma indication are anticipated to remain well within the 
established exposure margins for this compound.  The starting dose of necitumumab in Part A
(patients with Stage IV NSCLC) will be at dose level -1 of the MTD (600 mg on Days 1 and 8 
Q3W).  Since this is the first time these 2 mAbs are combined in a clinical setting, the 
recommended, biologically active dose of pembrolizumab was selected and it was chosen to use 
a DLT-driven design to escalate necitumumab to MTD.
Patients with Stage IV NSCLC who have progressed after 1 platinum-based chemotherapy 
regimen will receive a combination of necitumumab and pembrolizumab.  Prior treatment with 
EGFR-TKI, VEGF/VEGFR-targeting agents, and ALK inhibitors is permitted.
In Part B, approximately 54 patients with Stage IV NSCLC with an approximately even split 
between squamous and nonsquamous histology will be enrolled to enable evaluation of safety 
and efficacy parameters by histology.
Provided there is an acceptable safety profile in Part A of this study, Part B will be initiated, 
which will include an interim safety analysis after the first 15 evaluable patients have completed 
2 cycles of study treatment (or otherwise discontinued study treatment).  Patients with squamous 
and nonsquamous NSCLC from Part A who received the recommended necitumumab dose for 
Part B will be included in the safety interim analysis.
In Part C, 6-12 Japanese patients with Stage IV NSCLC with squamous and nonsquamous 
histology will be enrolled to enable evaluation of safety and efficacy parameters using a fixed 

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200-mg dose of pembrolizumab given Q3W and necitumumab dose as determined in the Part A 
of the study.
The outcome will be hypothesis generating only, allowing for future consolidation of this 
regimen depending on the outcome.

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9.
Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study (Table JFCQ.9.1):
In Part A, patients will receive I.V. necitumumab 600 mg or 800 mg on Day 1 and Day 8 Q3W
in combination with pembrolizumab 200 mg as an absolute dose on Day 1 Q3W.
In Part B and Part C, the necitumumab dose identified from Part A will be given on Day 1 and 
Day 8 Q3W in combination with pembrolizumab 200 mg as an absolute dose Day 1 Q3W.
Pembrolizumab will be administered first followed by necitumumab.
Table JFCQ.9.1.
Treatment Regimens/Dosing Schedule
Part A
Cohort
Drug
Dose
Day of 21-day Cycle
Infusion Duration
Cohort 1
Pembrolizumab
200 mg absolute dose I.V. 
infusion
Day 1
Over 30 minutesa
Necitumumab
600 mg dose I.V. infusion
Days 1 and 8
Over 60 minutesb
Cohort 2
Pembrolizumab
200 mg absolute dose I.V. 
infusion
Day 1 
Over 30 minutesa
Necitumumab
800 mg dose I.V. infusion
Days 1 and 8
Over 60 minutesb
Part B and Part C
Drug
Dose
Day of 21-day Cycle
Infusion Duration
Pembrolizumab
200 mg absolute dose I.V. infusion
Day 1
Over 30 minutesa
Necitumumab
Recommended dose from Part A I.V. 
infusion
Days 1 and 8
Over 60 minutesb
Abbreviation: I.V. = intravenously.
a
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes −5 min/+10 min, i.e., between 25 to 40 minutes).
b
At the time of approval of the JFCQ(c) protocol amendment, all patients who are still on the study will be 
administered necitumumab I.V. infusion over 60 minutes.
Based on the independent necitumumab and pembrolizumab clinical development programs, 
the individual recommended doses are 800 mg on Day 1 and Day 8 Q3W for necitumumab 
and 200 mg on Day 1 for pembrolizumab. For this reason, further dose escalation beyond 
Cohort 2 will not be tested.

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Hypersensitivity/infusion-related reactions (IRRs) may occur during or following administration 
of necitumumab (see Section 9.4.1.3.1 for a definition of Grade 3 and 4 hypersensitivity/IRRs).  
As a routine precaution, patients treated with necitumumab should be observed closely for any 
potential adverse effects by the medical staff 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.
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 patient,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensing and collection, 

and returning all unused medication to Lilly or its designee at the end of the study.
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 study drug so that the situation can be assessed.
9.2.
Materials and Supplies
Necitumumab will be provided by Lilly and pembrolizumab will be provided by Merck (all 
materials will be packaged and shipped from Lilly, and will bear Lilly clinical trial material 
labeling).  Clinical trial materials will be labeled according to the country’s regulatory 
requirements.
Necitumumab is a sterile and preservative-free solution for I.V. infusion supplied in the 
following formulation:

Necitumumab solution for infusion at a final concentration of 16 mg/mL 
(800 mg/50 mL) contained in single-use vials, in a formulation of 10 mM 
citrate, 40 mM sodium chloride, 133 mM glycine, 50 mM mannitol, 0.01% 
polysorbate-80, pH 6.0.
All excipients used in the formulation of necitumumab are of pharmacopeial grade.  No 
animal-derived components are used in the manufacture of necitumumab excipients.  The drug 
product must be stored under refrigeration at 2°C to 8°C with protection from light.  Refer to 
necitumumab IB for detailed storage information.
Pembrolizumab drug product is available in 2 dosage forms: a white to off-white lyophilized 
powder, 50 mg/vial, and a liquid, 100 mg/vial, both in Type I glass vials intended for single use only.

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
Pembrolizumab Powder for Solution for Infusion, 50 mg/vial, is a lyophilized 
powder that is reconstituted with sterile water for injection prior to use.
Pembrolizumab is formulated with L-histidine as buffering agent, polysorbate 
80 as surfactant, sucrose as stabilizer/tonicity modifier, and may contain 
hydrochloric acid and/or sodium hydroxide for pH adjustment (if necessary).

Pembrolizumab Solution for Infusion 100 mg/vial is a liquid, manufactured 
fully formulated with L-histidine as a buffering agent, polysorbate 80 as a 
surfactant, and sucrose as a stabilizer/tonicity modifier.
Both pembrolizumab product dosage forms are stored under refrigerated conditions 2°C to 8°C
(36-46°F) and protected from light.  Refer to pembrolizumab IB for detailed storage information.
9.3.
Method of Assignment to Treatment
An interactive web response system (IWRS) will be utilized for drug dispensing for Parts A, B,
and C of the study.
For patients in Part B, enrollment will be balanced to include approximately 50% squamous and 
50% nonsquamous patients.  Patients will be registered in the IWRS, which consists of assigning 
a unique study identification number and entering the patient’s tumor histology type (squamous 
vs. nonsquamous).  Once the patient is registered in the IWRS, he or she is considered being 
enrolled in the study.  Enrollment into the IWRS will be disabled once enrollment goals have 
been met for both histology types.
9.4.
Selection and Timing of Doses
The first treatment will be administered within 7 days of enrollment.  Study treatment will be 
administered as described in Section 9.1.
A cycle is defined as an interval of 21 days.
Administration of pembrolizumab Day 1 dose, followed by necitumumab will trigger the start of 
a new cycle.  Infusions administered within 3 days before or after the planned infusion time point 
due to holidays, weekends, bad weather, or other unforeseen circumstances will be permitted and 
not counted as a protocol deviation.  The necitumumab Day 8 dose can be delayed up to 5 days.  
Beyond that, the Day 8 dose will have to be omitted in order to maintain the 21 day cycle.  A 
minimum of 7 days’ interval between any necitumumab doses must be maintained.
A patient may continue to receive study treatment until he or she meets 1 or more of the 
specified reasons for discontinuation (as described in Section 7.3), or complete remission is 
diagnosed (as described in Section 8.1).
9.4.1. Special Treatment Considerations
9.4.1.1.
Dose-Limiting Toxicity (Parts A and C)
A DLT is defined as one of the following AEs, occurring in Cycle 1 if considered to be 
definitely, probably, or possibly related to necitumumab and pembrolizumab. The following list 
will define DLT:

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
Grade 3 or 4 nonhematologic toxicity according to the NCI-CTCAE Version 4.0, 
except for skin toxicity, nausea, vomiting, diarrhea, or electrolyte disturbance (see 
below). For patients with ≤ Grade 2 hepatic transaminase levels at baseline as a 
result of liver metastases, a transaminase level ≥10x ULN lasting for >7 days will 
be considered a DLT.

Grade 4 nausea, vomiting, or diarrhea that persists more than 3 days despite 
maximal supportive intervention

Grade 3 thrombocytopenia with bleeding requiring transfusion

Grade 4 thrombocytopenia with or without bleeding

Grade 4 neutropenia  that persists more than 5 days

Grade 3 or 4 neutropenia with fever, defined as single temperature of >38.3°C 
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than one hour

Grade ≥3 skin toxicity despite best supportive care, with exception of Grade 3 
rash that resolves to Grade ≤2 within 14 days with appropriate supportive therapy

If a total at least 75% of the planned dose for both agents cannot be administered 
in the first cycle due to toxicity

Prolonged delay (>2 weeks) in initiating cycle 2 due to treatment-related toxicity

Grade 5 toxicity
DLT is defined by sponsor and principal investigator.
The following toxicities will not be considered DLTs if they are transient (<7 days):

Hypersensitivity and injection site reactions (If a Grade 3 or 4 hypersensitivity/
IRR to necitumumab or pembrolizumab occurs, this event will not be considered 
a DLT; the patient will not receive any further study therapy and will be replaced 
in the study by a new patient.)

Grade ≥3 myalgia, fatigue, or constipation, with full supportive therapy

Grade ≥3 increase or decrease of electrolytes

Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤1 within 7 days of 
appropriate supportive therapy 

Grade ≥3 elevation of serum creatine kinase level that is asymptomatic that 
returns to Grade ≤2 within 21 days of necitumumab treatment interruption
9.4.1.2.
Dose Adjustments and Delays
9.4.1.2.1. Pembrolizumab
9.4.1.2.1.1.
Pembrolizumab Dose Modifications
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or several 

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months after the last dose of treatment. Pembrolizumab must be withheld for drug-related
toxicities and severe or life-threatening AEs as per Table JFCQ.9.2.

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Table JFCQ.9.2.
Dose Modification Guides for Pembrolizumab Drug-Related 
Adverse Events
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting Treatment
Treatment Discontinuation
Diarrhea/Colitis
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
AST, ALT, or 
Increased Bilirubin
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose.
3-4
Permanently discontinue
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM or 
3-4
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure.
Resume pembrolizumab when patients are clinically and 
metabolically stable.
Hypophysitis
2-4
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can be 
continued while endocrine replacement 
therapy is instituted
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Hyperthyroidism
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted.
Infusion Reaction
2b
Toxicity resolves to Grade 0-1
Permanently discontinue if toxicity develops despite 
adequate premedication
3-4
Permanently discontinue
Permanently discontinue
Pneumonitis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
3-4
Permanently discontinue
Permanently discontinue
Renal Failure or
Nephritis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
3-4
Permanently discontinue
Permanently discontinue
All Other Drug-
Related Toxicityc
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
IRR = infusion-related reaction; T1DM = type 1 diabetes mellitus.
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that 
recurs or any life-threatening event.

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a
For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline and lasts for at least 1 week, then patients should be 
discontinued.
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise, dosing will be held until symptoms resolve 
and the patient should be given premedication for the next scheduled dose.  Refer to Table JFCQ.9.5 – IRR 
Treatment Guidelines for further management details.
c
Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with 
study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.
9.4.1.2.2. Necitumumab
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 Grade3-4 necitumumab-related toxicity (for example, 
fatigue, anorexia, and fever), administration of necitumumab will be at the 
reduced dose (refer to Section 9.4.1.2.2.1) or interrupted, but pembrolizumab 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.
9.4.1.2.2.1.
Necitumumab Dose Modifications
The following are general dose-modification guidelines for toxicity associated with 
necitumumab.  Please see Section 9.4.1.3 for specific information on the management of 
necitumumab-related hypersensitivity/IRRs, skin reactions, conjunctivitis, and hypomagnesemia.
For patients starting Cycle 1 in Part A and possible Part B of the study 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 pembrolizumab as a 
single agent.
For patients starting Cycle 1 at dose level 800 mg on Days 1 and 8 in Part A and possible Part B
and Part C of the study, 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 (Cycle 1 Parts A and C).  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 pembrolizumab as a single agent.

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Necitumumab dose adjustments are allowed both within a cycle and between cycles.
Necitumumab may be held up to 6 weeks (2 cycles) 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 
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 JFCQ.9.3.
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.  For dose modifications in response to specific AEs related to necitumumab, please 
see Section 9.4.1.3.
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, 
pembrolizumab need not be altered, and the planned pembrolizumab schedule should be 
maintained.  Similarly, necitumumab therapy should not be delayed for pembrolizumab-related 
toxicities.

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9.4.1.3.
Treatment Guidelines and Dose Modifications for Specific Adverse Events
Adverse events of special interest, which may or may not be associated with necitumumab 
and/or pembrolizumab therapy, include hypersensitivity/IRR, skin reactions, conjunctivitis, 
electrolyte abnormalities, pneumonia and sepsis, pneumonitis, diarrhea/colitis, type 1 diabetes 
mellitus, hypophysitis, hyper- or hypothyroidism, liver injury, renal failure/nephritis, and
thromboembolic events.
9.4.1.3.1. Hypersensitivity and Infusion-Related Reactions
Refer to the NCI-CTCAE Version 4.0 for grading for hypersensitivity and IRRs.
Consistent with usual medical practice, selected parenteral medications may be utilized as 
detailed below.  Additional treatments, chosen according to clinical symptoms and local 
standards, may be utilized at investigator discretion.
9.4.1.3.1.1.
Management of Infusion Reactions for Necitumumab
Hypersensitivity and IRRs were reported with necitumumab.  The onset of events usually 
occurred after the first or second administration of necitumumab.  Monitor patients during and 
following the infusion for signs of hypersensitivity and IRRs with resuscitation equipment 
readily available.
Table JFCQ.9.4 provides general treatment recommendations for hypersensitivity/IRRs to 
necitumumab.

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Table JFCQ.9.4.
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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9.4.1.3.1.2.
Management of Infusion Reactions for Pembrolizumab
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.
Table JFCQ.9.5 shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table JFCQ.9.5.
Pembrolizumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may include but is not 
limited to:
I.V. fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the 
investigator.
If symptoms resolve within one hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  Otherwise, dosing will be 
held until symptoms resolve and the patient should be 
premedicated for the next scheduled dose.
Patients who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration.
Patient may be premedicated 1.5 hr (± 30 
minutes) prior to infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic).
Grades 3 or 4
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
I.V. fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Patient is permanently discontinued from further trial 
treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration.
Abbreviations:  I.V. = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; NSAIDs = non-steroidal anti-inflammatory drugs; po = oral.
If a patient should have a hypersensitivity/IRR to necitumumab or pembrolizumab, all attempts 
should be made to obtain an anti-necitumumab antibody and PK blood samples for necitumumab 
as close to the onset of the event as possible, at the resolution of the event, and 30 days following 

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the event.  The procedure for sample collection and handling is described in a separate 
procedural manual.
9.4.1.3.2. Skin Reactions
9.4.1.3.2.1.
Reactive Treatment
Reactive treatment recommendations for skin reaction, based on the Canadian recommendations 
presented by Melosky et al. (2009), are summarized in Table JFCQ.9.6.
Skin rash (any grade) should be treated as per Table JFCQ.9.6.  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 JFCQ.9.6.
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.
If necitumumab therapy is delayed due to acneiform rash, pembrolizumab may be administered 
without interruption in the absence of disease progression.
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.

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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).
9.4.1.3.3. 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.
9.4.1.3.4. 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.
9.4.1.3.5. 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.
9.4.1.3.6. 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 
enrollment in a protocol amendment.  During the further conduct of this trial, only single 

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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 or neutropenia associated with necitumumab in this combination.
9.4.1.3.7. 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.
9.4.2. Supportive Care Guidelines for Pembrolizumab
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use 
of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.  Note that several 
courses of steroid tapering may be necessary, as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes, such as 
metastatic disease or bacterial or viral infection, which might require additional supportive care.
The treatment guidelines are intended to be applied when the investigator determines the events 
to be related to pembrolizumab.
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 9.4.1.2.1.1 for dose 
modification.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.
9.4.2.1.
Immune-Mediated Pneumonitis
Patients who experience Grade 2 events shall be treated with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over at least
4 weeks.
Grade 3-4 events shall immediately be treated with intravenous steroids.  Additional anti-
inflammatory measures can be administered, as needed.  Pembrolizumab shall be withheld for 
moderate (Grade 2) pneumonitis, and permanently discontinued pembrolizumab for severe
(Grade 3) or life-threatening (Grade 4) pneumonitis.

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Prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration shall be considered.
9.4.2.2.
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) 
or metabolic acidosis (DKA) or T1DM or Grade 3-4 Hyperglycemia
Insulin replacement therapy is recommended for type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria.
Patients shall be evaluated with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
9.4.2.3.
Immune-Mediated Hypophysitis
Grade 2 events shall be treated with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
Grade 3-4 events shall be treated with an initial dose of I.V. corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over at least 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered.
Pembrolizumab must be withheld for moderate (Grade 2) hypophysitis, withhold or discontinued 
for severe (Grade 3) hypophysitis, and permanently discontinued for life-threatening (Grade 4) 
hypophysitis.
9.4.2.4.
Immune-Mediated Hyperthyroidism or Hypothyroidism
Thyroid disorders can occur at any time during treatment. Patients shall be monitored for 
changes in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
In hyperthyroidism, non-selective beta-blockers (for example, propranolol) are suggested as 
initial therapy. Thyroid hormone replacement therapy, with levothyroxine or liothyronine, is 
indicated per standard of care. Isolated hypothyroidism may be managed without treatment
interruption and without corticosteroids.
Grade 3-4 hyperthyroidism
Treatment with an initial dose of I.V. corticosteroid followed by oral corticosteroids is 
recommended. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered.
Pembrolizumab must be withheld for severe (Grade 3) hyperthyroidism, and permanently 
discontinued for life-threatening (Grade 4) hyperthyroidism.

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9.4.2.5.
Hepatic Injury
For Grade 2 immune-mediated hepatitis, liver function tests must be monitored more frequently 
until returned to baseline values (consider weekly).  Treatment with I.V. or oral corticosteroids
shall be considered.
For Grade 3-4 immune-mediated hepatitis, intravenous corticosteroids are recommended for 
24 to 48 hours.
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over 
no less than 4 weeks.
If a patient experiences elevated ALT >3× ULN and/or elevated total bilirubin >2× ULN, clinical 
and laboratory monitoring may be initiated, at the discretion of the investigator.  For patients 
with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases 
by greater than or equal to 50% relative to baseline and lasts for at least 1 week, then patients 
should be discontinued.
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 Site Guidance Document for 
Drug-Induced Liver Injury (DILI).
9.4.2.6.
Renal Failure or Immune-Mediated Nephritis
In case of Grade 2 events, treatment with corticosteroids is recommended.
Patients that experience Grade 3-4 events shall be treated with systemic corticosteroids.
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
Pembrolizumab must be withheld for moderate (Grade 2) nephritis, and permanently 
discontinued for severe (Grade 3) or life-threatening (Grade 4) nephritis.
9.5.
Blinding
This is an open-label study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the CRF.  Concomitant medications and supportive 
care therapies must also be documented at the time of discontinuation and at the 30-day 
short-term follow-up visit.
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy or biological therapy, immunotherapy not specified in this 
protocol, hormonal cancer therapy, radiation, surgery for cancer, or experimental medications 
will be permitted while patients are on study treatment.
Palliative radiotherapy, unless required due to PD, is permitted during the study.

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
Radiation therapy to a symptomatic solitary lesion or to the brain may be considered on 
an exceptional case-by-case basis after consultation with the sponsor.  The patient must 
have clear measurable disease outside the radiated field.  Administration of palliative 
radiation therapy will be considered clinical progression for the purposes of determining 
PFS.
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial are not allowed.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. 
Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed. 
However, intranasal influenza vaccines (for example, Flu - Mist®) are live attenuated vaccines 
and are not allowed.
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE of 
suspected immunologic etiology are not permitted.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the sponsor. Inhaled steroids are 
allowed for management of asthma; similarly, intranasal steroids for rhinitis and/or sinusitis are 
allowed.
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Patients may receive other 
medications that the investigator deems to be medically necessary.
The exclusion criteria describe other medications that are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
9.6.1. Supportive Care
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to all patients on this trial.  Supportive care measures may include but 
are not limited to antidiarrheal agents, antiemetic agents, opiate and nonopiate analgesic agents, 
appetite stimulants, and granulocyte and erythroid growth factors.  Details of interventions, 
procedures, or blood products (for example, blood cells, platelets, or fresh frozen plasma 
transfusions) should be recorded on the eCRF.  Please see Section 9.4.1.3 for specific 
information on the management of necitumumab-related hypersensitivity/IRRs, skin reactions, 
conjunctivitis, electrolyte abnormalities, pneumonia and sepsis, and serious thromboembolic 
events.  Guidelines regarding the use of other specific supportive care agents are presented 
below.
9.6.2. Colony-Stimulating Factors and Erythropoiesis-Stimulating 
Agents
The use of colony-stimulating factors (CSFs) or erythropoiesis-stimulating agents (ESAs) are
permitted during investigational therapy at the discretion of the investigator.
Because recommendations on the use of CSFs/ESAs are rapidly evolving, investigators should 
frequently refer to the local, national, or international standards (for example, European

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Organisation for Research and Treatment of Cancer, European Society for Medical Oncology, 
National Comprehensive Cancer Network, American Society of Clinical Oncology, American 
Society of Hematology, and/or Centers for Medicare and Medicaid Services Web sites) for the 
latest guidelines.
9.6.3. Therapy for Diarrhea/Colitis
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).
In the event of diarrhea, the following supportive measures are allowed:  hydration, octreotide, 
and antidiarrheals.
All patients who experience diarrhea/colitis should be advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted 
via I.V. infusion.  For Grade 2 or higher diarrhea, consider gastrointestinal consultation and 
endoscopy to confirm or rule out colitis.

For Grade 2 diarrhea/colitis, oral corticosteroids are recommended.

For Grade 3 or 4 diarrhea/colitis, intravenous steroids followed by high dose oral 
steroids are recommended. 

When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
(Grade 3 or 4) neutropenia, broad-spectrum antibiotics must be prescribed.  Patients with 
Grade ≥3 diarrhea or any diarrhea associated with Grade ≥3 nausea or vomiting must be 
hospitalized for intravenous hydration and correction of electrolyte imbalances.  Events that 
require a patient to be hospitalized are considered SAEs (see Section 10.2.1.1).
Pembrolizumab shall be withheld for moderate (Grade 2) or severe (Grade 3) colitis, and 
permanently discontinued for life-threatening (Grade 4) colitis.
9.6.4. Antiemetic Therapy
The use of antiemetic agents is permitted during this study.
9.6.5. Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.
9.6.6. Bisphosphonates and RANK-L Targeted Agents
Patients with bone metastases present on baseline imaging are allowed treatment with 
bisphosphonates or receptor activator of nuclear factor kappa-B ligand (RANK-L) targeted 
agents (for example, denosumab), per respective approved labels.  Initiation of treatment with 
bone-modifying agents must begin at least 7 days prior to enrollment.  Patients receiving 
bisphosphonates or RANK-L targeted agents should not switch treatments (for example, replace 

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a bisphosphonate with denosumab) while on study treatment.  However, exceptional cases 
without evidence of PD may be considered in consultation with the Lilly CRP.  These 
exceptional cases will not incur a protocol deviation.
9.6.7. Therapy for Febrile Neutropenia
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation of 
intravenous antibiotic therapy.  Events that require a patient to be hospitalized are considered 
SAEs (see Section 10.2.1.1).
9.7.
Treatment Compliance
Pembrolizumab and necitumumab will be administered I.V. at the investigational site, under the 
direction of the investigator. As a result, a patient’s compliance with study drug administration 
is ensured.  Patients should attend scheduled clinic visits and must comply with study criteria 
under their control.
Patients who are significantly noncompliant will be discontinued from the study.  A patient will 
be considered significantly noncompliant if he or she delays therapy for more than 6 weeks 
following Day 1 of the most recent cycle during the study.
The study medication will be administered only at the investigational sites by the authorized 
study personnel.  As a result, treatment compliance is ensured.
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP before any determination is made to discontinue the patient.

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10. Efficacy, Safety Evaluations, Sample Collection and 
Testing, and Appropriateness of Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.
Study procedures related to efficacy, safety, and sample collection and testing assessments and 
their timing are described in the sections below and shown in the Study Schedule 
(Attachment 1).
10.1. Efficacy Measures
10.1.1. Efficacy Assessments at Baseline and during Study Treatment
Within 21 days before the first dose of study drug, baseline tumor measurements will be 
performed on each patient.  Throughout the study, patients will be evaluated for response 
according to RECIST 1.1 (Eisenhauer et al. 2009). For the purpose of patient management, 
RECIST 1.1 with adaptation (irRECIST) will be used to assess tumor response (see 
Section 10.1.5.1).
A contrast computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain 
will be performed at pretreatment only, and thereafter approximately every 6 weeks ± 5 days, if a 
patient had brain metastases at study entry or if clinically indicated.
Computed tomography, including spiral CT, scans and MRI are the preferred methods of 
measurement.
The method of assessment used at baseline must be used consistently during the course of each 
patient’s evaluation during the study.
Imaging studies required to investigate known disease should be repeated every 6 weeks 
(± 5 days) following the first dose of study therapy, regardless of any treatment delays, until 
radiographic documentation of PD as defined by RECIST 1.1, with adaptation described below 
in more detail (irRECIST; see Section 10.1.5.1). 
CT of the chest and CT or MRI of the abdomen and pelvis is required at each time point;
CT/MRI of the brain must be performed if baseline assessment identified any lesion in this area 
(or if clinically indicated).
Responses (CR or PR) must be confirmed at least 28 days from the first evidence of response.  
Thereafter, a responding patient will be followed approximately every 6 weeks (±5 days) until 
objective progression is observed.
For patients continuing treatment after study completion (continued access period), efficacy 
assessments (frequency and type of assessments) will be at the discretion of the investigator, 
based on the standard of care.
Response assessments during the ongoing trial (and related treatment decisions) will be 
performed by the treating investigator at the site in cooperation with the local radiologist(s).

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10.1.2. Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1).
For those patients who discontinue study treatment without objectively measured PD, the 
investigative sites will continue to monitor patients and periodically evaluate tumor response at 
the same frequency and by the same method used at baseline and throughout the study until the 
patient has objective disease progression, starts a new anticancer therapy, or until study 
completion, whichever occurs first. After the patient has objective disease progression (as 
determined using methodology described below) or starts a new anticancer therapy, radiologic 
tests are no longer required and the patient will be followed up approximately every 3 months
[7 days] until the patient’s death or overall study completion, whichever comes first.
Response (CR or PR) should be confirmed before the initiation of additional anticancer therapy. 
However, initiation of new therapy should not be delayed solely to confirm response.
After patients have discontinued study treatment, they may receive additional anticancer therapy 
at the discretion of the investigator.  These postdiscontinuation therapies must be documented on 
the CRF.
10.1.3. Primary Efficacy Measure (Part B only)
10.1.3.1. Tumor Imaging and RECIST Assessment
Local site study team reading (investigator assessment with site radiology reading) based on 
RECIST 1.1 will be used to determine patient eligibility.  Tumor imaging should be performed 
by CT (preferred).  MRI should only be used when CT is contraindicated or for imaging in the 
brain, but the same imaging technique should be used in a patient throughout the trial.
Imaging should include the chest, abdomen, and pelvis.
10.1.3.1.1.Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 21 days prior to the date of the first 
dose of trial treatment.  The site study team must review screening images to confirm the patient
has measurable disease per RECIST 1.1. 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 21 days prior to the date of first dose.
10.1.3.1.2.On Study Tumor Imaging
The first on-study imaging assessment should be performed at 6 weeks (±5 days) from the date 
of first dose of trial treatment. Subsequent tumor imaging should be performed every 6 weeks 
(±5 days) or more frequently only if clinically indicated.  Imaging should not be delayed for 
delays in any of the study drug dosing. Continue to perform imaging until whichever of the 
following occurs first: 

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•
Initial site-assessed disease progression is confirmed (Section 10.1.5.1)
•
The start of new anti-cancer treatment
•
Withdrawal of consent
•
Death 
•
The end of the study
10.1.3.2. Tumor Response Assessment
The primary efficacy measure is ORR as defined by RECIST 1.1 (Eisenhauer et al. 2009)
provided in Attachment 5.  A responder is defined as any patient who exhibits a confirmed CR or 
PR.
Best response is determined from the sequence of responses assessed.
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor imaging 
assessment. A second assessment must be performed 28 days after the first evidence of 
response or at the next scheduled scan (that is, 6 weeks later), whichever is clinically indicated.  
Two objective status determinations of CR before progression are required for a best response of 
CR.  Two determinations of PR or better before progression, but not qualifying for a CR, are 
required for a best response of PR.  Best response of SD is defined as disease that does not meet 
the criteria for CR, PR, or PD and has been evaluated at least 1 time, at least 6 weeks after the 
start of study treatment.
Best response will be derived to encompass all tumor assessments from baseline until the earliest 
of objective progression or start of new anticancer therapy.  Any responses observed after 
objective progression or the start of new anticancer therapy are excluded from the determination
of best response.
The date of first documented objective disease progression must be recorded on the CRF even if 
it occurs after the patient has started a new therapy.
10.1.4. Secondary Efficacy Measures
The secondary efficacy measures, including DCR, DOR, PFS, and OS, will be collected at the 
times shown in the Study Schedule (Attachment 1).
10.1.5. Exploratory Efficacy Measures
10.1.5.1. Adapted RECIST 1.1 (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses. The response 
patterns seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions.  Standard RECIST 1.1 assessment may not 

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provide an accurate response assessment of immunotherapeutic agents such as pembrolizumab.  
Therefore, RECIST 1.1 will be used with the following adaptations:

If radiologic imaging verifies initial PD, tumor assessment should be repeated ≥4 weeks 
later in order to confirm PD with the option of continuing treatment per Table JFCQ.10.1
below while awaiting radiologic confirmation of progression.

If repeat imaging shows <20% tumor burden compared to nadir, stable or improved 
previous new lesion (if identified as cause for initial PD), and stable/improved non-target 
disease (if identified as cause for initial PD), treatment may be continued/resumed.

If repeat imaging confirms PD due to any of the scenarios list below, patients will be 
discontinued from study therapy and proposed best alternative available.
In determining whether or not the tumor burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden remains ≥20% and at least 5-mm absolute increase compared to nadir

Non-target disease resulting in initial PD is worse (qualitative) 

New lesion resulting in initial PD is worse (qualitative)

Additional new lesion(s) since last evaluation
In patients who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a patient on study treatment until repeat imaging is obtained.  This 
clinical judgment decision should be based on the patient’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Patients may receive 
pembrolizumab and necitumumab treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG PS, apart from change from PS0 to PS1

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (for example, cord compression) 
requiring urgent alternative medical intervention
When feasible, patients should not be discontinued from study therapy until progression is 
confirmed.  This allowance to continue treatment despite initial radiologic progression takes into 
account the observation that some patients can have a transient tumor flare in the first few 
months after the start of immunotherapy, but with subsequent disease response.  Patients that are 
deemed clinically worsening/deteriorating are not required to have repeat imaging for 
confirmation of progressive disease (see Table JFCQ.10.1).

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Table JFCQ.10.1.
General Guidance for Decision Making on Repeated Radiologic 
Assessment in Patients with Initial PD based on Clinical Status
Clinically Stable
Clinically Worsening/Deterioration
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging at 
≥4 weeks to 
confirm PD
May continue 
study treatment at 
the local site 
investigator’s 
discretion while 
awaiting 
confirmatory scan
by irRECIST
Repeat imaging at 
≥4 weeks to confirm 
PD if possible
Discontinue study 
treatment
Repeat scan confirms 
PD by irRECIST at the 
local site
No additional 
imaging required
Discontinue study 
treatment
(exception is 
possible upon 
consultation with 
sponsor)
No additional imaging 
required 
N/A
Repeat scan shows SD, 
PR, or CR (compared 
to scan showing first 
radiologic evidence of 
PD) by irRECIST at 
the local site
Continue 
regularly 
scheduled 
imaging 
assessments every 
6 weeks 
(± 5 days)
Continue study 
treatment at the 
local site 
investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments every 
6 weeks (± 5 days)
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion
Abbreviations:  CR = complete response; N/A = not applicable; PD = progressive disease; PR = partial response; 
SD = stable disease.
NOTE: 

If a patient has confirmed radiographic progression (i.e., 2 scans at least 4 weeks apart 
demonstrating progressive disease) per irRECIST, but the patient is achieving a clinically 
meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the Sponsor. 

Any patient deemed clinically unstable should be discontinued from trial treatment at first
radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.

In patients who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using 
the same imaging schedule used while on treatment every 6 weeks (± 5 days), until (1) 
the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of 
the study, whichever occurs first.

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The following exploratory efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1). Confirmation by 2 consecutive observations at least 4 weeks apart is 
required for CR, PR, and PD for both assessments to assign best response for each patient:

immune-related CR (irCR): disappearance of all lesions

immune-related PR (irPR): ≥30% decrease of total tumor burden from baseline

immune-related PD (irPD): ≥20% increase of total tumor burden from the nadir

immune-related SD (irSD): fail to meet criteria for irCR or irPR in the absence of irPD
10.1.6. Resource Utilization
Investigators will be asked to document the use of best supportive care measures, concomitant 
medications, transfusions, and treatment-related hospitalization days.  Such assessments are to be 
taken throughout the study through the 30-day short-term postdiscontinuation follow-up visit.
10.2. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered 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 investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, or that caused the patient to discontinue 
before completing the study.  The patient should be followed until the event is resolved or 
explained.  Frequency of follow-up evaluation is left to the discretion of the investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JFCQ.10.2 presents a summary of AE and SAE reporting guidelines.  Table JFCQ.10.2
also shows which database or system is used to store AE and SAE data.

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Table JFCQ.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study treatment
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study treatment that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.2.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from electrocardiograms (ECGs), labs, vital sign 
measurements, or other procedures that result in a diagnosis should be reported to Lilly or its 
designee.
Cases of pregnancy that occur during maternal or paternal exposures to study treatment should 
be reported.  Data on fetal outcome and breast-feeding are collected for regulatory reporting and 
drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.

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In addition, all AEs occurring after the patient receives the first dose of study treatment must be 
reported to Lilly or its designee via eCRF.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, or study treatment via eCRF.
The investigator will decide whether he or she interprets the observed AEs as either reasonably 
possibly related to disease, to the study medication, study procedure, or other concomitant 
treatment or pathologies.  The investigator answers Yes/No to make this assessment in relation to 
study treatment and study procedure.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
The NCI-CTCAE v 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the NCI-CTCAE v 4.0 criteria, the investigator will be responsible 
for selecting the appropriate system organ class (SOC) and assessing severity grade based on the 
intensity of the event.
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA™) dictionary.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.2.1.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

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 adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed informed consent and has 
received study treatment.  If a patient experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will not be reported as serious unless the investigator 
feels the event may have been caused by a protocol procedure.

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Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  If study site 
personnel contact Lilly or its designee by telephone regarding an SAE, study site personnel must 
also immediately provide official notification on study-specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
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 are already recorded in the 
patient’s medical history at the time of study 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 due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study treatment.
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, if an investigator becomes aware of an SAE 
occurring after the patient’s participation in the trial has ended, and the investigator believes that 
the SAE is related to a protocol procedure or study treatment, the investigator should report the 
SAE to the sponsor, and the SAE will be entered in the Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
10.2.1.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information in the necitumumab IB and the Reference Safety 
Information in the pembrolizumab IB, and that the investigator identifies as related to the 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.
10.2.1.3. Events of Clinical Interest - Pembrolizumab
The 2 categories of events of clinical interests (ECIs) for pembrolizumab include:
1. an overdose of pembrolizumab (≥1000 mg [5 times the dose]) not associated with clinical 
symptoms or abnormal laboratory results, and

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2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal (ULN) and an elevated total bilirubin lab value that is greater than or equal to 2X 
ULN and, at the same time, an alkaline phosphatase lab value that is less than 2X ULN, 
as determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.  Please refer to the Site Guidance Document for Drug-induced Liver Injury.
Section 9.4.2 describes supportive care measures for each selected pembrolizumab nonserious 
and serious adverse events.
10.2.2. Other Safety Measures
10.2.2.1. Electrocardiograms
For each patient, 12-lead digital ECGs will be collected according to the Study Schedule 
(Attachment 1) as single ECGs.  Patients must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection.
ECGs 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.
ECGs will be interpreted by a qualified physician (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/corrected QT 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, 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, and any alert 
reports.
10.2.3. 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 or 
designee 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 

adverse events 

If a patient experiences elevated ALT >3× ULN and/or elevated total bilirubin >2× ULN, 
clinical and laboratory monitoring may be initiated, at the discretion of the investigator
(see Section 9.4.2.5).

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
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 Site Guidance 
Document for DILI.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by Lilly in aggregate periodically during the course of the trial may be found in 
the respective study drug IB. In the NSCLC populations, the occurrence of
fatigue/weakness/asthenia, pain/chest pain, dyspnea, cough, nausea, anorexia/decreased appetite,
disease progression, metastasis, hemoptysis, and pleural effusion are reasonably anticipated due 
to the underlying malignancy.
10.2.4. Complaint Handling
Lilly collects product complaints on study drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and to facilitate process and product improvements.
Complaints related to concomitant drugs/drug delivery systems are reported directly to the 
manufacturers of those drugs/devices in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.3. Sample Collection and Testing
Samples collected for this study will be coded with the patient number.  The samples and any 
data generated from them can be linked back to the patient only by investigator site personnel.
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.
Attachment 6 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
10.3.1. Samples for Study Qualification and Health Monitoring
Standard laboratory tests, including chemistry, hematology, coagulation, and pregnancy testing 
(if applicable in women of childbearing potential), will be performed and analyzed centrally. 
Urinalysis will be assayed by investigator-designated (local) laboratory. Attachment 2 lists the 
laboratory tests that will be performed for this study.  Central laboratory results will be used to 

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determine patient eligibility at baseline. Local laboratory results may be used for on-study 
dosing decisions; if so, testing must also still be performed by the central laboratory. These 
central laboratory results will be used for subsequent safety analyses. In the event of minor 
discrepancies between local and central laboratory results, the investigator may use the local 
results for treatment decisions, and the central laboratory results will remain part of the safety 
database.
Blood and urine samples will be collected at the times specified in the Study Schedule
(Attachment 1).
Based on laboratory safety values, unscheduled hepatic monitoring tests (see Site Guidance 
Document for DILI) may be performed as part of patient follow-up, in consultation with the Lilly
CRP.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.3.2. Samples for Pharmacogenetics and Translational Research
Collection of samples for translational research is also part of this study (see Attachment 1 and 
Attachment 6).
Required samples for biomarker research to be collected from all patients in this study are the 
following:

Tumor tissue:  archived tumor tissue available for biomarker analyses, or patient is 
willing to undergo a tumor biopsy of an extra-CNS lesion. Submission of FFPE tumor 
tissue sample blocks is preferred.

Whole blood samples

Plasma samples
Whole blood, plasma, and tissue samples will be collected to explore biomarkers related to 
variable response to necitumumab and/or pembrolizumab, the EGFR pathway, innate and 
adaptive immunity, immune functioning, and/or the pathogenesis of lung cancer.  Analyses may 
include potential nucleic acid and protein markers to better understand the disease process, and 
to develop predictive biomarkers and diagnostics.
10.3.2.1. Whole Blood Sample for Genetic Research
A blood sample will be collected for pharmacogenetic analysis as specified in the Study
Schedule (Attachment 1), where local regulations allow.

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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.  These studies may include 
but are not limited to EGFR pathway, immune cells/function, and the mechanism of action of 
necitumumab and pembrolizumab to evaluate their association with observed response to study 
treatment.
All pharmacogenetic samples will be coded with the patient number.  These samples and any 
data generated can be linked back to the patient only by the investigator 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 regulatory 
questions, and investigation of variable response that may not be observed until later in drug 
development or when the drug is commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, candidate gene studies, and epigenetic analyses.  
Regardless of the technology utilized, genotyping data generated will be used only for the 
specific research scope described in this section.
10.3.2.2. Tumor Tissue Collection
The availability of tumor tissues is important to better characterize the relationship of tumor 
biology and response evaluation in this study.

If a prior archived tumor specimen is available, and unless restricted by local regulations, 
submission of archived tumor tissue is mandatory.  If an archived specimen is not 
available, submission of a newly obtained biopsy (obtained at baseline, during elective 
surgery, or at the specified time points) is required.

Tumor tissue should be provided in formalin or as an FFPE block, or unstained slides.  
Due diligence should be used to make sure that tumor specimen (not a normal adjacent or 
a tumor margin sample) is provided.  Pathology notes/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. FFPE blocks will be sectioned and 
returned to the site. Newly obtained blocks or tissue submitted in formalin and slides will 
not be returned.
Tumor tissue will be examined for biomarkers related to NSCLC, necitumumab, pembrolizumab,
and/or the mechanism of action under investigation (for example, EGFR pathway and immune 
cells/function).
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 

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regulatory questions, and investigation of variable response that may not be observed until later 
in drug development or when the drug is commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  However, existing approaches 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.
10.3.2.3. Plasma and Whole Blood Samples for Biomarker Research
Plasma and whole blood samples for non-pharmacogenetic biomarker research will be collected 
at the times specified in the Sampling Schedule (Attachment 6), where local regulations and 
ERBs allow.
Samples will be used for research on EGFR pathway and immune cells/function associated with 
NSCLC, mechanism of action of necitumumab and pembrolizumab, and/or research method or 
in validating diagnostic tools or assay(s) related to NSCLC.
All biomarker samples will be coded with the patient number.  These samples and any data 
generated can be linked back to the patient only by the investigator 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 ERBs impose shorter time limits, at a facility selected 
by the sponsor.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in drug 
development or when the drug is commercially available.
10.3.3. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine antibody production 
against necitumumab.  Immunogenicity will be assessed by a validated assay designed to detect 
anti-drug antibodies in the presence of the necitumumab and pembrolizumab.  Antibodies may 
be further characterized and/or evaluated for their ability to neutralize the activity of 
necitumumab.
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to necitumumab.  
The duration allows the sponsor to respond to regulatory requests related to necitumumab.
10.3.4. Samples for Drug Concentration Measurements 
Pharmacokinetics
Pharmacokinetic (PK) venous blood samples (also known as bioanalytical samples) for 
measurement of necitumumab serum concentrations will be collected as specified in the 
Pharmacokinetic, Immunogenicity, and Blood-Based Markers Sampling Schedule 
(Attachment 6).
Sampling times were selected to coincide with expected maximum concentration and minimum 
concentration of necitumumab and with consideration to draw minimum volume of blood from 

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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 each 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.
Serum concentrations of necitumumab will be determined using validated enzyme-linked 
immunosorbent assays at laboratories approved by the sponsor.
Bioanalytical samples collected to measure necitumumab concentrations will be retained for a 
maximum of 1 year following last patient visit for the study.
10.4. Appropriateness of Measurements
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials.

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11. 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 laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-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 
generic labs system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
A total of approximately 78 patients for Part A, Part B, and Part C will be enrolled.  Part A 
requires up to 12 treated patients (3-6 for Cohort 1 and 6 for Cohort 2).  Patients with squamous 
and nonsquamous NSCLC from Part A who received the recommended necitumumab dose for 
Part B will also be analyzed together with Part B.  These Part A patients who received the 
recommended necitumumab dose for Part B will also be included in the interim analyses as 
described in Section 12.2.12.
An evaluable patient for Part B will include any patient enrolled in Part A and treated at the 
recommended Phase 2 doses of necitumumab and pembrolizumab.  In addition, patients will be 
entered strictly to Part B (with approximately 54 evaluable patients in Part B).  To be evaluable 
for the efficacy analysis of study, these patients must meet the following criteria:
(1)
The patient has received at least 1 dose each of necitumumab and pembrolizumab.
(2)
The patient has a complete radiographic assessment at baseline.
In Part C, approximately 6-12 Japanese patients will be enrolled and treated with necitumumab 
at the recommended dose from Part A in combination with pembrolizumab.
The primary analysis of the Part A and Part B will take place approximately 6 months after the 
last patient evaluable for Part B portion of the study has been enrolled.  The primary Part B 
outcome variable in this study will be ORR.  The Part B statistical null hypothesis states that the 
true ORR associated with the regimen of necitumumab and pembrolizumab is 20%, whereas the 
research hypothesis states that the true ORR associated with the combination regimen is 35%.
If the research hypothesis of a 35% ORR is true, there is an 83% chance of rejecting the null 
hypothesis.  If the null hypothesis of a 20% ORR is true, then there is at most a 10% chance of
rejecting the null hypothesis. Therefore, the sample size of 54 evaluable patients in Part B has a 
nominal one-sided alpha level of 0.10, with statistical power of 83%.
The analysis of Part C will take place approximately after all the patients from Part C have 
completed 8 cycles or discontinued early.  At the same time, some of the efficacy of Part B may
be updated, where appropriate.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
The primary analysis will be as described in Section 12.1.
All efficacy summary analyses will be performed for all evaluable patients (as defined in Section 
12.1). All safety summary analyses will be performed for all treated patients (those enrolled in 
the study who receive any amount of study drug [necitumumab and/or pembrolizumab]).

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Minor changes or clarifications to any statistical analyses described in this protocol may be
presented in the final statistical analysis plan (SAP) for this study.
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided.  It will include:

total number of patients enrolled; and

total number of patients treated (safety population).
A detailed summary of reasons for patient discontinuation from treatment will be provided.  
A summary of all identified important (as defined in the SAP) protocol violations will be 
provided.
12.2.3. Patient Characteristics
A detailed description of patient characteristics at baseline will be provided, including:

patient demographics;

baseline disease characteristics; and

medical history.
12.2.4. Concomitant Therapy
Concomitant medications will be summarized for the safety population.
12.2.4.1. Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.
12.2.5. Treatment Compliance
The number of dose omissions, reductions, and delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients.
12.2.6. Primary Outcome and Methodology
The primary efficacy endpoint of ORR and its exact 80% CI and 95% CI will be estimated.
12.2.7. Analyses of Efficacy
In addition to the analyses described in Section 12.1, this section provides additional details of 
planned efficacy analyses.  For time-to-event variables, the Kaplan-Meier method will be used to 
estimate parameters (for example, medians, quartiles, 6 months, and 1-year event rates). See 
also the SAP for additional details.
ORR: The denominator of ORR includes each evaluable patient. The numerator includes those 
patients counted in the denominator with a best overall tumor response of PR or CR.
DCR:  Using the same denominator as for ORR, the numerator of the DCR includes those 
patients counted in the denominator with a best tumor response of SD, PR, or CR.

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DOR:  The DOR is defined only for responders (patients with a confirmed CR or PR, as defined 
in Section 10.1.1).  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.
PFS:  The PFS time is measured from the date of first dose to the date of objective progression 
or the date of death due to any cause, whichever is earlier.  The censoring is taken in the 
following order:

if a patient does not have a complete baseline disease assessment, then the PFS time 
will be censored at the first dose 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.
OS:  OS duration is measured from the date of first dose to the date of death from any cause.  
For each patient who is not known to have died as of the data-inclusion cutoff date for a 
particular analysis, OS will be censored for that analysis at the last known alive date.  ORR, 
DCR, DOR, and PFS will be assessed based on RECIST 1.1.
12.2.7.1. Exploratory Outcome and Methodology
The irORR, irDCR, irDOR, and irPFS accessed based on adapted RECIST 1.1 (irRECIST) will 
be used for exploratory analysis of ORR, DCR, DOR, and PFS. See also the SAP for additional 
details.
12.2.8. Pharmacokinetic and Immunogenicity Analyses
PK Analyses:
PK analyses for necitumumab will be conducted on patients who have received at least 1 dose of 
necitumumab and have had samples collected.
Summary statistics of necitumumab data will be presented graphically as well as in tabulated 
form.  Additional exploratory analyses using PopPK approach may be performed if warranted by 
data. Patient or study factors that may influence the PK of necitumumab, when given in 
combination with pembrolizumab, may be explored. The relationship between necitumumab 
exposure, when given in combination with pembrolizumab, and selected safety outcomes may 
also be explored.
Immunogenicity Analyses:
Immunogenicity (anti-necitumumab antibody) incidence will be tabulated, and correlation to 
necitumumab drug level, activity, and safety will be assessed, as appropriate, respectively.  The 
measures that will be analyzed include baseline presence and level of anti-drug(s) antibodies 

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(ADA), treatment-emergent ADA, levels of neutralizing ADA, and incidence and levels of ADA 
related to IRRs.
Interim analysis:
Interim analysis may be conducted to facilitate exploratory analyses of PK, pharmacodynamics
(safety), and immunogenicity.  Interim data may also be pooled with final and interim data from 
other clinical studies of necitumumab and analyzed using a population PK/pharmacodynamic
approach.  Since the study is unblinded, study objectives will not be compromised by the interim 
analysis.
12.2.9. Translational Research Analyses
Biomarker results will be summarized and correlated with clinical outcomes.
12.2.10.
Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.2.
Overall exposure to study drugs, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for entire treatment period.  The number of patients with dose 
reductions, dose delays, or dose omissions will also be summarized, as will the reasons for dose 
adjustments.
An overall summary of AEs will be provided for AEs deemed by the investigator to be related to 
study treatment, and repeated for events regardless of study drug causality.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened between the first dose of study treatment and 30 days after the last dose of study 
treatment and related SAEs reported beyond 30 days after the last dose of study treatment.
The number of patients who experienced a TEAE, SAE, AE related to study treatment, died, or 
discontinued from the study treatment due to an AE will be summarized.
Common Terminology Criteria for Adverse Events v 4.0 will be used to report AEs by CTCAE 
terms.
Laboratory and non-laboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grade, including the total for maximum Grade 3 and above.  These summaries will be 
provided for events deemed by the investigator to be related to study treatment and repeated for 
events regardless of causality.
MedDRA Version 17.0 (or higher) will be used when reporting AEs by MedDRA terms.  
Treatment-emergent adverse events will be summarized by SOC and by decreasing frequency of 
Preferred Term within SOC.
Reasons for death will be summarized separately for on-therapy and within 30 days of last dose 
of study drug.  Serious adverse events will be summarized by Preferred Term.

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Hospitalizations and transfusions during the study treatment period or during the 30-day 
short-term follow-up period will be summarized.
12.2.11.
Subgroup Analyses
Exploratory subgroup analyses by histology will be performed to look for evidence of any 
differences in efficacy or safety that might depend on histology.
12.2.12.
Interim Analyses
An interim safety analysis will be performed after the first 15 evaluable patients in Part B have 
completed 2 cycles of study treatment (or otherwise discontinued study treatment).  
Patients with squamous and nonsquamous NSCLC from Part A who received the recommended 
necitumumab dose for Part B will be included in the interim analyses.
The interim safety analyses will be conducted to permit evaluation of safety data by Lilly.
The results from the interim safety analyses will be examined by an internal assessment 
committee, which will be established prior to enrollment of the first patient in the 
trial. The internal assessment committee will consist of a Lilly medical director, a Lilly 
CRP/clinical research scientist, a PK scientist, and a statistician and will make recommendations 
about the trial. Enrollment will continue while the interim safety analysis is being 
performed. Interim safety analysis results will not be disseminated outside of the assessment 
committee, unless emerging safety outcomes warrant such a disclosure.  In case a disclosure is 
warranted, the outcome of the interim safety analyses will be documented, and a written letter 
will be submitted to the ERB(s) and the investigators for documentation purposes.
Interim efficacy analyses may be performed as needed to aid in the planning of future 
trials. There is no plan to stop the study for positive efficacy, the type-1 error for final primary 
analysis will not be affected and hence is not adjusted.  

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13. Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including 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.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or, 
where permitted by local law or regulation, by the patient's legal representative.  This includes 
obtaining the appropriate signatures and dates on the ICF prior to the performance of any 
protocol procedures and prior to the administration of study treatment.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at the investigative sites.  
All ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline 
on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites. 
The ERB should include or consult with experts who are knowledgeable in pediatric ethical, 
clinical, and psychosocial issues.
The study site’s ERBs should be provided with the following:

the current IB or package labeling and updates during the course of the study

the ICF

relevant curricula vitae
13.3. 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 
International Ethical Guidelines

ICH GCP Guideline (E6)

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
applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of Lilly will 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.
13.3.1. Investigator Information
Physicians with a specialty in treating patients with lung cancer will participate as investigators 
in this clinical trial.
13.3.2. Protocol Signatures
The sponsor’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.
13.3.3. Final Report Signature
The clinical study report 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 chosen by Lilly will serve as the clinical study report coordinating investigator.  
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the clinical study report coordinating investigator.
The Lilly responsible medical officer and statistician will sign/approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.

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2015.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll 
DM, Topalian SL, Chen L.  Colocalization of inflammatory response with B7-h1 expression in 
human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci 
Transl Med. 2012;4(127):127-137.
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, randomized, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763-774.
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate 
anti-tumor immunity. Curr Opin Immunol. 2012;24(2):207-212.
Vectibix (panitumumab) [package insert]. Thousand Oaks, CA: Amgen Inc; 2014.
Vectibix (panitumumab) [Summary of Product Characteristics]. Breda, The Netherlands: Amgen 
Europe B.V.; 2014.
Yao S, Chen L. PD-1 as an immune modulatory receptor. Cancer J. 2014;20(4):262-264.

I4X-MC-JFCQ(d) Clinical Protocol
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Zaiss DM, van Loosdregt J, Gorlani A, Bekker CP, Gröne A, Sibilia M, van Bergen en 
Henegouwen PM, Roovers RC, Coffer PJ, Sijts AJ. Amphiregulin enhances regulatory T cell-
suppressive function via the epidermal growth factor receptor. Immunity. 2013;38(2):275-284.

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Attachment 1.Protocol JFCQ Study Schedule

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Study Schedule, Protocol I4X-MC-JFCQ
Perform procedure as indicated in the following schedules.
Baseline Schedule, I4X-MC-JFCQ
Baseline
Cycle
BL
Visit
0
Relative day within a cycle
≤21
≤14
≤7
Procedure 
Category
Protocol 
Section
Procedure
Comments
Study Entry/ 
Enrollment
13.1
Informed consent form signed
X
ICF must be signed prior to performing any protocol-specific tests/procedures.
7.1, 7.2
Inclusion/exclusion evaluation
X
Medical History
12.2.3
Initial history/preexisting conditions
X
12.2.3
Historical illnesses
X
Habits assessment
X
Smoking 
Physical 
Examination
Height
X
Weight
X
Blood pressure/pulse/temperature
X
Att. 3
ECOG performance status
X
Efficacy
Assessment
10.1.1
Radiologic imaging/Tumor 
Assessment (according to RECIST 
v1.1) 
X
A contrast CT scan or MRI of the brain will be performed if the patient is known to have CNS 
metastasis.
Adverse Events
10.2.1
AE collection and CTCAE grading
X
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Concomitant 
Medications
9.6
Concomitant medication notation
X

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Baseline
Cycle
BL
Visit
0
Relative day within a cycle
≤21
≤14
≤7
Procedure 
Category
Protocol 
Section
Procedure
Comments
Laboratory/
Diagnostic Tests
Att. 2
Hematology (central)
X
Att. 2
Chemistry (central)
X
Att. 2
Coagulation (central)
X
Att. 2
T3, free T4, TSH (central)
X
Att. 2
Urinalysis (local)
X
Att. 2
Pregnancy test (central)
X
In women of childbearing potential
10.3.2.1
Whole blood for genetic research
Refer to Attachment 
6.
10.3.4
PK sampling (central)
Refer to Attachment 
6.
10.3.3
Immunogenicity:  Anti-necitumumab 
antibodies
Refer to Attachment 
6.
10.3.2
Plasma and Whole blood samples for 
Biomarker Analysis
Refer to Attachment 
6.
10.3.2
Tumor tissue sample
X
To meet study eligibility criteria, and therefore mandatory for study participation, patients must 
have an evaluable and archived FFPE block or a minimum 15 slides (freshly cut slides should be 
submitted to the testing laboratory within 14 days from when the slides are cut), available for 
biomarker analyses, or if not available, patient is willing to undergo a tumor biopsy of an extra-
CNS lesion (core or excisional biopsy). 
See Section 10.3.2 for further details.
10.2.2.1
ECG (local)
X
Abbreviations:  AE = adverse event; Att. = Attachment; BL = baseline; CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formaldehyde fixed-paraffin embedded; ICF = informed consent form; MRI = magnetic resonance imaging; PD = 
progressive disease; PK = pharmacokinetic; RECIST = Response Evaluation Criteria In Solid Tumors; SAEs = serious adverse events; TSH = thyroid-stimulating factor.

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Treatment Period Schedule, I4X-MC-JFCQ
Comments
Repeat every 3 weeks
Cycle
(3-week cycle)
1-X
Visit
1-X
Relative day within a 
cycle
1
8
Except for the Cycle 1, Day 1 visit, allowable cycle windows are ±3 days, unless indicated otherwise (see 
Section 9.4).
Procedure 
Category
Protocol 
Section
Procedure
Physical 
Examination
Weight
X
Blood pressure/pulse
X
X
Blood pressure will be collected pre-infusion and post-infusion of pembrolizumab and necitumumab.
Att. 3
ECOG performance status
X
Tumor 
Assessment
10.1.1
Radiologic imaging (according 
to RECIST v1.1) and tumor 
measurement
X
To be performed every 6 weeks ±5 days after the first dose of study therapy, regardless of treatment delays, 
until there is confirmed radiographic documentation of PD as defined by the adapted RECIST 1.1, unless 
patient is clinically unsuitable to wait for confirmatory scan.  A contrast CT scan or MRI of the brain will 
be performed if the patient is known to have CNS metastasis or if clinically indicated.
Adverse 
Events
10.2.1
AE collection and CTCAE 
grading
X
X
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly Safety 
System.
Concomitant 
Medications
9.6
Concomitant medication 
notation
X
X
IP
9.2
Necitumumab
X
X
9.2
Pembrolizumab
X

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Comments
Repeat every 3 weeks
Cycle
(3-week cycle)
1-X
Visit
1-X
Relative day within a 
cycle
1
8
Except for the Cycle 1, Day 1 visit, allowable cycle windows are ±3 days, unless indicated otherwise (see 
Section 9.4).
Procedure 
Category
Protocol 
Section
Procedure
Laboratory/
Diagnostic 
Tests
Att. 2
Hematology
X
X
Investigator-designated (local) laboratory can be used to perform additional tests for on-study dosing 
decisions. If so, the test must also still be performed by the central laboratory.
Pretreatment laboratory data may not be older than 72 hours (Day 1 of each cycle) or 24 hours (Day 8).
Hepatic monitoring tests (see Site Guidance Document for DILI) to be done in the event of a treatment-
emergent hepatic abnormality.
In case of neutropenia, thrombocytopenia Grade 4 during Cycle 1 (dose finding part only), repeat every 2 
days until recovery.
Att. 2
Chemistry 
X
X
Investigator-designated (local) laboratory can be used to perform additional tests for on-study dosing 
decisions. If so, the test must also still be performed by the central laboratory.
Pretreatment laboratory data may not be older than 72 hours (Day 1 of each cycle) or 24 hours (Day 8).
Hepatic monitoring tests (see Site Guidance Document for DILI) to be done in the event of a treatment-
emergent hepatic abnormality.
Grade 3 elevation of transaminases, bilirubin, change of electrolytes (see DLT criteria), repeat every 2 days 
until recovery.
Att. 2
Coagulation (central)
X*
* To be performed every second cycle starting from Cycle 2
Att. 2
T3, free T4, TSH (central)
X*
* To be performed every second cycle starting from Cycle 2
Att. 2
Urinalysis (local)
X*
* To be performed every second cycle starting from Cycle 2
Att. 2
Pregnancy test (local) 
X*
Local urine test can be performed.  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.
* To be performed every cycle in women of childbearing potential
10.3.4
PK sampling (central)
Refer to Attachment 6.
Note: If a patient experiences an IRR to necitumumab at any time during the study, blood samples for both immunogenicity and PK 
analysis should be drawn, with no more than 15 minutes’ time difference.  Samples 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.
10.3.3
Immunogenicity:  Anti-
necitumumab antibodies
10.3.2
Plasma and Whole blood
samples for Biomarker 
Analysis
Refer to Attachment 6.
10.3.2.1
Whole blood for genetic 
evaluation
Refer to Attachment 6.
10.2.2.1
ECG (local)
X*
* To be performed every second cycle starting from Cycle 2

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Abbreviations:  AE = adverse event; Att. = Attachment; CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; 
ECG = electrocardiogram; DILI = drug-induced liver injury; DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology Group; IP = investigational product; IRR = infusion-related 
reaction; MRI = magnetic resonance imaging; PD = progressive disease; PK = pharmacokinetic; RECIST = Response Evaluation Criteria In Solid Tumors; SAEs = serious adverse events; TSH = 
thyroid-stimulating hormone.

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Postdiscontinuation Follow-up Schedule, I4X-MC-JFCQ
Postdiscontinuation Follow-up
Cycle
Short-Term 
Follow-up
Long-Term 
Follow-up
Visit
801
802-8XX
Relative day 
within a cycle
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination
Weight
X
Blood pressure/pulse
X
Att. 3
ECOG performance status
X
Tumor 
Assessment
10.1.1
Radiologic imaging 
(according to RECIST v1.1) 
and tumor measurement
X
X
Patients who discontinue study treatment for any reason other than PD will continue to undergo 
radiographic tumor assessments every 6 weeks (±5 days) until PD, the initiation of a new anticancer 
therapy, or overall study completion, whichever occurs first.
After the patient has objective (confirmed or unconfirmed) disease progression, radiologic tests are no 
longer required and the patient will be followed approximately every 3 months (±7 days) until the patient’s 
death or overall study completion, whichever occurs first.
Survival 
information
10.1.4
Collection of survival 
information
X
Collection of survival data every 3 months (±7 days).  Whenever possible, survival follow-up is conducted 
in person.  If an in-person visit is not possible, the site may confirm survival by contacting the patient 
directly via telephone.
Adverse 
Events
10.2.1
AE collection and CTCAE 
grading
X
X
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly Safety 
System.  During Postdiscontinuation long-term follow-up, only SAEs that are related to protocol procedures 
or study treatment will be collected.
Concomitant 
Medications
9.6
Concomitant medication 
notation
X
Laboratory/
Diagnostic 
Tests
Att. 2
Hematology
X
Att. 2
Chemistry
X
10.3.2
Plasma and Whole blood
samples for Biomarker 
Analysis
X
When applicable, EDTA plasma should be collected as near as possible to the time of progression disease, 
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 at (or by) the short-term follow-up visit. The post progression 
sample should be collected before the initiation of any new anticancer therapy.
Att. 2
Pregnancy test (local)
X
In women of childbearing potential.  Local urine test can be performed.  If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.
Att. 2
T3, free T4, TSH (central)
X
Att. 2
Urinalysis (local)
X
10.3.4
PK
Refer to Attachment 6.
If a patient experiences an IRR to necitumumab at any time during the study, blood samples for both 
immunogenicity and PK analysis should be drawn, with no more than 15 minutes’ time difference.  Samples 
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.
10.3.3
Immunogenicity:  Anti-
necitumumab 
10.2.2.1
ECG (local)
X

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Postdiscontinuation Follow-up Schedule, I4X-MC-JFCQ (concluded)
Abbreviations:  AE = adverse event; Att. = Attachment; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
IRR = infusion-related reaction; PD = progressive disease; PK = pharmacokinetic; RECIST= Response Evaluation Criteria In Solid Tumors; SAEs = serious adverse events; TSH = thyroid-
stimulating hormone.
Short-Term Follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts at least 30 days (+ 0-7 days; ie, at least 30 days but no 
more than 37 days).
Long-Term Follow-up begins the day after Short-Term Follow-up is completed and continues until the patient’s death or overall study completion.  Patients who discontinue study treatment for reasons 
other than PD will continue to undergo radiographic tumor assessments every 6 weeks (±5 days) until PD, the initiation of a new anticancer therapy, or overall study completion, whichever occurs 
first.  Patients will be followed for survival every 3 months (±7 days) until the patient’s death or overall study completion, whichever occurs first.

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Continued Access Schedule, I4X-MC-JFCQ
Continued Access Period
Treatment Period
Continued Access 
Follow-up
Cycle
X-Y
Follow-up
Visit
501-5XX
901
Relative day within 
a cycle
1
8
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination
Weight
X
Adverse 
Events
10.2.1
AE collection and CTCAE grading
X
X
X
Data on SAEs that occur before the end of trial will be stored in 
the collection database and the Lilly safety system.
Laboratory/
Diagnostic 
Tests
10.3.4
PK
Refer to Attachment 6.
If a patient experiences an IRR to necitumumab, blood samples 
for both immunogenicity and PK analysis should be drawn, with 
no more than 15 minutes’ time difference.  Samples 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.
10.3.3
Immunogenicity:  Anti-necitumumab 
antibodies
Study 
Treatment
9.2
Necitumumab
X
X
9.2
Pembrolizumab
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction; PK = pharmacokinetic; SAEs = serious adverse events.
Continued Access Period begins after study completion and ends at the end of trial.  During the Continued Access period, patients on study treatment who continue to experience clinical benefit and no 
undue risks may continue to receive study treatment until one of the criteria for discontinuation is met.  The Continued Access period includes Continued Access Follow-up.
Continued Access Follow-up begins the day after the patient and the investigator agree that the patient will no longer continue treatment in the Continued Access period and lasts at least 30 days (+ 0-7 
days; ie, at least 30 days but no more than 37 days).
Note:  Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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Attachment 2.Protocol JFCQ Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistrya:
Hemoglobin
Hematocrit
Erythrocyte count (RBC)
Mean cell volume (MCV)
Mean cell hemoglobin concentration (MCHC)
Leukocytes (WBC)
Neutrophils, segmented and bands
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Serum concentrations of:
Sodium
Magnesium
Potassium
Phosphate
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Blood urea nitrogen (BUN)
Creatinineb
Uric acid
Calcium
Glucose, nonfasting
Albumin
Cholesterol
Creatine kinase (CK)
Thyroid Function Teste:
Thyroid-stimulating hormone (TSH) 
Total triiodothyronine (T3) 
Free thyroxine (T4) 
Urinalysisc:
Color
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Urine leukocyte esterase
Pregnancy Test (females of childbearing 
potential only)d
Coagulation Testse:
INR and PT
PTT
Fibrin D dimer
Protein C activity (baseline only)
Protein S activity (baseline only)
Abbreviations:  IDMS = isotope dilution mass spectrometry; INR = International Normalized Ratio; 
PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated (central) laboratory. Investigator-designated (local) laboratory can be used to 
perform additional tests for on-study dosing decisions. If so, the test must also still be performed by the central 
laboratory.
b
IDMS for United States sites.
c
Assayed by investigator-designated (local) laboratory.
d
For fulfilling Inclusion Criterion 12, a central serum pregnancy test is mandatory.  During treatment and 
postdiscontinuation periods, a local urine test can be performed. If the local urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.
e
Assayed by Lilly-designated (central) laboratory.

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Attachment 3.Protocol JFCQ ECOG Performance Status
Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to 
carry out any work activities. Up and about more than 
50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. 
Totally confined to bed or chair
5
Dead.
Source:  Oken et al. 1982.

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Attachment 4.Protocol JFCQ 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.
Reference:  Cockcroft and Gault 1976.  

C CI
I 4 X-M C -J F C Q ( d) Cli ni c al Pr ot o c ol
P a g e 1 0 4

I 4 X-M C -J F C Q ( d) Cli ni c al Pr ot o c ol
P a g e 1 0 5
L Y 3 0 1 2 2 1 1
C CI
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 

I 4 X-M C -J F C Q ( d) Cli ni c al Pr ot o c ol
P a g e 1 0 6
L Y 3 0 1 2 2 1 1
C CI
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
C CI
C CI

I 4 X-M C -J F C Q ( d) Cli ni c al Pr ot o c ol
P a g e 1 0 7
L Y 3 0 1 2 2 1 1
C CI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI

I 4 X-M C -J F C Q ( d) Cli ni c al Pr ot o c ol
P a g e 1 0 8
L Y 3 0 1 2 2 1 1
 
 
 
 
 
 
  
 
 
 
C CI
 
 
C CI
C CI

I 4 X-M C -J F C Q ( d) Cli ni c al Pr ot o c ol
P a g e 1 0 9
L Y 3 0 1 2 2 1 1
 
C CI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
C CI
C CI

I 4 X-M C -J F C Q ( d) Cli ni c al Pr ot o c ol
P a g e 1 1 0
L Y 3 0 1 2 2 1 1
 
 
 
 
 
C CI

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Attachment 6.Protocol JFCQ Pharmacokinetic, 
Immunogenicity, and Blood-Based Markers Sampling 
Schedule
PK and Immunogenicity samples will be collected for necitumumab only. It is essential that the 
exact infusion start and stop times (actual clock readings) 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 I.V. site 
as the drug infusion.
Predose samples should be taken as close as possible to the start of first infusion, but can be 
drawn up to 1 hour (60 minutes) prior first infusion, and exact clock reading should be recorded.  
Post-dose (post-end of infusion) samples for PK for necitumumab should be drawn immediately 
after end of necitumumab infusion (range = after end of infusion +10 minutes) and exact clock 
reading should be recorded.
In addition, if a patient experiences an IRR, blood samples for both immunogenicity (anti-
necitumumab antibody,) and PK (necitumumab concentration) should be drawn, with no more 
than 15 minutes’ time difference between PK and immunogenicity samples.  Samples 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.

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Pharmacokinetic, Immunogenicity, Biomarker, and Pharmacogenetic Sample Collection for Part A, Part B, and Part C
Biomarker and 
Pharmacogenetic 
Visit/Cycle Day
Study 
Day
Sample Time 
(relative to 
start of 
pembrolizumab 
infusion)
(HR:MIN)a
Necitumumab PKc
(Serum)
Necitumumab 
Immunogenicityc
(Serum)
Plasma
and Whole 
Blood for 
Biomarker
Whole 
Blood for 
Genetics
Cycle 1 Day 1 
(Pembrolizumab and 
Necitumumab infusion)
1
0:00 hr Predose 
sampleb,e  
X (collect prior to start of first 
infusion)
X 
X
X
1:30 hr
Postdose 
sampled,e 
X (collect immediately after 
Necitumumab infusion ends) 
Cycle 1 Day 8
(Necitumumab infusion 
only)
8
0:00 hr Predose 
sample
X
Cycle 2 Day 1 
(Pembrolizumab and 
Necitumumab infusion)
22
0:00 hr Predose 
sampleb,e  
X (collect prior to start of first 
infusion)
X
X
1:30 hr
Postdose 
sampled,e 
X (collect immediately after 
Necitumumab infusion ends) 
Cycle 4 Day 1 
(Pembrolizumab and 
Necitumumab infusion)
64
0:00 hr Predose 
sampleb,e  
1:30 hr
Postdose 
sampled,e 
X (collect prior to start of first 
infusion)
X (collect immediately after 
Necitumumab infusion ends) 
X
X

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Biomarker and 
Pharmacogenetic 
Visit/Cycle Day
Study 
Day
Sample Time 
(relative to 
start of 
pembrolizumab 
infusion)
(HR:MIN)a
Necitumumab PKc
(Serum)
Necitumumab 
Immunogenicityc
(Serum)
Plasma
and Whole 
Blood for 
Biomarker
Whole 
Blood for 
Genetics
Cycle 6 Day 1 
(Pembrolizumab and 
Necitumumab infusion)
106
0:00 hr Predose 
sampleb,e  
X (collect prior to start of first 
infusion)
X
X
1:30 hr
Postdose 
sampled,e 
X (collect immediately after 
Necitumumab infusion ends) 
Cycle 8 Day 1 
(Pembrolizumab and 
Necitumumab infusion)
148
0:00 hr Predose 
sampleb,e  
1:30 hr
Postdose 
sampled,e 
X (collect prior to start of first 
infusion)
X (collect immediately after 
Necitumumab infusion ends) 
X
X
30 days Post treatment DC
Anytimef
X 
X
X
Abbreviations: DC = Discontinuation; eCRF = electronic case report form; PK = pharmacodynamics; IK = immunokinetics/immunogenicity; IRR = infusion-related reaction.
Note: 30-minute pembrolizumab infusion is given first followed by 60-minute necitumumab infusion.
a All sample times are relative to start of first infusion. 
b Pre-dose sample for necitumumab PK, and/or IK should be preferably collected within 1 hour  prior to start of first infusion.
c In the event of an IRR, blood samples will be collected for necitumumab PK and IK analysis at the following time points within 15 minutes of one another:  (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.
d Postdose samples should be collected after the end of necitumumab infusion, preferably within a 10 minute time window.
e While best effort should be done to draw the blood sample for PK/IK within the time windows provided above, it is more important to ensure predose sample is actually collected before the start of first 
infusion and postdose infusion samples are collected after infusion has actually completed. It is also equally important to record ACTUAL date and time of blood collection for PK/IK sample on the 
Requisition Form AFTER drawing the sample and to accurately record the ACTUAL infusions start and end dates and times on the eCRF to be able to use the data for analyses.  Sample collection for 
PK/IK must be from the opposite arm to that used for study drug infusion. If drug was administered via a central venous catheter, the sample collection should be from a different site.
f Record ACTUAL date and time of blood collection for PK/IK sample on the Requisition Form AFTER drawing the sample.  PK/IK sample should be taken within 15 minutes of one another.

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Attachment 7.Protocol Amendment I4X-MC-JFCQ(d)
Summary An Open-Label, Multicenter, Phase 1b Study with 
an Expansion Cohort to Evaluate Safety and Efficacy of the 
Combination of Necitumumab with Pembrolizumab in 
Patients with Stage IV Non-Small Cell Lung Cancer
Overview
Protocol I4X-MC-JFCQ, An Open-Label, Multicenter, Phase 1b Study with Expansion Cohorts
to Evaluate Safety and Efficacy of the Combination of Necitumumab with Pembrolizumab in 
Patients with Stage IV Non-Small Cell Lung Cancer, has been amended.  The new protocol is 
indicated by amendment (d) and will be used to conduct the study in place of any preceding 
version of the protocol.
The overall change and rationale for the change made to this protocol are as follows:

A second dosage form is available for pembrolizumab.  Details of the pembrolizumab 
solution for infusion (100 mg/vial) have been added to Section 2 (Synopsis) and Section 9.2 
(Materials and Supplies).

I4X-MC-JFCQ(d) Clinical Protocol
Page 115
LY3012211
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2.
Synopsis
Test Product, Dosage, and Mode of Administration:  

Necitumumab is a sterile, preservative-free, intravenous infusion supplied in 50-mL vials containing 
16 mg/mL (800 mg/50 mL) of product, and administered over 60 minutes at a dose of 600 mg or 800 mg on 
Days 1 and 8 of each 21-day cycle.

Pembrolizumab drug product is available in 2 dosage forms intended for intravenous administration: dosage 
form is a lyophilized powder, 50 mg/vial, ready to be reconstituted with sterile water for injection prior to use, 
and a liquid, 100 mg/vial, both in Type I glass vials intended for single use only. Pembrolizumab is and 
administered over 30 minutes (-5 min/+ 10 min) at a dose of 200 mg on Day 1 of each 21-day cycle.
9.2
Materials and Supplies
Pembrolizumab drug product is available in 2 dosage forms: is a white to off-white lyophilized 
powder, 50 mg/vial, and a liquid, 100 mg/vial, both in Type I glass vials intended for single use only.

Pembrolizumab powder Powder for solution Solution for infusionInfusion, 50 
mg/vial, is a lyophilized powder that is reconstituted with sterile water for 
injection prior to use. Pembrolizumab is formulated with L-histidine as 
buffering agent, polysorbate 80 as surfactant, sucrose as stabilizer/tonicity
modifier, and may contain hydrochloric acid and/or sodium hydroxide for pH 
adjustment (if necessary).

Pembrolizumab Solution for Infusion 100 mg/vial is a liquid, manufactured 
fully formulated with L-histidine as a buffering agent, polysorbate 80 as a 
surfactant, and sucrose as a stabilizer/tonicity modifier.
Both The pembrolizumab product dosage forms are is stored under refrigerated conditions (2°C 
to 8°C) (36-46°F) and protected from light. Refer to pembrolizumab IB for detailed storage 
information.

P P D
L e o  D o c u m e n t  I D  =  3 1 d d 0 4 4 a - c d 9 5 - 4 2 4 c - a 8 6 f - 4 c e 3 c e c c 7 9 5 e
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 7 - S e p - 2 0 1 8  1 4 : 3 8 : 0 9  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 7 - S e p - 2 0 1 8  1 4 : 3 9 : 2 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D