JUNIPER: A Randomized Phase 3 Study of Abemaciclib Plus Best Supportive Care Versus Erlotinib Plus Best Supportive Care in Patients With Stage IV NSCLC With a Detectable KRAS Mutation Who Have Progressed After Platinum-Based Chemotherapy
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer
Sponsor: Eli Lilly and Company

I3Y-MC-JPBK 
 
 
I3Y-MC-JPBK: A Randomized Phase 3 Study of Abemaciclib plus Best Supportive Care versus 
Erlotinib plus Best Supportive Care in Patients with Stage IV NSCLC with a Detectable KRAS 
Mutation Who Have Progressed After Platinum-Based Chemotherapy 
 
 
NCT02152631 
 
 
Approval Date: December 20, 2016 
 

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1. Protocol I3Y-MC-JPBK(e)
JUNIPER:  A Randomized Phase 3 Study of Abemaciclib
plus Best Supportive Care versus Erlotinib plus Best 
Supportive Care in Patients with Stage IV NSCLC with a 
Detectable KRAS Mutation Who Have Progressed After 
Platinum-Based Chemotherapy
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
abemaciclib (LY2835219), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments are subject to United States Freedom of Information Act Exemption 4.
Abemaciclib (LY2835219)
This study is a global, multicenter, randomized, open-label, Phase 3 trial in patients with 
Stage IV NSCLC whose tumors have a detectable KRAS mutation in codons 12 or 13 and 
who have progressed after platinum-based chemotherapy and received 1 other prior 
therapy or are ineligible for further chemotherapy randomized to receive either abemaciclib
plus best supportive care or erlotinib plus best supportive care.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Approved by Lilly:  13 May 2014
Amendment (a) Approved by Lilly:  19 December 2014
Amendment (b) Approved by Lilly:  20 July 2015
Amendment (c) Approved by Lilly:  16 June 2016
Amendment (d) Approved by Lilly:  19 September 2016
Amendment (e) Electronically Signed and Approved by Lilly
on date provided below.
Approval Date: 20-Dec-2016 GMT

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2. Synopsis
Study Rationale
Patients with metastatic non-small cell lung cancer (NSCLC) that harbor KRAS mutations (25%) 
have a poor prognosis compared to NSCLC patients who are KRAS wild-type. The 
p16INK4A-cyclin D-cyclin-dependent kinases (CDK) 4 and 6-retinoblastoma pathway is 
frequently dysregulated in NSCLC and therefore this pathway represents an attractive 
therapeutic target.  Abemaciclib is a potent and selective small molecule inhibitor of CDK4 and 
CDK6 that has shown acceptable safety/tolerability as well as evidence of clinical activity in 
multiple tumor types.
The Phase 3 Study I3Y-MC-JPBK (JPBK) study will evaluate the clinical activity of abemaciclib
plus best supportive care (BSC) versus erlotinib plus BSC for patients with Stage IV NSCLC 
whose tumors have a detectable KRAS mutation and who have progressed after prior platinum-
based therapy and received 1 other prior therapy or are not eligible for further chemotherapy.
Clinical Protocol Synopsis:  Study I3Y-MC-JPBK
Name of Investigational Product:  Abemaciclib
Title of Study:  JUNIPER:  A Randomized Phase 3 Study of Abemaciclib plus Best Supportive Care versus 
Erlotinib plus Best Supportive Care in Patients with Stage IV NSCLC with a Detectable KRAS Mutation Who Have 
Progressed after Platinum-Based Chemotherapy.
Number of Planned Patients:
Entered:  2500
Enrolled/Randomized:  approximately 450
Completed: approximately 450
Phase of Development:  3
Length of Study:  Approximately 47 months
Planned first patient visit:  September 2014
Planned last patient visit: excluding the extension period:  November 2017
Planned interim analysis:  Analysis for safety will occur every 6 months.  One futility analysis will occur after 
approximately 100 progression-free survival (PFS) events have been observed.
Objectives:  The primary objective of this study is to compare abemaciclib plus BSC versus erlotinib plus BSC in 
patients with Stage IV NSCLC whose tumors have detectable KRAS mutations and who have progressed after prior 
platinum-based therapy and 1 other prior therapy or are not eligible for further chemotherapy with respect to:

overall survival (OS)
The secondary objectives of the study are to compare abemaciclib plus BSC to erlotinib plus BSC with respect to:

overall response rate (complete response + partial response)

progression-free survival (PFS)

changes in patient-reported pain and disease-related symptoms collected via the MD Anderson Symptom 
Inventory (MDASI-LC) and changes in health status via European Quality of Life – 5 Dimensions –
5 Level (EQ-5D 5L)

safety and tolerability

resource utilization (for example, analgesic type, hospitalization, transfusion)
An additional secondary objective is to examine the pharmacokinetic (PK)/pharmacodynamic (PD) properties of 
abemaciclib.
The exploratory objectives of the study are as follows:

to explore biomarkers relevant to abemaciclib and the disease state and to correlate these markers to 
clinical outcome and to abemaciclib

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Study Design:  Study I3Y-MC-JPBK is a multicenter, randomized, open-label, parallel, comparator-controlled trial 
in patients with Stage IV NSCLC whose tumors have a detectable KRAS mutation in codons 12 or 13 and who have 
progressed after platinum-based chemotherapy and received 1 other prior therapy or are ineligible for further 
chemotherapy after platinum-based therapy.
Diagnosis and Main Criteria for Inclusion and Exclusions:  Patients will be males or females who are 18 years 
of age with a confirmed diagnosis of stage IV NSCLC according to American Joint Committee on Cancer Staging 
Handbook 7th edition.  The patient’s tumor will have a mutation in codon 12 or 13 of the KRAS oncogene, and the 
patient must have progressed after platinum-based chemotherapy (with or without maintenance therapy), AND have 
received 1 additional therapy, which may include an immune checkpoint inhibitor or other anti-cancer therapy for 
advanced and/or metastatic disease, OR is judged by the physician as ineligible for further standard second-line 
chemotherapy.  Patients may not have received prior epidermal growth factor receptor (EGFR)-targeted therapy, 
including any multi-target tyrosine kinase inhibitors, which may inhibit EGFR.  Patients will have measureable 
disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), adequate tumor-derived 
material from biopsy or surgery for analysis of KRAS status, an Eastern Cooperative Oncology Group performance 
status (ECOG PS) of 0 or 1, and adequate organ function.  Patients will be excluded from the study if they have a 
personal history of certain heart disease, presence of unstable central nervous system metastasis, or history of any 
other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless in complete remission 
with no therapy for a minimum of 3 years.
Test Product, Dosage, and Mode of Administration:  Abemaciclib 200 mg administered orally as capsules every 
12 hours
Planned Duration of Treatment:
Treatment period:  until disease progression or unacceptable toxicity occurs (or both)
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  until death or study completion
Reference Therapy, Dose, and Mode of Administration:  Erlotinib 150 mg administered orally as a tablet every 
24 hours
Criteria for Evaluation:
Efficacy: Efficacy assessments include imaging studies/tumor assessments, according to RECIST v. 1.1, performed 
every 8 weeks, and survival.
Safety:  Safety will be evaluated based on recorded adverse events (AEs), physical examinations, vital sign 
measurements, and clinical laboratory assessments.  Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA™).  Adverse events and clinical laboratory values will be graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v. 4.03).
Health Outcomes:  Health outcomes will be assessed using standardized instruments, MDASI-LC and EQ-5D 5L. 
Investigators will report resource utilization such as concomitant medications, transfusions, radiation therapy, 
surgery, and treatment-related hospitalization days.
Pharmacokinetics:  The plasma concentrations of abemaciclib and its metabolites LSN2839567, LSN3106726, and 
LSN3106729 will be measured for patients receiving abemaciclib.
Biomarkers:  
KRAS mutation assessment: all tumor tissue samples (surgical resection, core needle biopsy, or fine needle aspirate)
will be analyzed for KRAS mutation status.  The same sample may also be used for evaluation of codons 12 and 13 
via Sanger sequencing.
Other biomarkers:  additionally, whole blood, plasma, and tissue samples will be tested for biomarkers relevant to 
abemaciclib and the disease state and to correlate these markers to clinical outcome and to abemaciclib.

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Statistical Methods:
Statistical:  The study will enroll approximately 450 patients in 3:2 randomization (approximately 270 patients in 
the abemaciclib arm and 180 patients in the erlotinib arm).  The final analysis will occur when approximately 304
OS events have been observed.
Assuming an OS HR of 0.72, this sample size yields approximately 80% statistical power to detect superiority of the 
abemaciclib arm over erlotinib arm with the use of a 2-sided log-rank test and a type I error of .05.  If the true 
median OS for the erlotinib arm is 6.5 months, then the HR of 0.72 amounts to an approximately 2.5-month 
improvement in median OS for the abemaciclib arm under an additional assumption of exponential survival 
distribution.
Efficacy:   Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is defined as 
all patients randomized to study treatment.  For OS and PFS, the comparison of the survival curves between 
treatment groups will be conducted by a stratified log-rank test with the following stratification variables:  number 
of prior chemotherapy regimens (1 versus 2), ECOG PS (0 versus 1), gender (male versus female), and KRAS
mutation (GLY12CYS [G12C] vs. all others).  In addition, the Kaplan-Meier method (Kaplan and Meier 1958) will 
be used to estimate the survival curves as well as survival rates at 3, 6, 9, and 12 months for each treatment group.  
As supportive analysis of OS and PFS, the Cox proportional hazard model will be used to estimate treatment HR 
and corresponding 95% confidence interval (CI) after adjusting for the same randomization variables specified for 
the primary analysis.  All randomized patients, according to the ITT principle, will be included in the analysis of this 
endpoint.
Safety: All safety summaries and analyses will be based upon the Safety Population, defined as all enrolled patients 
receiving at least 1 dose of any study drug.  Overall exposure to study drug, the numbers of patients completing each 
cycle, and the dose intensity will be summarized using descriptive statistics.  An overall summary of AEs will be 
provided for AEs deemed by the investigator to be possibly related to study drug, and repeated for events regardless 
of study drug causality.  Incidence rates of these events will be compared between treatment arms using Chi square 
test.  CTCAE v 4.03 will be used to report AEs by CTCAE terms.  Laboratory and nonlaboratory CTCAEs will be 
summarized by CTCAE term and maximum CTCAE grade, including the total for maximum Grade 3 and 4.  The 
MedDRA Version 17.0 (or higher) will be used when reporting AEs by MedDRA terms.  The MedDRA Lower 
Level Term will be used in the treatment-emergent computation.  Treatment-emergent AEs will be summarized by 
System Organ Class (SOC) and by decreasing frequency of Preferred Term (PT) within SOC.
Health Outcomes: The MDASI-LC will be summarized for each assessment period.  EQ-5D 5L responses for each 
item will be summarized by frequency and corresponding percentages.  Descriptive statistics for the index and 
visual analog scale will be calculated.

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Pharmacokinetics: Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and inter-individual PK variability will be computed using nonlinear mixed effect 
modeling (NONMEM).  Covariate effects (such as age, weight, sex, creatinine clearance, and plasma protein levels) 
on the PK parameters of abemaciclib in plasma will also be investigated.  The mean population PK properties of 
abemaciclib metabolites LSN2839567, LSN3106726, and LSN3106729 in plasma may also be analyzed by means 
of NONMEM.
Biomarkers:
KRAS mutation assessment: Concordance (agreement) analysis will be performed on samples with valid KRAS
status (mutation positive and mutation negative) using both the investigational assay and the reference method 
(Sanger sequencing). Measures of agreement between the investigational KRAS assay and the reference method, 
including positive percent agreement, negative percent agreement, and overall percent agreement, and their 
corresponding exact 2-sided 95% CI, will be estimated for the overall mutation status; that is, mutation detected or 
not detected for the 7 mutations of KRAS gene. A secondary agreement analysis between the investigational KRAS
assay and the reference method will be performed for each of the tumor tissue sample types (surgical resection, fine 
needle aspirate, and core needle biopsy). The data will also be summarized for each of the 7 KRAS mutations 
separately.
Other biomarkers: the distributions of biomarkers will be summarized for the patient population for which samples 
are available. Associations between clinical endpoints and biomarker will be evaluated using data from patients 
who have an evaluable sample for each biomarker of interest, and such evaluation will be done on an individual 
marker basis.

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3. Table of Contents
JUNIPER:  A Randomized Phase 3 Study of Abemaciclib plus 
Best Supportive Care versus Erlotinib plus Best Supportive 
Care in Patients with Stage IV NSCLC with a Detectable 
KRAS Mutation Who Have Progressed After Platinum-Based 
Chemotherapy
Section
Page
1.
Protocol I3Y-MC-JPBK(e) JUNIPER:  A Randomized Phase 3 Study 
of Abemaciclib plus Best Supportive Care versus Erlotinib plus Best 
Supportive Care in Patients with Stage IV NSCLC with a Detectable 
KRAS Mutation Who Have Progressed After Platinum-Based 
Chemotherapy.....................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................6
4.
Abbreviations and Definitions...........................................................................................13
5.
Introduction ......................................................................................................................18
5.1.
Rationale for Amendment (a).......................................................................................20
5.2.
Rationale for Amendment (b).......................................................................................20
5.3.
Rationale for Amendment (c).......................................................................................21
5.4.
Rationale for Amendment (d).......................................................................................22
5.5.
Rationale for Amendment (e).......................................................................................22
6.
Objectives.........................................................................................................................24
6.1.
Primary Objective ........................................................................................................24
6.2.
Secondary Objectives...................................................................................................24
6.3.
Exploratory Objectives.................................................................................................24
7.
Study Population...............................................................................................................25
7.1.
Inclusion Criteria..........................................................................................................25
7.2.
Exclusion Criteria ........................................................................................................28
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................28
7.3.
Discontinuations ..........................................................................................................29
7.3.1.
Discontinuation of Patients...................................................................................29
7.3.2.
Discontinuation of Study Sites .............................................................................30
7.3.3.
Discontinuation of the Study................................................................................30
8.
Investigational Plan...........................................................................................................31
8.1.
Summary of Study Design............................................................................................31
8.1.1.
Study Completion and End of Trial......................................................................32

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8.1.2.
Extension Period..................................................................................................33
8.2.
Discussion of Design and Control ................................................................................34
9.
Treatment..........................................................................................................................35
9.1.
Treatments Administered .............................................................................................35
9.2.
Materials and Supplies .................................................................................................35
9.3.
Method of Assignment to Treatment ............................................................................36
9.4.
Selection and Timing of Doses.....................................................................................36
9.4.1.
Dose Rationale.....................................................................................................37
9.4.2.
Special Treatment Considerations ........................................................................37
9.4.2.1.
Immune Checkpoint Inhibitors........................................................................37
9.4.2.2.
Dose Adjustments and Delays ........................................................................39
9.4.2.2.1.
Abemaciclib..............................................................................................39
9.4.2.2.2.
Erlotinib ...................................................................................................41
9.5.
Blinding .......................................................................................................................43
9.6.
Concomitant Therapy...................................................................................................44
9.6.1.
Best Supportive Care............................................................................................44
9.6.1.1.
Palliative Radiotherapy...................................................................................45
9.6.1.2.
Supportive Management for Diarrhea .............................................................45
9.6.1.3.
Antiemetic Agents..........................................................................................45
9.6.1.4.
Analgesic Agents............................................................................................45
9.6.1.5.
Appetite Stimulants ........................................................................................46
9.6.1.6.
Granulocyte-Colony Stimulating Factors (G-CSF)..........................................46
9.6.1.7.
Growth Factors...............................................................................................46
9.6.1.8.
Bone-Modifying Agents .................................................................................46
9.6.1.9.
Therapy for Febrile Neutropenia.....................................................................46
9.7.
Treatment Compliance .................................................................................................46
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................48
10.1. Efficacy Measures........................................................................................................48
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................48
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................48
10.1.3.
Primary Efficacy Measure....................................................................................49
10.1.4.
Secondary Efficacy Measures...............................................................................49
10.2. Health Outcome/Quality of Life Measures ...................................................................50
10.2.1.
Patient-Reported Outcomes..................................................................................50
10.2.1.1.
MDASI-LC ....................................................................................................50

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10.2.1.2.
EQ-5D 5L.......................................................................................................50
10.2.2.
Resource Utilization.............................................................................................51
10.3. Safety Evaluations........................................................................................................51
10.3.1.
Adverse Events ....................................................................................................52
10.3.1.1.
Serious Adverse Events ..................................................................................53
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................55
10.3.2.
Other Safety Measures .........................................................................................55
10.3.2.1.
Electrocardiograms.........................................................................................55
10.3.3.
Safety Monitoring ................................................................................................56
10.3.4.
Complaint Handling.............................................................................................56
10.4. Sample Collection and Testing.....................................................................................56
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................57
10.4.2.
Samples for KRAS Mutation Determination.........................................................57
10.4.2.1.
Central Laboratory Result...............................................................................57
10.4.2.2.
Local Laboratory Result .................................................................................58
10.4.3.
Samples for Other Biomarkers .............................................................................59
10.4.3.1.
Archived Tumor Tissue ..................................................................................59
10.4.3.2.
Whole Blood Samples for Pharmacogenetic Evaluations ................................59
10.4.3.3.
Plasma Samples for Exploratory Biomarker Evaluations.................................60
10.4.4.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................60
10.5. Appropriateness of Measurements................................................................................61
11.
Data Quality Assurance.....................................................................................................62
11.1. Data Capture System....................................................................................................62
12.
Sample Size and Statistical Methods .................................................................................63
12.1. Determination of Sample Size ......................................................................................63
12.2. Statistical and Analytical Plans.....................................................................................63
12.2.1.
General Considerations ........................................................................................63
12.2.2.
Patient Disposition...............................................................................................64
12.2.3.
Patient Characteristics..........................................................................................64
12.2.4.
Concomitant Therapy...........................................................................................64
12.2.4.1.
Postdiscontinuation Therapy...........................................................................64
12.2.5.
Treatment Compliance .........................................................................................64
12.2.6.
Primary Outcome and Methodology.....................................................................65
12.2.7.
Secondary Outcome and Methodology.................................................................65
12.2.8.
Sensitivity Analysis..............................................................................................66
12.2.9.
Pharmacokinetic Analyses....................................................................................67
12.2.10. Biomarker Analyses.............................................................................................67

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12.2.10.1. KRAS Mutation Assessment............................................................................67
12.2.10.2. Other Biomarkers ...........................................................................................67
12.2.11. Health Outcome/Quality of Life Analyses............................................................68
12.2.11.1. MDASI-LC ....................................................................................................68
12.2.11.2. Health State Utility.........................................................................................68
12.2.11.3. Use of Pain Medications.................................................................................68
12.2.12. Safety Analyses....................................................................................................69
12.2.13. Subgroup Analyses ..............................................................................................70
12.2.14. Interim Analyses..................................................................................................70
12.2.14.1. Safety Interim Analyses..................................................................................70
12.2.14.2. Efficacy Interim Analyses...............................................................................70
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................72
13.1. Informed Consent.........................................................................................................72
13.2. Ethical Review.............................................................................................................72
13.3. Regulatory Considerations ...........................................................................................73
13.3.1.
Investigator Information.......................................................................................73
13.3.2.
Protocol Signatures ..............................................................................................73
13.3.3.
Final Report Signature .........................................................................................73
14.
References ........................................................................................................................74

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List of Tables
Table
Page
Table JPBK.9.1.
Treatment Regimens/Dosing Schedule ...................................................35
Table JPBK.9.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for 
Study JPBK............................................................................................39
Table JPBK.9.3.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBK ..................41
Table JPBK.9.4.
Erlotinib Dose Reduction Schedule ........................................................42
Table JPBK.9.5.
Erlotinib Dose Modification Table..........................................................43
Table JPBK.10.1.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........52
Table JPBK.10.2.
Schedule for Electrocardiogram Collection.............................................55
Table JPBK.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival.......................................................................66
Table JPBK.12.2.
World Health Organization Pain Scale....................................................69

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List of Figures
Figure
Page
Figure JPBK.8.1.
Illustration of study design......................................................................31
Figure JPBK.8.2.
Study period and extension period diagram.............................................33

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JPBK Study Schedule...............................................................77
Attachment 2.
Protocol JPBK Clinical Laboratory Tests................................................83
Attachment 3.
Protocol JPBK Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................84
Attachment 4.
Protocol JPBK ECOG Performance Status .............................................85
Attachment 5.
Protocol JPBK RECIST Criteria 1.1 .......................................................86
Attachment 6.
Protocol JPBK Sampling Summary ........................................................93
Attachment 7.
Protocol JPBK Pharmacokinetic
Sampling Schedule .................................................................................94
Attachment 8.
Protocol JPBK Inducers and Strong Inhibitors of CYP3A4 or 
Substrates of CYPs with Narrow Therapeutic Range ..............................95
Attachment 9.
Protocol JPBK CTCAE 4.03 Diarrhea Definition ...................................96
Attachment 10.
Protocol JPBK Amendment(e) Summary
JUNIPER:  A Randomized Phase 3 Study of Abemaciclib plus 
Best Supportive Care versus Erlotinib plus Best Supportive Care in 
Patients with Stage IV NSCLC with a Detectable KRAS Mutation 
Who Have Progressed After Platinum-Based Chemotherapy ..................97

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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event
Any untoward medical occurrence in a patient or clinical investigation subject 
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.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and risks involved in participating 
in a study (required by some institutional review boards [IRBs]). 
AST
aspartate aminotransferase
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).
BOR
best overall response
BSC
best supportive care
CDK
p16INK4A-cyclin D-cyclin-dependent kinases
CI
confidence interval
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
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.

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CNS
central nervous system
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.
CR
complete response
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DMC
data monitoring committee
ECG
electrocardiogram
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.
ERB
ethical 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.
EQ-5D 5L
European Quality of Life – 5 Dimensions – 5 Level
extension period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit may continue to receive study 
therapy until one of the criteria for discontinuation is met.
FDA
US Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
G12C
GLY12CYS: a mutation in codon 12 of the KRAS gene resulting in an amino acid 
substitution from glycine to cysteine

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GCP
good clinical practice
G-CSF
Granulocyte-Colony Stimulating Factors
GPS
(Lilly) Global Patient Safety
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
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.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial.
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.
ITT
intention-to-treat
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IV
intravenous
KRAS
kirsten rat sarcoma
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.
LLT
Lower Level Term
MDASI-LC
MD Anderson Symptom Inventory – Lung Cancer

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MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NONMEM
nonlinear mixed effect modeling
NSCLC
non-small cell lung cancer
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
progressive disease
PET
positron emission tomography
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic
PFS
progression-free survival
PO
orally
PR
partial response
pRb
phosphorylated retinoblastoma
Pre-screen
The act of determining if an individual meets minimum requirements to be an 
appropriate candidate for screening for a clinical study.  In this study, prescreening 
involves diagnostic testing of an archived NSCLC tumor sample for mutations in 
codons 12 and 13 of the KRAS oncogene. Informed consent for this prescreening test 
shall be obtained; this consent may be separate from obtaining consent for the study.
PS
performance status
PT
Preferred Term
Q12H
every 12 hours
QTc
corrected QT interval
RANKL
nuclear factor kappa B ligand
randomize
the process of assigning patients to an experimental group on a random basis
RECIST
Response Evaluation Criteria in Solid Tumors

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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
screen
The act of determining if an individual meets the 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, x-rays, blood 
draws).  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
This study will be considered complete after the final analysis of overall survival is 
performed.  
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.
topoIIα
topoisomerase II alpha
TKI
tyrosine kinase inhibitor
ULN
upper limits of normal
US
United States
VAS
visual analog scale
WBC
white blood cells

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JUNIPER:  A Randomized Phase 3 Study of Abemaciclib plus 
Best Supportive Care versus Erlotinib plus Best Supportive 
Care in Patients with Stage IV NSCLC with a Detectable 
KRAS Mutation Who Have Progressed After Platinum-Based 
Chemotherapy
5. Introduction
Patients with metastatic non-small cell lung cancer (NSCLC) that harbor KRAS mutations (25%) 
have a poor prognosis compared to NSCLC patients who are KRAS wild-type (Guan et al. 2013). 
The p16INK4A-cyclin D-cyclin-dependent kinases (CDK) 4 and 6-retinoblastoma pathway is 
frequently dysregulated in NSCLC and therefore this pathway represents an attractive 
therapeutic target. Importantly, synthetic lethal interaction between KRAS mutation and CDK4 
inhibition indicates a potential therapeutic application for CDK4 and CDK6 inhibitors in NSCLC 
(Puyol et al. 2010).
LY2835219 (hereafter, abemaciclib) is a potent and selective small molecule inhibitor of CDK4
and CDK6.  Abemaciclib administered orally demonstrates single-agent activity in xenograft 
models of human NSCLC.  In the Phase 1 study I3Y-MC-JPBA (JPBA), abemaciclib has shown 
acceptable safety/tolerability, as well as evidence of clinical activity in multiple tumor types.  In 
addition, Study JPBA included a NSCLC expansion cohort that enrolled 57 patients with 
advanced and/or metastatic NSCLC.  The KRAS status of the tumors from 53 of the 57 patients 
has been identified.  For patients with KRAS mutant tumors (N=29), 16 patients had a Response 
Evaluation Criteria In Solid Tumors (RECIST) response of stable disease (SD) or better (disease 
control rate [DCR=55.2%]); for patient with KRAS wild-type tumors (N=24), 9 had a response of 
SD or better (DCR=37.5%).
In clinical trials, the most frequently reported adverse events (AEs) related to abemaciclib have 
been diarrhea, nausea, fatigue, and vomiting.  These AEs have generally been low-grade events.
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of abemaciclib may be found in the Investigator’s Brochure (IB).  Information on AEs expected 
to be related to abemaciclib 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 erlotinib may be 
found in the following: Tarceva Package Insert or Summary of Product Characteristics (SmPC).
An investigational in vitro diagnostic medical device, or companion diagnostic, will be used to 
evaluate KRAS mutations in formalin-fixed paraffin-embedded (FFPE) NSCLC tumor tissue.
The QIAGEN® therascreen® KRAS Rotor-Gene Q (RGQ) Polymerase Chain Reaction (PCR) Kit
NSCLC is a real-time qualitative PCR assay used for the detection of 7 somatic mutations in 
codons 12 and 13 in the KRAS oncogene. Potential risks to patients have been evaluated by 

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Eli Lilly and Company’s (Lilly’s) Global Patient Safety (GPS). Physicians will consider each 
patient’s disease, KRAS test result, and other factors to reach the appropriate therapeutic 
decision. No treatment decision shall be made solely on the basis of the KRAS test result.  In the 
event abemaciclib would be administered to a patient for whom it is not indicated based on the 
result of the KRAS test result, there is no evidence from clinical studies indicating that this might 
cause or contribute to any serious harm of a patient, other than potentially delaying another 
treatment option for a patient.  It is unlikely that an incorrect result would be generated by the 
in vitro diagnostic medical device and highly likely that an incorrect result would be detected by 
laboratory personnel.
Erlotinib is indicated for the treatment of patients with locally advanced or metastatic NSCLC 
after failure of at least 1 prior chemotherapy regimen (Tarceva United States [US] package insert 
[USPI], 2010).  Until recently, unlike the use of erlotinib for first-line treatment of patients with 
NSCLC, second- and third-line treatment has no limitation with regard to epidermal growth 
factor receptor (EGFR) or KRAS mutation status.  In October 2016 the FDA modified the 
erlotinib label to include only those patients with tumors with common EGFR mutations, del 19 
and exon 21 L858R substitutions.  Before this action, there had been some concern regarding the 
activity of erlotinib in treating NSCLC with KRAS mutations due to results from 3 studies.  First, 
in the original BR-21 study, a subgroup evaluation of 30 patients with KRAS mutant tumors 
randomized between placebo and erlotinib demonstrated a nonsignificant better survival outcome 
in the placebo group (Zhu et al. 2008).  Second, in TITAN, a second-line study of erlotinib 
versus chemotherapy, 35 patients with KRAS mutant tumors had inferior outcome on erlotinib 
compared to chemotherapy (Ciuleanu et al. 2012).  Lastly, a meta-analysis of response rate 
showed numerically inferior response rate in patients with KRAS mutant tumors treated with 
EGFR tyrosine kinase inhibitors (TKIs, such as erlotinib and gefitinib) (Linardou et al. 2008).  In 
the TAILOR study comparing docetaxel to erlotinib as second-line therapy, overall survival (OS) 
favored docetaxel treatment in patients with both KRAS wild-type and KRAS mutant tumors 
(hazard ratio [HR] = 0.79 and 0.81, respectively); similarly, progression-free survival (PFS)
favored docetaxel (HR = 0.68 and 0.89) for KRAS wild-type and KRAS mutant, respectively
(Garassino et al. 2013). There was not a significant treatment interaction based on KRAS status.  
However, the SATURN study of erlotinib maintenance therapy demonstrated that improved PFS
was preserved in a subset of 90 patients with KRAS mutant tumors (HR = 0.77 erlotinib 
compared to placebo) (Brugger et al. 2011).  Overall, the data remain conflicting and after 
extensive review of the literature, Langer stated, “KRAS mutation cannot be used at this time to 
preclude NSCLC patients from receiving anti-EGFR TKI’s” (Langer 2011).  A more recent 
evaluation of pooled results from four Phase 3 studies of erlotinib showed that KRAS mutation 
was not predictive of treatment outcome with tyrosine kinase inhibitors (Zer et al. 2015).  The 
selection of treatment depends on the overall benefit/risk for the patient.  Given the differences in 
toxicity profile for available treatments, and the limited treatment options for patients, erlotinib is 
an acceptable control arm as the only oral drug available for patients with lung cancer, and only 
approved drug for treatment of third-line patients in selected geographies.
The Phase 3 Study I3Y-MC-JPBK (JPBK) study will evaluate the clinical activity of abemaciclib
plus best supportive care (BSC) versus erlotinib plus BSC for patients with Stage IV NSCLC 

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whose tumors have a detectable KRAS mutation and who have progressed after prior platinum 
based therapy and received 1 other prior therapy or are not eligible for further chemotherapy.
5.1.
Rationale for Amendment (a)
The protocol was amended based on the US Food and Drug Administration (FDA) feedback to 
provide a rationale for the selected dose and schedule of abemaciclib for the intended patient 
population and to add specified provider-conducted history and physical examination to be 
performed during screening and before each cycle.
Further modifications were performed for clarity:  1) Inclusion Criterion [4] revised to include 
adjuvant, neoadjuvant, and chemoradiation for locally advanced disease; furthermore, prior 
immunotherapy, such as anti-PD-1 therapy, does NOT count as a prior line of therapy
2) Exclusion Criterion [18] modified to replace LY2835219 to a CDK4 and CDK6 inhibitors; 3) 
the extension period is also applicable for patients randomized to the erlotinib arm and who are 
experiencing ongoing clinical benefit; 4) supportive management for diarrhea modified; and 
5) clarification with respect to the timing and purpose of the interim analyses added.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.2.
Rationale for Amendment (b)
This protocol was amended to clarify the allowed use of immunotherapy as prior line of therapy. 
Nivolumab, a fully human IgG4 immune checkpoint inhibitor antibody, was recently approved in 
the US for treatment of patients with advanced (metastatic) squamous NSCLC who have 
progressed after a platinum-based chemotherapy. In the CheckMate 017 study, 272 patients
received either nivolumab (135 patients) or docetaxel (137 patients). The interim analysis 
showed a median OS of 9.2 months and 6 months (HR 0.59; 95% CI: 0.44 to 0.79; p<.0.001) 
and PFS 3.5 months and 2.8 months (HR 0.62; 95% CI: 0.47 to 0.81; p<0.001) with nivolumab 
and docetaxel, respectively (Brahmer et al. 2015).  The results of this study and ongoing studies 
with nivolumab and other immune checkpoint inhibitors demonstrate that an immune checkpoint 
inhibitor may be a suitable second-line treatment option for patients with metastatic NSCLC. 
Inclusion Criterion [4] has been updated to include an immune checkpoint inhibitor as one of the 
possible second-line therapies for inclusion into Study JPBK. In addition, it has been clarified 
that patients who have received first-line platinum-based therapy followed by standard 
chemotherapy and subsequently an immune checkpoint inhibitor are also eligible for enrollment 
in Study JPBK in the third-line setting.
Further modifications were performed for clarity:  1) supportive management for diarrhea; 
2) rescreening of patients; 3) dose delays related to toxicity; 4) the timing of study procedures 
and 5) potential CYP interactions.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.

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5.3.
Rationale for Amendment (c)
This protocol was amended to address the challenges identified with tissue for KRAS testing by
the central laboratory. As multiple biomarker targets are recognized within NSCLC (for 
example, EGFR, ALK, and KRAS) and tested locally, obtaining tissue of sufficient quality and 
quantity to enable eligibility testing with the QIAGEN® therascreen® KRAS RGQ PCR Kit 
NSCLC at the Study JPBK central laboratory has been a challenge, and ultimately has impacted 
enrollment. This protocol amendment will permit study inclusion for no more than 10% of 
randomized patients with a positive local KRAS result. A review of approximately 1740 KRAS
sample submissions indicated that approximately 260 samples were resulted as “indeterminate”, 
“no neoplastic cell in tissue”, or “insufficient sample” or ‘quantity not sufficient”.  In many 
cases, additional tissue to submit for re-testing is not available and the patient is not a candidate 
for re-biopsy to obtain more tissue. Those patients who have a positive local KRAS result for one 
of the 7 specific mutations identified by the QIAGEN® therascreen® KRAS RGQ PCR Kit 
NSCLC will be allowed to enter into the study with this result in the absence of a central 
laboratory KRAS positive result. Additionally, patients with no tissue available for testing with 
the QIAGEN® therascreen® KRAS RGQ PCR Kit NSCLC will be allowed to enter into the study 
with a positive local KRAS result.  The investigator will require approval from the study team to 
confirm patient eligibility prior to randomization to study treatment as outlined in 
Section 10.4.2.2. Inclusion Criterion [3] has been modified to include local KRAS mutation 
results.
This protocol amendment also revises the timing of primary PFS analysis to allow for adequate 
time to observe additional OS events.  The primary PFS analysis will be performed after 
approximately 338 PFS events have occurred, or approximately 1 month after study enrollment 
completion, whichever comes later. The interim OS analysis will be conducted at the time of 
primary PFS analysis. The final OS analysis will be conducted after approximately at least 407 
OS events have been observed. If the primary PFS analysis is significant, two-sided 
alpha=0.0112 will be spent in the interim OS analysis and alpha=0.0466 will be used in the final 
OS analysis based on O’Brien and Fleming alpha-spending approach using East® 6.3 (Lan and 
DeMets 1983). If the primary PFS is not significant, two-sided alpha=0.0096 will be spent in the 
interim OS analysis and alpha= 0.0420 will be used in the final OS analysis.  A fallback 
procedure (Wiens 2003) will be used to maintain a study-wise alpha level of .05.
Additional clarity was added in the unblinding plan for potential positive interim efficacy results.  
If the data monitoring committee (DMC) recommends to stop the trial based on positive outcome 
of OS interim analysis, in light of the critical importance of obtaining unbiased results of final 
OS analysis in the study, the unblinded database will be accessible to a limited number of 
individuals who need to have such access to perform analyses and make critical decisions (for 
example, regulatory submission).
An extra plasma biomarker sample was added at baseline prior to randomization. This additional 
sample will be obtained for the biomarker exploratory analysis and may assist in future 
development of a liquid biopsy test for KRAS. Further information regarding plasma biomarker 
samples is discussed in Section 10.4.3.3.

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Lastly, updates to the dose adjustments for abemaciclib in case of hematologic toxicities were 
completed for consistency with the abemaciclib program. These updates include specific 
guidelines for managing Grade 3 hematologic toxicities, including dose omission and reductions,
and the use of blood cell growth factors.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.4.
Rationale for Amendment (d)
According to the US label and EU SmPC of immune checkpoint inhibitors nivolumab and 
pembrolizumab, delayed immune-related adverse reactions (AE) such as hepatitis, pancreatitis, 
hypophysitis, or thyroiditis may occur in patients, even after discontinuation of therapy. Wide
variation exists in the reported times of onset of immune-mediated AEs with PD-1 inhibitors 
(Medina and Adams 2016). For example, pembrolizumab’s FDA label reports a delayed 
immune-related adverse event of autoimmune nephritis that occurred in 1 patient 11.6 months 
after the first dose of pembrolizumab (5 months after the last dose). 
Study JPBK was amended to include the following recommendations for monitoring and 
treatment of potential delayed immune-related adverse reactions associated with immune 
checkpoint inhibitors:

Patients who have received prior immune checkpoint inhibitor or other immunotherapy 
should be monitored for potential signs of a delayed toxicity after discontinuation of 
immunotherapy. 

Treatment of a suspected toxicity should be according to the immune checkpoint 
inhibitor’s label and may include immediate use of corticosteroids, an immune-
suppressive therapy, and increased laboratory monitoring and physical assessments.

Current recommendations for monitoring for delayed toxicity range between 90 days and 
1 year after treatment discontinuation (Champiat et al. 2016).
In addition, updates to the frequency of the hematological and clinical chemistry laboratory tests
during Cycles 1 and 2 were made to align with newer studies within the abemaciclib program.  
For patients enrolled in Amendment (d), hematological and chemistry samples will be collected 
on Days 1 and 15 during Cycles 1 and 2. Beginning with Cycle 3, these samples will be 
collected on Day 1 of each cycle.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.5.
Rationale for Amendment (e)
Due to recent changes in the FDA ertlotinib label and National Comprehensive 
Cancer Network (NCCN) Guidelines, the Sponsor amended the protocol to address the
impact on study enrollment completion, and the need for a larger improvement in OS than that 
historically targeted for NSCLC patients. In addition, OS is considered the preferred primary 
endpoint for regulatory approval and hence PFS is removed from the primary objective so all 

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statistical power can be reallocated to enhance the success for OS. The amendment updates 
include the followings:

PFS is removed as a co-primary endpoint and changed to a secondary endpoint. With 
this change OS becomes the sole primary endpoint. 

The final OS analysis will occur when approximately 304 OS events have been 
observed, a reduction from the current protocol requirement of 407 OS events. With this 
change, the study will provide 80% statistical power for a new targeted hazard ratio of 
0.72. 

Due to the reduced number of targeted OS events, a smaller sample size of 
approximately 450 patients will be sufficient to reach the 304 OS events for the final 
analysis (note that current protocol requires 550 patients). 
While amending the protocol, the Lilly study team remains blinded to aggregate data and will not 
be unblinded until the final OS analysis per Section 9.5.
Previously, erlotinib was indicated for the treatment of patients with locally advanced or 
metastatic NSCLC after failure of at least 1 prior chemotherapy regimen (Tarceva® United States 
[US] package insert [USPI], 2010) based upon the BR-21 study.  In addition, NCCN Guidelines 
(April 2015) supported erlotinib use as an option for subsequent second line or third line 
treatment in NSCLC patients (all histologies) for PS 0-3. 
On 18 October 2016, the FDA modified the indication for erlotinib (Tarceva®) for treatment of 
NSCLC, limiting the use to patients whose tumors have specific EGFR mutations (exon 19 
deletions or exon 21 L858R substitutions). This labeling supplement occurred based on study 
results of the IUNO Study (a randomize, double-blind, placebo controlled, trial of erlotnib 
administered as maintenance therapy in advanced NSCLC patients who had not experienced 
disease progression or unacceptable toxicity during four cycles of platinum-based first-line 
chemotherapy).  The results showed no observed benefits in PFS, ORR, DCR or OS ( median OS 
was 9.7 and 9.5 months with ‘early’ and ‘late erlotinib’, respectively (HR, 1.02, 95% CI: 
0.85−1.22; log-rank p = 0.82) in patients receiving erlotinib as maintenance therapy (“early 
erlotinib”) compared to second-line treatment (“late erlotinib”) in patients whose tumor did not 
harbor an EGFR-activating mutation. 
However, safety results were consistent with the 
established safety profile of erlotinib. Furthermore, in light of the FDA labeling supplement, the 
NCCN Guidelines removed erlotinib from recommended therapies in patients who progress on 
platinum therapy and who do not have EGFR mutations (NCCN Guidelines October 2016). 
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.

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6. Objectives
6.1.
Primary Objective
The primary objective of this study is to compare abemaciclib plus BSC versus erlotinib plus 
BSC in patients with Stage IV NSCLC whose tumors have detectable KRAS mutations and who 
have progressed after prior platinum-based therapy and 1 additional therapy which may include 
an immune checkpoint inhibitor and/or other anti-cancer treatment; or are not eligible for further 
chemotherapy with respect to:

overall survival (OS)
6.2.
Secondary Objectives
The secondary objectives of the study are to compare abemaciclib plus BSC to erlotinib plus 
BSC with respect to:

overall response rate (complete response [CR] + partial response [PR])

progression-free survival (PFS)

changes in patient-reported pain and disease-related symptoms collected via the MD 
Anderson Symptom Inventory (MDASI-LC) and changes in health status via European 
Quality of Life – 5 Dimensions – 5 Level (EQ-5D 5L).

safety and tolerability

resource utilization (for example, analgesic type, hospitalization, transfusion)
An additional secondary objective is to examine the pharmacokinetic (PK)/pharmacodynamic 
(PD) properties of abemaciclib.
6.3.
Exploratory Objectives
The exploratory objectives of the study are as follows:

to explore biomarkers relevant to abemaciclib and the disease state and to correlate these 
markers to clinical outcome and to abemaciclib

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7. Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  When re-screening is performed, the individual must sign a new informed consent 
form (ICF) and will be assigned a new identification number. Patients may only be rescreened 
once.
Patients may be eligible for rescreening in any of the following circumstances:

Patients who have become eligible to enroll in the study as the result of a protocol 
amendment.

Patients whose status has changed such that the eligibility criterion that caused the patient 
to screen fail would no longer cause the patient to screen fail again.

Patients who complete screening and meet all inclusion and exclusion requirements but 
are unable to be enrolled due to extenuating circumstances (such as severe weather, death 
in family, or child illness).
The investigator should contact the Lilly clinical research physician (CRP) prior to re-screening 
a patient.
If a KRAS mutation positive result was obtained for an individual under their first patient 
number, this result can be linked to their new number in an effort to preserve patient tissue. If a 
KRAS mutation result was not successfully obtained for an individual under their first patient 
number, then the investigator can submit a new sample for this individual (as well as one repeat
if needed) to the central lab with the new patient number.
Repeating laboratory tests (including one re-test for KRAS) during the pre-screening and 
screening period does not constitute re-screening. Patients who prescreened for KRAS mutation 
and their result was either indeterminate or insufficient tissue will be permitted to resubmit tissue 
if adequate tissue is available. 
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]
have confirmed diagnosis of stage IV NSCLC according to the American Joint 
Committee on Cancer Staging Handbook (Edge et al. 2009).
[2]
have availability of adequate FFPE tumor-derived material (tumor blocks or slides) 
from a biopsy, surgery or fine needle aspirate for analysis of KRAS mutation status.  
This sample should be the most recent available sample containing adequate material.  
Tumor sample requirements are described in Section 10.4.2.1.  The sponsor will not 
request re-biopsy solely for the purpose of testing of KRAS status.
[2A] For patients who do not have adequate FFPE tumor-derived material for KRAS
mutation status analysis, eligibility may be considered based upon a local 

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KRAS mutation result as described in Section 10.4.2.2. The sponsor will not 
request re-biopsy solely for the purpose of testing of KRAS status.
[3]
determined to have detectable mutations in codons 12 or 13 of the KRAS oncogene by 
an investigational assay at the Study JPBK central laboratory
[3A] A KRAS positive mutation result in codons 12 or 13 of the KRAS oncogene 
from tumor tissue per local laboratory will be permitted in no more than 10% 
of the randomized patients; thus, requirement of a central laboratory KRAS
positive mutation result is waived. No serum or plasma KRAS mutation results 
are permitted for consideration.
[4]
have progressed after platinum-based chemotherapy (with or without maintenance 
therapy [see below]) AND have received 1 additional therapy which may include an 
immune checkpoint inhibitor or other anti-cancer therapy for advanced and/or 
metastatic disease; OR is judged by the physician as ineligible for further standard 
second-line chemotherapy. Patients who have progressed after platinum-based 
chemotherapy and an immune checkpoint inhibitor (immunotherapy) e.g.
pembrolizumab or nivolumab alone or in combination with other agents are eligible.

Prior adjuvant or neoadjuvant therapy for an earlier stage of NSCLC counts as an 
appropriate line of therapy in case the patient progressed within 6 months of 
completing the platinum-based adjuvant or neoadjuvant therapy. The time from 
the completion of the last cycle of adjuvant or neoadjuvant therapy to progression 
must be less than 6 months.  For radiotherapy for locally advanced disease with 
curative intent with platinum-based chemotherapy, the time of completion of 
platinum-based chemotherapy or radiotherapy, whichever finishes last, to 
progression must be less than 6 months to count as a line of therapy.

The patient may not have received prior EGFR-targeted therapy, including any 
multi-target TKIs, which may inhibit EGFR (for example, vandetanib) in any 
setting for NSCLC.

The patient may have received prior therapy with bevacizumab.

The patient may have received maintenance therapy.  Maintenance treatment is 
defined as therapy given approximately within 42 days after the last dose of 
platinum-based chemotherapy in patients that have not progressed (complete 
response, partial response, or stable disease) after platinum-based, first-line 
induction chemotherapy. A minor delay eg. up to 30 additional days in the start 
of maintenance therapy is acceptable.

If the patient has received prior immunotherapy, such as anti-PD-1 therapy, after 
platinum-base therapy plus 1 additional line of therapy, the patient is eligible to 
participate in study. The immunotherapy does not count as a prior line of therapy 
in this case. This patient would be entering the study as third line treatment.
[5]
have measureable disease as defined by the Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1, Eisenhauer et al. 2009)

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[6]
have a performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology 
Group (ECOG) scale (see Attachment 3)
[7]
have discontinued all previous therapies for cancer (including chemotherapy, 
radiotherapy, immunotherapy, and investigational therapy) for at least 21 days 
for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior 
to receiving study drug
[8]
recovered from the acute effects of therapy (treatment related toxicity resolved 
to baseline) except for residual alopecia
[9]
have adequate organ function, including:

hematologic:  absolute neutrophil count (ANC) 1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 8 g/dL.  Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator.  Initial treatment must not begin until the day after the 
erythrocyte transfusion.

hepatic:  bilirubin 1.5 × the upper limit of normal (ULN), 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 1.5 × ULN
[10]
are 18 years of age
[11a] are a man and agree to use a reliable method of birth control and to not donate 
sperm during the study and for at least 3 months following the last dose of 
study drug(s) or country requirements, whichever is longer, OR
[11b] are a woman of child-bearing potential who tests negative for pregnancy at the 
time of enrollment based on a serum pregnancy test and agrees to use a 
reliable method of birth control during the study and for 3 months following 
the last dose of the study drug(s) or country requirements, whichever is longer
[12]
have an estimated life expectancy of at least 12 weeks
[13]
have given written informed consent/assent prior to any study-specific 
procedures
[14]
are able to swallow oral medications
[15]
are reliable and are willing to follow study procedures

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7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[16]
are currently receiving treatment in a clinical trial involving an investigational 
product or non-approved use of a drug or device (other than the study 
drug/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
[17]
have received treatment with a drug that has not received regulatory approval 
for any indication within 14 or 21 days of the initial dose of study drug for a 
nonmyelosuppressive or myelosuppressive agent, respectively
[18]
have previously completed or withdrawn from this study or any other study 
investigating a CDK4 and CDK6 inhibitors, or have received treatment with a 
prior CDK4 and CDK6 inhibitors
[19]
have a personal 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
[20]
have the presence of unstable central nervous system (CNS) metastasis. 
History of CNS metastasis or stable CNS metastases is allowed (no longer 
requiring active therapy such as steroid medications).  Patients with a history 
of CNS metastases must have a brain scan (for example, MRI) within 28 days 
of randomization to document stability, even if there have been no changes in 
symptoms. A brain MRI performed up to 45 days is permitted and does not 
need to be repeated during baseline.
[21]
have a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy
for that disease for a minimum of 3 years
[22]
have serious preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study
[23]
females who are pregnant or lactating
[24]
have active bacterial, fungal, and/or known viral infection (for example, 
human immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen, 
or hepatitis C antibodies).  Screening for active infections is not required for 
enrollment.
7.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion [19] is necessary because the effects of abemaciclib on corrected QT (QTc)
prolongation are unknown; these conditions may put the patient at additional risk.  Exclusion 
Criterion [20] is necessary because patients with unstable CNS metastasis are not likely to 
receive sufficient study treatment, preventing a full assessment of the agents administered in this 

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study.  Exclusion Criterion [23] is necessary because the effects of abemaciclib on the 
developing fetus are unknown.
7.3.
Discontinuations
7.3.1. Discontinuation of 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 drug 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.
In addition, patients will be discontinued from the study drugs and/or from the study in the 
following circumstances:

disease progression

unacceptable toxicity

the patient has had 2 dose reductions and experiences an AE that would cause a third 
dose reduction.

the patient is significantly noncompliant with study procedures and/or treatment

investigator decision
o
the investigator decides that the patient should be discontinued from the study or 
study drug for any reason (for example, the patient becomes pregnant)
o
if 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 drug occurs prior to introduction of the new agent

patient decision
o
the patient or the patient’s designee (for example, parents or legal guardian) 
requests to be withdrawn from the study or study drug

sponsor decision
o
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 good clinical practice

enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

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The reason for and date of discontinuation will be collected for all patients.  All randomized
patients who discontinue regardless of whether or not they received study drug will have 
procedures performed as shown in the Study Schedule (Attachment 1).
7.3.2. 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 it necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).
7.3.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it 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 I3Y-MC-JPBK is a multicenter, randomized, open-label, parallel, comparator-controlled 
trial in patients with Stage IV NSCLC whose tumors have a detectable KRAS mutation in codons 
12 or 13 and who have progressed after platinum-based chemotherapy and received 1 other prior 
therapy or are ineligible for further chemotherapy after platinum-based therapy.
Figure JPBK.8.1 illustrates the study design.
Abbreviations:  ECOG = Eastern Cooperative Oncology Group; N = number of patients; NSCLC = non-small cell 
lung cancer; PD = progressive disease; PO = orally; PS = performance status; Q12H = every 12 hours; 
Q24H = every 24 hours.
Figure JPBK.8.1.
Illustration of study design.
Terms used to describe the periods during the study are defined below:

Pre-screening:  begins when the pre-screening informed consent form (ICF) is signed for 
evaluation of FFPE tissue by Study JPBK central laboratory and ends once the KRAS
mutation status of the tissue is determined (or at discontinuation, if the study ICF is not 
signed).  Pre-screening for KRAS mutation status determination is optional.  If 
pre-screening did not occur, determination of KRAS mutation status will occur at 
baseline.

Baseline:  begins when the study 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 extension 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.
o
Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.  All 

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randomized patients must be followed during postdiscontinuation regardless of 
whether study treatment was received.
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.  During long-term 
follow-up, patients will have a follow-up visit every 60 days (±14 days).

Extension Period:  begins after study completion and ends at the end of trial.  During the 
extension period, patients on study therapy who continue to experience clinical benefit 
may continue to receive study therapy until one of the criteria for discontinuation is met.  
The extension period includes extension period follow-up.
o
Extension period follow-up:  begins 1 day after the patient and the investigator 
agree that the patient will no longer continue treatment in the extension period 
and lasts approximately 30 days.
8.1.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study
completion]) following the final analysis of overall survival, as determined by Lilly.  
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 
(Figure JPBK.8.2).  The end of trial occurs after study completion and after the last patient has 
discontinued study treatment and completed extension period follow-up (if applicable).

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Abbreviations:  OS = overall survival.
a
Lilly will notify sites when this begins and ends.
Figure JPBK.8.2.
Study period and extension period diagram.
8.1.2. Extension Period
Patients experiencing ongoing clinical benefit may continue to receive abemaciclib or erlotinib in 
the extension period until 1 of the criteria for discontinuation is met (Section 7.3).  There is no 
cross-over between the 2 study treatment arms.  Lilly will notify investigators when the 
extension period begins.
Patients who are in short-term follow-up when the extension period begins will continue in 
short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the extension period begins will be discontinued 
from long-term follow-up.
During the extension period, all AEs, SAEs, and study drug exposure will be reported on the 
CRF.  Serious adverse events will also be reported to Lilly GPS (see Section 10.3.1).  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.

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Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly
will not routinely collect the results of these assessments.
8.2.
Discussion of Design and Control
A randomized, controlled design is being used in this study.  Randomization minimizes 
systematic bias in the selection and assignment of patients to study therapy and provides 
justification for inferential statistical methods to be used on data from this study.  It is expected 
that abemaciclib will produce better efficacy outcomes than the control; therefore, this study uses 
a 3:2 randomization.  Using an appropriate concurrent control arm enables direct statistical 
estimation of benefits and harms due to study therapy and minimizes bias in the assessment and 
interpretation of observed treatment effects. Patients will be stratified for differences in factors 
thought to be associated with clinical outcomes to further reduce the potential for bias and 
improve the power of the analyses.

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9. Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study:

Experimental Arm A:  Abemaciclib 200 mg orally every 12 hours plus BSC on Days 1 to 
28 of a 28-day cycle.  The total daily dose of abemaciclib is 400 mg.

Control Arm B:  Erlotinib 150 mg orally every 24 hours plus BSC on Days 1 to 28 of a 
28-day cycle.
Table JPBK.9.1 shows the treatment regimens.
Table JPBK.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose Day 1-28
Abemaciclib
Treatment/28-day cycle
200 mg PO Q12H
Erlotinib
Treatment/28-day cycle
150 mg PO Q24H
Abbreviations:  PO = orally; Q12H = every 12 hours; Q24H = every 24 hours.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and the planned duration of each individual’s 
treatment to the patient, site personnel, and/or the patient’s legal representative,

verifying that instructions are followed properly,

maintaining accurate records of study drug dispensing and collection,

and returning all unused drug to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the study drug 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
Abemaciclib will be supplied by Lilly as capsules for oral administration. Abemaciclib capsules
should be stored according to the temperature range listed on the product label, and should not be 
opened, crushed, or chewed.
Erlotinib will be supplied where required as tablets for oral consumption.  Erlotinib should be 
stored according to the temperature range listed on the product label.
All study drug provided by Lilly will be labeled according to local country regulatory 
requirements. All medication should be kept out of the reach of children and stored in the 
original packaging/container provided.

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9.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomly assigned to receive either 
abemaciclib or erlotinib. If possible, treatment should begin as soon as possible when study drug 
is available.
Randomization will be stratified by the following factors:

number of prior chemotherapy regimens (1 versus 2)
o
For purposes of stratification, immunotherapy does not count as a chemotherapy 
regimen. However, immunotherapy may be considered a prior treatment for 
eligibility as described in Section 7.1 (for example, if a patient received platinum-
based therapy followed by immunotherapy, the number of prior chemotherapies 
for stratification is one).

performance status (0 versus 1)

gender (male versus female)

KRAS mutation (GLY12CYS [G12C] versus all others)
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web response system.
The chosen stratification factors have been identified as variables with the foremost influence on 
the primary objective of OS. Randomization will be performed separately within each of the 
16 strata (or cells) defined by all combinations of these 4 variables.
9.4.
Selection and Timing of Doses
Abemaciclib will be taken orally every 12 (±approximately 2) hours on Days 1 through 28 of a 
28-day cycle, for a total of 56 doses per cycle. On Cycle 1 Day 1, only one 200-mg dose of 
abemaciclib will be taken. Chronic oral administration of abemaciclib approximately every 12 
hours will be initiated on Cycle 1 Day 2 and continue throughout every cycle. During all cycles, 
abemaciclib should be taken at approximately the same times each day.  If a patient misses or 
vomits a dose, that dose should be omitted.
Erlotinib will be taken orally once daily (approximately every 24 hours) on Days 1 through 28 of 
a 28-day cycle, for a total of 28 doses per cycle.  During all cycles, erlotinib should be taken at 
approximately the same time each day.  If a patient misses or vomits a dose, that dose should be 
omitted.
A cycle is defined as the planned treatment interval of 28 days plus any subsequent delay prior to 
the start of the next cycle. A delay of a cycle due to holidays, weekends, bad weather, or other 
unforeseen circumstances will be permitted up to 7 days and not counted as a protocol deviation.  
Abemaciclib will be dispensed for 56 doses (28-day supply).  Erlotinib will be dispensed with a 
30 day supply, but only 28 doses should be taken per cycle. 
A patient may continue to receive study drug until he or she meets 1 or more of the specified 
reasons for discontinuation (as described in Section 7.3.1).

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9.4.1. Dose Rationale
The abemaciclib dose of 200 mg administered every 12 hours corresponds to the maximum 
tolerated dose (MTD) determined in I3Y-MC-JPBA (hereafter designated Study JPBA). 
Study JPBA is the Phase 1 dose-escalation and tumor cohort-expansion study in advanced cancer 
patients that included a cohort expansion in NSCLC patients.  Selection of 200 mg every 
12 hours for assessment during the Phase 3 Study JPBK is based on safety, clinical activity, and 
PK and PD data from patients with NSCLC enrolled in the ongoing Study JPBA.
The safety profile of abemaciclib is acceptable, with manageable and monitorable toxicities.  The 
most common treatment-emergent adverse events (TEAEs) possibly related to study drug for 
patients in Study JPBA included diarrhea, nausea, fatigue, neutropenia, vomiting, leukopenia, 
thrombocytopenia, anemia, decreased appetite, and blood creatinine increased.  For the patients 
enrolled in the Study JPBA NSCLC expansion cohort, the safety profile was similar to that for 
all patients in the study.
Preliminary analysis of the PK data obtained in Study JPBA for abemaciclib from a total of 
124 patients dosed repeatedly with abemaciclib at 150 and 200 mg every 12 hours suggests that 
the dose of 200 mg administered every 12 hours yields slightly higher and more consistent 
steady-state plasma concentration levels for abemaciclib.  In particular, the mean minimum 
steady-state concentration for abemaciclib is more consistently maintained at a value of 
approximately 200 ng/mL, which represents a threshold value associated with more robust and 
sustained CDK4 and CDK6 inhibition and cell cycle arrest, as indicated by the decrease in 
phosphorylated retinoblastoma (pRb) and topoisomerase II alpha (topoIIα) expression measured 
in skin biopsies.  Furthermore, these findings are in agreement with PK/PD analyses previously 
performed on data obtained from mouse xenograft tumor models.
Importantly for patients who may require a dose reduction, there was no apparent difference in 
the magnitude of the decrease in pRb and topoIIα expression between the 150-mg and 200-mg 
dose groups. In addition, given the variability in abemaciclib pharmacokinetics, there is overlap 
in exposures across the dose range of 50 to 200 mg.
Collectively, these findings indicate that the MTD of 200 mg orally every 12 hours demonstrates 
an acceptable safety profile, evidence of target inhibition and cell cycle arrest in skin, and 
clinical activity against NSCLC.  The dose of 200 mg administered every 12 hours is therefore 
recommended for further assessment in the Phase 3 Study JPBK.
9.4.2. Special Treatment Considerations
9.4.2.1.
Immune Checkpoint Inhibitors
Immune therapies are potentially associated with delayed toxicity (see Section 5.4). Patients 
who have received prior immune checkpoint inhibitor or other immunotherapy should be 
monitored for potential signs of a delayed toxicity after discontinuation of immunotherapy. If a 
suspected delayed immune-mediated toxicity associated with prior immunotherapy occurs while 
participating in Study JPBK, additional treatment may be considered in addition to the dose 
adjustment recommendations listed in Section 9.4.2.2. Treatment of a suspected toxicity should 

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be according to the immune checkpoint inhibitor’s label and may include immediate use of 
corticosteroids, an immune-suppressive therapy, and increased laboratory monitoring and 
physical assessments. Current recommendations for monitoring for delayed toxicity range 
between 90 days and 1 year after treatment discontinuation (Champiat et al. 2016).

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9.4.2.2.
Dose Adjustments and Delays
9.4.2.2.1. Abemaciclib
Table JPBK.9.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for 
Study JPBK
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Section 9.4.2.2.1
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion.
Hematologic Toxicity
Section 9.4.2.2.1
Recurrent Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic Toxicity
Section 9.4.2.2.1
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic toxicity: Patient 
requires administration of 
blood cell growth factors
Sections 9.4.2.2.1 and 9.6.1.7
Regardless of severity
(Growth factors use according to 
ASCO Guidelines)
Dose MUST be suspended 
for at least 48 hours after 
the last dose of blood cell 
growth factors was 
administered and until 
toxicity resolves to at least 
Grade 2.
Dose MUST be reduced 
by 1 dose level unless 
already performed for 
incidence of toxicity that 
lead to the use of growth 
factor.
Nonhematologic Toxicity 
(except diarrhea)
Section 9.4.2.2.1
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 7 days 
to baseline or Grade 1
Dose MAY be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Nonhematologic Toxicity
Section 9.4.2.2.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Section 9.4.2.2.1
Requires hospitalization or Grade 3 
or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Sections 9.4.2.2.1 and 9.6.1.2
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 
24 hours to at least Grade 1
Dose SHOULD be 
suspended until toxicity 
resolves to at least Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Diarrhea
Sections 9.4.2.2.1 and 9.6.1.2
Diarrhea recurs despite maximal 
supportive measures after resuming 
same dose level after initial 
Grade 2 diarrhea
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Abbreviation:  ASCO = American Society of Clinical Oncology.
Before the start of each cycle, hematologic toxicity possibly related to abemaciclib must resolve 
to at least Grade 2.  If a patient experiences Grade 4 hematologic toxicity possibly related to 

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abemaciclib, then dosing must be suspended (until the toxicity resolves to at least Grade 2) and 
the dose of abemaciclib must be reduced by 1 dose level as outlined in Table JPBK.9.3. If a 
patient experiences Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of abemaciclib may be reduced by 1 dose level 
as outlined in Table JPBK.9.3 at the discretion of the investigator.  If the patient experiences a 
recurrent episode of Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of blinded study must be reduced by 1 dose 
level.
If a patient requires administration of blood cell growth factors, the dose of abemaciclib must be 
suspended for at least 48 hours after the last dose of blood cell growth factors was administered 
and until toxicity resolves to at least Grade 2, then must be reduced by 1 dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.
Before the start of each cycle, nonhematologic toxicity (except alopecia and fatigue) possibly 
related to abemaciclib must resolve to either baseline or at least Grade 1.  Refer to 
Section 9.6.1.2 for guidance and supportive measures of diarrhea toxicity possibly related to 
abemaciclib.  If a patient experiences ≥Grade 3 nonhematologic toxicity (except diarrhea: refer 
to Section 9.6.1.2) possibly related to abemaciclib, then dosing must be suspended (until the 
toxicity resolves to either baseline or Grade 1) and the dose of abemaciclib must be reduced by 
1 dose level as outlined in Table JPBK.9.3.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea, 
refer to Section 9.6.1.2) possibly related to abemaciclib that does not resolve with maximal 
supportive measures within 7 days to either baseline or Grade 1, then dosing may be suspended 
(until the toxicity resolves to either baseline or Grade 1) and the dose of abemaciclib may be 
reduced by 1 dose level as outlined in Table JPBK.9.3.
The start of a cycle may be delayed to allow sufficient time for recovery from toxicity possibly 
related to study drug.  Patients not recovering from such toxicity within 14 days beyond the last 
day of the prior cycle will be considered for discontinuation from the study. In rare 
circumstances, a delay >14 days may be permitted before discontinuing the patient from 
treatment as long as the patient demonstrates clinical benefit without objective progression and is 
recovering from the toxicity.  Such circumstances should be discussed and documented with the 
Lilly CRP.
If a patient receiving the 100-mg dose of abemaciclib requires a further dose reduction, the 
patient should be discontinued from study treatment.  If a patient who, in the judgment of the 
investigator, is receiving clinical benefit from study therapy requires further dose reduction than 
is outlined in Table JPBK.9.3, then the investigator must discuss with the Lilly CRP prior to any 
further dose reduction.
Dose omissions are allowed within a cycle.  If a patient requires omission of more than 25% of 
doses during a cycle for tolerability, then treatment may continue if the investigator determines 
the patient is receiving clinical benefit. If the patient does well after a dose reduction and is 

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receiving clinical benefit, the investigator may contact the Lilly CRP to discuss possible dose 
re-escalation.  After re-escalation, subsequent dose adjustments should be based on the dose of 
abemaciclib that the patient is currently receiving.
Table JPBK.9.3.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBK
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Every 12 hours
1
150 mg
Every 12 hours
2
100 mg
Every 12 hours
A patient experiencing diarrhea requiring hospitalization (irrespective of grade that is, requiring 
intravenous [IV] rehydration) or severe diarrhea (Grade 3 or 4; see Attachment 9) must have 
study treatment suspended (until the toxicity resolves to either baseline or at least Grade 1) and
the dose of abemaciclib must be reduced by 1 dose level as outlined in Table JPBK.9.3.  If a 
patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve with maximal 
supportive measures (refer to Section 9.6.1.2) within 24 hours to at least Grade 1, then study 
treatment should be suspended (until the toxicity resolves to at least Grade 1) and the dose of 
abemaciclib may be reduced by 1 dose level as outlined in Table JPBK.9.3. If the same dose 
level was resumed and diarrhea recurs despite maximal supportive measures, the dose of 
abemaciclib must be reduced by 1 dose level as outlined in Table JPBK.9.3.
9.4.2.2.2. Erlotinib
Patients should be treated following the recommendations, warnings, and precautions given for 
erlotinib in the SmPC of erlotinib. Patients receiving erlotinib can have the erlotinib dose 
reduced if the toxicity is specifically attributable to erlotinib.
The daily dose of erlotinib will be decreased in 50-mg decrements to a minimum dose of 50 mg 
daily (Table JPBK.9.4).  Re-escalation of erlotinib dosing is allowed at the investigator’s 
discretion, except after Grade 3 diarrhea when re-escalation is not allowed.  Dose reductions 
must be documented within the current cycle so that treatment compliance can be determined.
In addition to the common erlotinib toxicities in Table JPBK.9.5, if a patient experiences other 
Grade 3 or 4 events that are considered at least possibly related to erlotinib, erlotinib 
administration may be omitted until the event resolves.  Patients not recovering from such 
toxicity within 14 days beyond the last day of the prior cycle will be considered for 
discontinuation from the study. In rare circumstances, a delay >14 days may be permitted before 
discontinuing the patient from treatment as long as the patient demonstrates clinical benefit 
without objective progression and is recovering from the toxicity.  Such circumstances should be 
discussed and documented with the Lilly CRP.

If the event resolves to ≤ Grade 1 or baseline, the patient may restart erlotinib treatment 
at a reduced dose (Table JPBK.9.4).

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
If the event has not resolved to ≤ Grade 1 or baseline within 7 days, or another AE occurs 
during therapy at the reduced dose, a second dose reduction is permitted at the 
investigator’s discretion.
If the patient does not tolerate at least the 50-mg daily erlotinib dose, erlotinib must be 
discontinued.
Table JPBK.9.4.
Erlotinib Dose Reduction Schedule
Dose Adjustment
Oral Dose
Frequency
0
150 mg/day
Daily
1
100 mg/day
Daily
2
50 mg/day
Daily
Table JPBK.9.5 shows the dose modification criteria and guidelines for management of common 
erlotinib toxicities. The investigator may use judgment on management of Grade 1 toxicities if 
not specified below.

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Table JPBK.9.5.
Erlotinib Dose Modification Table
Event and Gradea
Erlotinib Dose Modifications
Guidelines for Management
Pulmonary Events
All grades (acute onset of new or 
progressive pulmonary symptoms 
such as dyspnea, cough, or fever)
Interrupt, pending the diagnostic 
evaluation; if interstitial lung disease is 
diagnosed, discontinue study treatment 
and institute appropriate treatment
Diarrhea
Grade 1
None
Consider loperamide: 4 mg at 
first onset, followed by 2 mg 
every 2 to 4 hours until diarrhea-
free for 12 hours
Grade 2
Reduce if diarrhea persists over 48 to 
72 hours despite optimal medical 
management
Manage as for Grade 1
Grade 3 or any grade unresponsive 
to loperamide, or diarrhea that 
causes dehydration
Interrupt until resolution to Grade ≤1 
and restart at next reduced dose; do not 
re-escalate
Manage as for Grade 1
Grade 4
Discontinue erlotinib treatment 
Manage as for Grade 1
Rash
Tolerable rash (Grade 2 or 3)
None 
Any of the following: 
minocycline, topical tetracycline, 
topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, 
oral prednisone (short course)
Intolerable rash
Consider interruption or dose reduction 
if unresponsive to symptomatic 
management.
Manage as described for Grade 2 
or 3
Grade 4
Discontinue erlotinib treatment
Manage as described for Grade 2 
or 3
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.
a
CTCAE (Version 4.03; NCI 2009).
9.5.
Blinding
This is a randomized, open-label study. Randomization will occur using an interactive web 
response system. Assignment to treatment groups will be determined by a computer-generated 
random sequence. Each patient in this study will be aware of his or her own assigned treatment 
group. At each investigative site, all staff involved in treating and caring for study patients will 
have full knowledge of treatment assignments for the patients under their care.
In order to maintain the scientific integrity of this trial, access to study data will be strictly 
controlled prior to the interim and final analyses. For the accumulated group-level data, 
treatment assignment will not be included, and other parameters that can disclose treatment 
assignment will be scrambled. Therefore, the sponsor and all investigative sites will remain 

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blinded to treatment group assignments for the summary statistics and reports until the database 
lock for the final analysis. Scrambled treatment assignments will be used in the reporting 
database for Lilly trial-level safety review until the final database lock. Interim analyses will be 
carried out approximately every 6 months by an independent DMC (external to Lilly) to monitor 
safety and efficacy.  The DMC is unblinded and the Statistical Analysis Center (SAC), which is 
also external to Lilly, will carry out analyses for the DMC.  Until the primary analyses, only the 
SAC and the DMC will be unblinded to the summary statistics and reports. 
For the interim PK analysis to occur prior to the interim/primary analyses, the list of individuals 
that will have access to unblinded data will be provided with the PK/PD analysis plan, and 
documentation concerning their access to the data will be retained.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, concomitant 
medications, and supplements 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.
The results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study 
indicate that oxidative metabolism of abemaciclib is primarily catalyzed by CYP3A4.   However, 
the extent of oxidative metabolism responsible for the systemic clearance of abemaciclib in 
humans is presently unknown.  Based on these in vitro findings, grapefruit juice as well as 
inducers (for example, phenytoin or carbamazepine) and strong inhibitors of CYP3A4 should be 
substituted or avoided if possible (Attachment 8).  In addition, in vitro studies in cultured human 
hepatocytes indicate that abemaciclib and its major metabolites LSN2839567 and LSN3106726 
down regulate mRNA of 1 or more CYPs, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, and CYP3A, at clinically relevant concentrations.  The mechanism of down regulation 
and its clinical relevance are presently not understood.  Therefore, care should be taken when 
coadministering substrate drugs of the above CYPs with narrow therapeutic margin.
Erlotinib is also metabolized predominantly by CYP3A4; therefore, grapefruit juice as well as 
inducers (for example, phenytoin or carbamazepine) and strong inhibitors of CYP3A4 should be 
substituted or avoided if possible (Attachment 8).
9.6.1. Best 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 (for 
example, medications such as sedatives, antibiotics, analgesics, antihistamines, steroids, or 
erythroid-stimulating agents), procedures (for example, paracentesis or thoracentesis), or blood 
products (for example, blood cells, platelets, or fresh frozen plasma transfusions) should be 
recorded on the electronic case report forms (eCRFs).  If it is unclear whether a therapy should 
be regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 

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supportive care therapy should be reported on the CRFs. Guidelines regarding the use of other 
specific supportive care agents are presented below.
Additional concurrent chemotherapy, radiation therapy (except as noted in Section 9.6.1.1), 
biologic response modifiers, or other investigational agents may not be administered to patients 
on this study.
9.6.1.1.
Palliative Radiotherapy
Palliative radiotherapy, unless required due to progressive disease, is permitted during the study.
9.6.1.2.
Supportive Management for Diarrhea
At enrollment, patients should receive instructions for diarrhea management.  In the event of 
diarrhea (see Attachment 9), supportive measures should be initiated as early as possible. These 
include the following:

At the first sign of loose stools, the patient should initiate antidiarrheal therapy (for 
example, loperamide) and notify the investigator for further instructions and appropriate 
follow-up.

Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to at least Grade 1, 
dosing should be suspended until diarrhea is resolved to at least Grade 1.

When study drug recommences, dosing should be adjusted as outlined for abemaciclib 
(Section 9.4.2.2.1 and Table JPBK.9.3) or erlotinib (Section 9.4.2.2.2 and
Table JPBK.9.4 and Table JPBK.9.5).
In severe cases of diarrhea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe (Grade 3 or
4) neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed.
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting should 
be carefully monitored and given fluid (IV hydration) and electrolyte replacement.
Sites may also follow local practice for management of diarrhea.
9.6.1.3.
Antiemetic Agents
The use of antiemetic agents is permitted during this study and at the discretion of the 
investigator.  However, it is recommended to follow the guidelines of the Multinational 
Association of Supportive Care in Cancer and American Society of Clinical Oncology (ASCO); 
dexamethasone may be sufficient, but 5-HT3 antagonists and NK1 antagonists may be used (Kris 
et al. 2006; Gralla et al. 2010).
9.6.1.4.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.

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9.6.1.5.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.  Acceptable 
agents include, but are not limited to, megestrol acetate and dronabinol.
9.6.1.6.
Granulocyte-Colony Stimulating Factors (G-CSF)
The use of granulocyte-colony stimulating factor (G-CSF) is permitted during investigational 
therapy at the discretion of the investigator.  G-CSF or similar agents are strongly recommended 
following Grade 3 or 4 neutropenia of duration >5 days or following any incidence of febrile 
neutropenia (ANC <1.0 x 103/µL [1.0 x 109/L] with a single temperature ≥38.3°C or a sustained 
temperature of ≥38.0°C for >1 hour).
9.6.1.7.
Growth Factors
Growth factors should not be administered to a patient to satisfy study inclusion criteria.
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2015).  
Dosing of abemaciclib must be suspended if the administration of growth factors is required and 
must not be recommenced within 48 hours of the last dose of growth factors having been 
administered.  Following the administration of growth factors, the dose of abemaciclib must be
reduced by 1 dose level on recommencement, if a dose reduction for the specific event 
necessitating the use of the growth factors has not already occurred.
9.6.1.8.
Bone-Modifying Agents
The use of approved bone-modifying agents (for example, bisphosphonates or receptor activator 
of nuclear factor kappa B ligand [RANKL] targeting agents) is allowed on study if a patient had 
initiated treatment with such agents at least 14 days prior to randomization.  Patients who started 
the study while receiving bisphosphonates or RANKL targeted agents are not allowed to switch 
treatments (for example, replace bisphosphonates with denosumab) during study treatment.  
Patients are not permitted to begin treatment with bisphosphonates or RANKL-targeted agents 
while receiving study treatment.
9.6.1.9.
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 10.3.1.1).
9.7.
Treatment Compliance
Patient compliance with study drug will be assessed at each visit.  Compliance will be assessed 
by counting returned tablets/capsules.  Patients may use a diary to record study drug intake.
Patients who are significantly noncompliant will be discontinued from the study.  Unless 
required secondary to toxicity, a patient will be considered significantly noncompliant if he or 
she misses 8 or more consecutive days of study drug (full doses), or more than 25% of the
cumulative days of study drug (full doses) during a cycle.  Persistent noncompliance may be a 
reason for discontinuation from study therapy.  Similarly, a patient will be considered 
significantly noncompliant if he or she is judged by the investigator to have intentionally or 

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repeatedly taken more than the prescribed amount of medication. Dose suspensions or delays
related to toxicity are permitted and will not result in a patient being considered as noncompliant.  

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10.
Efficacy, Health Outcome/Quality of Life Measures, 
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, health outcome/quality of life measures, 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
Imaging studies are performed locally and transmitted for central review.
Baseline tumor measurements will be performed on each patient. Computed tomography (CT), 
including spiral CT, scans, and magnetic resonance imaging (MRI) are the preferred methods of 
measurement.  Tumor assessments should include the chest and abdominal region. Imaging 
studies performed ≤30 days from date of first dose are permitted as baseline assessment and do 
not need repeated.
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with intravenous and oral contrast). A PET scan alone or as part of a PET-CT 
may be performed for additional analyses but cannot be used to assess response according to 
RECIST.
The method of assessment used at baseline must be used consistently for tumor assessment and 
must be repeated every other cycle, beginning with Cycle 3 Day 1 until progressive disease is 
determined.  Radiological assessments may be performed up to ±7 of the scheduled Day 1 visit.  
If progressive disease is determined per RECIST Version 1.1 after the start of a new cycle, the 
patient should be notified and treatment discontinued. If a cycle is delayed, tumor assessment 
should be concurrent with Day 1 of the new cycle. If the assessment was completed before Day 
1 of the next cycle and the patient has a delay in starting the next cycle, the radiological scan 
does not need to be repeated again when Day 1 of the next cycle is resumed.
For patients continuing treatment after study completion (that is, during the extension phase), 
efficacy assessments (frequency and type of assessments) will be at the discretion of the 
investigator, based on the standard of care.
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).

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For those patients who discontinue study treatment without objectively measured progressive 
disease (PD), the investigative sites will continue to monitor patients and periodically evaluate 
tumor response approximately every 8 weeks by the same method used at baseline until the 
patient has objective disease progression, or study completion.  After the patient has objective 
disease progression, radiologic tests are no longer required and the patient will be followed up 
approximately every 60 days (14 days) until the patient’s death or overall study completion.
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.
Efficacy assessments (frequency and type of assessments) for patients still on treatment during 
the extension phase will be at the discretion of the investigator, based on the standard of care.
10.1.3. Primary Efficacy Measure
This primary efficacy measure of the study is OS.
Overall survival duration is measured from the date of randomization 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 date of last contact prior to 
the data inclusion cutoff date (contacts considered in the determination of last contact date 
include adverse event date, lesion assessment date, visit date, and last known alive date).
10.1.4. Secondary Efficacy Measures
Tumor response is defined by RECIST v1.1 (Eisenhauer et al. 2009) provided in Attachment 5.  
To derive the overall response rate, a responder is defined as any patient who exhibits a
confirmed CR or PR. Best response is determined from the sequence of responses assessed.
A second assessment must be performed 28 days after the first evidence of response.  The next 
scheduled scan at 56 days (8 weeks) would qualify for response confirmation.  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.
Progression-free survival will be defined as the time from randomization until the first evidence 
of objective progression as defined by RECIST v1.1 (Eisenhauer et al. 2009), or death from any 
cause, whichever is earlier. Patients who are not known to have either progressed or died at the 
time of analysis will be censored at the day of their last radiographic tumor assessment, if 
available, or the date of randomization if no postbaseline radiographic assessment is available. 
The detailed censoring rules are described in Table JPBK.12.2.

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The PFS analysis will be based on the local investigator’s tumor assessments.
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. Lilly or its designee will collect and store all 
tumor measurement images on all enrolled patients throughout the study.  A central review of 
imaging scans may be performed by Lilly or its designee.
10.2. Health Outcome/Quality of Life Measures
10.2.1. Patient-Reported Outcomes
Patient-reported outcomes will be measured using standardized instruments, MDASI-LC and 
EQ-5D 5L.
Patient-reported questionnaires should be completed by patients when a language translation is 
available in which the patient is fluent or literate.
At each time point identified in the Schedule of Events (Attachment 1), a paper copy of the 
questionnaire should be administered to the patient prior to extensive interaction with site staff 
and study drug administration.
10.2.1.1. MDASI-LC
The MDASI-LC (Mendoza et al. 2011) is a 22-item instrument that includes 13 core symptoms, 
6 core interference items, and 3 lung-specific symptoms (coughing, constipation, and sore 
throat). An additional MDASI page will include 11 exploratory items that are not a standard part 
of the MDASI-LC instrument. Advanced lung cancer is a leading source of brain metastases, 
and symptoms related to brain metastases are described by 8 of these exploratory items 
(weakness on 1 side of body, difficulty understanding, difficulty speaking, seizures, difficulty 
concentrating, vision, change in appearance, and irritability). These 8 exploratory items for this 
study are also included as brain-specific items in the MDASI-Brain Tumor instrument. The 
remaining 3 exploratory items address an additional brain symptom (headache) and expected 
treatment-related toxicities (diarrhea, rash, or skin change).
“Worst pain” is the first MDASI-LC item, and use of pain medication will be assessed in 
conjunction with the MDASI-LC assessment as described in Section 10.2.2.
Responses for the MDASI-LC items are captured through the use of 11-point numeric rating 
scales anchored at 0 (not present or does not interfere) and ranged through 10 (as bad as you can 
imagine or completely interferes).  The MDASI-LC recall period is 24 hours, and typical 
completion time for this instrument is less than 5 minutes.
10.2.1.2. EQ-5D 5L
The EuroQol 5-Dimension 5 Level (EQ-5D 5L) is a self-reported standardized measure of health 
status, and will allow for comparison with other tumor types and disease states (Janssen et al. 
2008).

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Specifically, this questionnaire is included in this trial to evaluate health-state utilities associated 
with advanced lung cancer.  These utility measures are an important input for economic 
evaluations concerning the value of treatment interventions.
The EQ-5D 5L is designed to be used in conjunction with other patient-reported measures.  
Patients will complete the 5-dimension (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), 5-level (no problem, slight, moderate, severe, or extreme problem) 
assessment according to the Study Schedule (Attachment 1).  A visual analog scale 
"thermometer" measures current health state.  EQ-5D 5L responses may be incorporated into 
cost utility analyses and will be summarized in the clinical study report (CSR).
Administration is preferably scheduled after the MDASI-LC, and before extensive contact with 
study personnel or clinicians, which could result in biased patient response.  The recall period is 
“today.”  The EQ-5D 5L is designed for self-completion by respondents and expected 
completion time is 1 to 2 minutes.
10.2.2. Resource Utilization
Investigators will be asked to report the use of all concomitant medications (in particular, 
analgesics, bisphosphonates, and RANK-L targeted agents), blood product transfusions, 
radiation therapy, surgery, and hospitalization days.
Data on each individual prescription and over-the-counter analgesic medication will be recorded 
on the Concomitant Medication eCRF.  The use of pain medications from the previous visit 
should be reviewed with the patient at each subsequent visit.  Any changes to analgesic use 
based on this information should be recorded on the Concomitant Medication eCRF, and the 
term “any changes” includes new or stopped analgesics. Data on neurosurgical blocks will be 
recorded on the analgesic and/or surgery forms as appropriate.  This information should be 
collected during the study and at the 30-day follow-up visit.
10.3. 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.
Investigators must document their review of each laboratory safety report.
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 JPBK.10.1 presents a summary of AE and SAE reporting guidelines.  Table JPBK.10.1
also shows which database or system is used to store AE and SAE data.

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Table JPBK.10.1.
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 drug
x
x
Extension period
All AEs
x
All SAEs
x
x
Extension period 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 therapy and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study drug that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1. 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; for example, QTc 
prolongation), labs, vital sign measurements, other procedures, and so on that result in a 
diagnosis should be reported to Lilly or its designee.  All non-clinically significant findings must 
be documented in the patient record as not clinically significant and therefore will not be 
documented in the eCRF.
Cases of pregnancy that occur during maternal or paternal exposures to study drug 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.  All non-clinically significant findings must be documented in the patient record as not 
clinically significant and therefore will not be documented in the eCRF.

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After the study 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.
In addition, all AEs occurring after the patient receives the first dose of study drug 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 drug via eCRF.
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study drug, study procedure, or other concomitant treatment or pathologies.  To assess the 
relationship of the AE to the study drug or procedure, the following terminologies are defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study 
treatment
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study drug/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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03 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 4.03 criteria, the investigator will be responsible for 
selecting the appropriate system organ class 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.
10.3.1.1. Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

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
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 the study ICF and has 
received study drug.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving study drug, the event will not be reported as serious unless the investigator feels the 
event may have been caused by a protocol procedure.
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 alerts are 
issued via telephone, they are to be immediately followed with official notification on study-
specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
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 therapy 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 drug.
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 
drug, 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.

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10.3.1.2. 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 IB and that the investigator identifies as 
related to the abemaciclib 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.
10.3.2. Other Safety Measures
10.3.2.1. Electrocardiograms
For each patient receiving abemaciclib, 12-lead digital ECGs will be collected according to the 
Study Schedule (Attachment 1) and Table JPBK.10.2 as single ECGs.  For each patient receiving 
erlotinib, an ECG will be collected at baseline only.  Patients must be supine for approximately 5 
to 10 minutes before ECG collection and remain supine but awake during ECG collection.
Table JPBK.10.2.
Schedule for Electrocardiogram Collection
Electrocardiogram
Cycle and Day
Timing
1
Baseline
≤14 Days
2
Cycle 1 Day 1
Predosea
3
Cycle 1 Day 1
4 to 6 hours postdose
4
Cycle 2 Day 1
4 to 6 hours postdose
5
Cycle 7 Day 1
4 to 6 hours postdose
6
Visit 801
30 days after study 
drug discontinuation
Abbreviations:  C1D1 = Cycle 1 Day 1; ECG = electrocardiogram.
a
If baseline ECG performed with 24 hours of C1D1 predose ECG, the C1D1 predose ECG may be omitted.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high-quality records.
Electrocardiograms will be interpreted by 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/QTc interval from baseline, or 
other clinically significant quantitative or qualitative change from baseline, is present, the 
investigator will assess the patient for symptoms (for example, palpitations, near syncope, or 
syncope) and to determine if the patient can continue in the study.  The investigator or qualified 
designee is responsible for determining if any change in patient management is needed and must 
document his/her review of the ECG printed at the time of evaluation.

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10.3.3. 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
will, as is appropriate, consult with the functionally independent GPS therapeutic area physician 
or clinical scientist, and review:

trends in safety data

laboratory analytes

adverse events

If a patient experiences elevated ALT >5× ULN and elevated total bilirubin >2× ULN, 
clinical and laboratory monitoring should be initiated by the investigator.

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific
recommended clinical information and follow-up laboratory tests (see Attachment 3).
10.3.4. 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.
If supplied by Lilly, complaints related to unblinded comparator drugs are reported to Lilly.  If 
sourced locally, complaints related to unblinded comparator drugs are reported directly to the 
manufacturers of those drugs 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.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study. For patients enrolling under 
Amendment (d), hematological and chemistry sample collections will occur on Day 1 and Day 
15 during Cycles 1 and 2. Beginning with Cycle 3, hematological and chemistry sample 
collections will be only on Day 1 of each cycle.  
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.  Enrollment and treatment decisions may be based 
upon results of tests performed locally.  If local laboratory tests are used for this purpose, then a 
duplicate specimen must be submitted to the central laboratory.  Discrepancies between the local 

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and central laboratory that may have an impact on eligibility or treatment decisions will not be 
considered protocol violations.
Attachment 6 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
10.4.1. Samples for Study Qualification and Health Monitoring
Blood samples will be collected to determine whether patients meet inclusion/exclusion criteria 
and to monitor patient health. Blood samples for chemistry and hematology may be drawn +/-3 
days prior to the day of the scheduled visit. If the baseline chemistry and hematology samples 
were drawn within 3 days of Cycle 1 Day 1, the chemistry and hematology samples do not need 
to be repeated on Cycle 1 Day 1. During Cycles 1 and 2, chemistry and hematology samples will 
be drawn on Days 1 and 15 (+/- 3 days). Beginning with Cycle 3, chemistry and hematology 
samples will be drawn on Day 1 (+/- 3 days) of each cycle.
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.
10.4.2. Samples for KRAS Mutation Determination
To meet study eligibility criteria, a KRAS mutation determination is mandatory for study 
participation.  KRAS mutation results will be obtained by submitting tissue to the Study JPBK 
central laboratory or, for no more than 10% of randomized patients, a prior local laboratory 
KRAS mutation result that is reviewed and approved by the sponsor.
10.4.2.1. Central Laboratory Result
Patients must have available FFPE tumor sample to submit tissue to the Study JPBK central 
laboratory for KRAS testing. While the tissue can be from either initial diagnosis or later (for 
example, at relapse), the most recent sample is preferred.  The sample can be either 8 serially cut 
unstained sections (preferred) or a tissue block. Sample collection methods may include surgical 
resection, core needle biopsy, or fine needle aspirate (FNA).  Fine needle aspirate, aspiration of 
solid tumor cells, is acceptable with subsequent processing to FFPE as a cell block and 
confirmation of the presence of malignant cells; however, other types of cytology specimens 
(e.g., pleural effusion) are not acceptable.  Due diligence should be used to make sure that tumor 
specimens (not a normal adjacent or a tumor margin sample) are provided.
KRAS mutation determination for study eligibility is made at the central laboratory using the 
QIAGEN® therascreen® KRAS RGQ PCR Kit NSCLC. Part of each patient’s tumor tissue may 
be retained for repeat testing during the development of that investigational assay.  The same 
sample used for KRAS mutant determination may also be used for evaluation of codons 12 and 
13 via Sanger sequencing, and potentially an additional method, to test concordance with the 
investigational assay.

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Prior local testing of KRAS status to informally assess eligibility for Study JPBK is highly 
discouraged. Submission of the investigational assay for potential regulatory approval requires a 
dataset containing evaluation of both KRAS mutant positive and negative samples.  If local 
testing is completed per a site’s standard of care, results should be disregarded when evaluating a 
patient’s eligibility for the study.
Details for the handling and shipping of tumor biopsy samples will be provided in a separate
document. Instructions and supplies required for the collection, processing, and shipment of the
patients’ samples will be provided by the sponsor.
The tumor tissue samples will be coded with the patient number and stored for up to a maximum
15 years after the last patient visit for the study unless otherwise determined by government or 
local law, at a facility selected by the sponsor. The samples and any data generated from them 
can only be linked back to the patient by investigator site personnel. The duration allows the 
sponsor to respond to regulatory requests related to the study drug. Tumor specimens submitted 
as a FFPE tissue block will be returned to the sites by end of study or upon request.
10.4.2.2. Local Laboratory Result
Local KRAS testing is not mandatory or considered a protocol required procedure. To address 
the challenges identified with tissue for KRAS testing by the central laboratory, a local KRAS
mutation result from tumor tissue may be used for patient eligibility for no more than 10% of the 
randomized patients. These patients, who have a positive local KRAS result for one of the 
7 specific mutations listed below, will be allowed to enter into the study with this result in the 
absence of a central laboratory KRAS positive result.  Instructions will be provided by the 
sponsor to request approval to use a local KRAS mutation result for patient eligibility.  The 
sponsor will review each request and provide approval to the site prior to the patient being 
randomized. Once approved and randomized to study using local laboratory KRAS result, no 
additional tumor tissue should be submitted to the central laboratory for KRAS testing.
In order for a patient with a local KRAS mutation result to be considered eligible, the following 
circumstances must be present:
(a) The local KRAS mutation result is one of the following mutations:

G12A (35G>C) (GLY12ALA)

G12S (34G>A) (GLY12SER)

G12D (35G>A) (GLY12ASP)

G12R (34G>C) (GLY12ARG)

G12C (34G>T (GLY12CYS)

G12V (35G>T) (GLY12VAL)

G13D (38G>A) (GLY13ASP)
(b) The reason for the request for approval to use local KRAS mutation test result for 
inclusion is due to one or more of the following:

No tissue available for submission to Study JPBK central laboratory that has a
documented confirmation by the investigator

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
Indeterminate designation obtained from initial sample submitted to Study JPBK
central laboratory

An inadequate sample designation (for example, Insufficient Tissue Received at 
Laboratory, No Neoplastic Cells in Tissue) obtained from initial sample submitted 
to Study JPBK central laboratory
Once enrollment of no more than 10% of randomized patients has been reached, the sponsor will 
communicate that enrollment by local KRAS mutation result has been suspended. No additional 
patients will be randomized using local KRAS mutation results.
10.4.3. Samples for Other Biomarkers
10.4.3.1. Archived Tumor Tissue
An archived tumor sample will be collected on Cycle 1 Day 1 in addition to the sample used to 
determine KRAS mutation status.  An FFPE tumor tissue sample OR 20 unstained slides are 
requested for further biomarker research.  The tissue sample will be tested for biomarkers 
relevant to abemaciclib and the disease state and to correlate these markers to clinical outcome 
and to abemaciclib.  Analyses may include, but are not limited to, nucleic acid and protein 
profiles to better understand the disease process and to develop predictive biomarkers.
Any whole block submitted will be returned to the site.  Any partial blocks or slides will either 
be returned or discarded within 15 years after last patient visit for the trial unless otherwise 
determined by government or local law.
Patients enrolled based upon a local KRAS mutation result are exempt from submitting additional 
archived tumor tissue for biomarker testing.
10.4.3.2. Whole Blood Samples for Pharmacogenetic Evaluations
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.
Where local regulations and ERBs allow, a whole blood sample will be collected for 
pharmacogenetic analysis (refer to Attachment 1).  Samples may be genotyped and analyses may 
be performed to evaluate a genetic association with response to abemaciclib.  These 
investigations may be limited to a focused candidate gene study or, if appropriate, genome-wide 
analysis may be performed to identify regions of the genome associated with the variability 
observed in drug response.  The pharmacogenetic biomarker samples will only be used for 
investigations related to disease and drug or class of drugs under study in the context of this 
clinical program.  They will not be used for broad exploratory unspecified disease or population 
genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
unless otherwise determined by government or local law after the last patient visit for the study 
at a facility selected by the sponsor.  The samples and any data generated from them can only be 

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linked back to the patient by investigator site personnel.  The duration allows the sponsor to 
respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
10.4.3.3. Plasma Samples for Exploratory Biomarker Evaluations
Plasma samples will be collected and analysis may be performed on circulating biomarkers that 
may play a role in the abemaciclib mechanism of action (refer to Attachment 1).  A plasma 
sample will be collected at baseline prior to randomization. Patients who have entered the study 
based on a local KRAS result may omit this baseline sample; however, it is not a deviation if 
submitted. This sample will be collected separately at the time of FFPE tumor tissue request.
For patients who submitted FFPE tumor tissue in pre-screening, the baseline plasma sample may 
be drawn at the time of other laboratory blood samples.  Additional plasma samples will be 
collected from all randomized patients on Cycle 1 Day 1 and Cycle 2 Day 1. The evaluation of 
these samples may involve analysis of DNA, RNA, KRAS mutations, and proteins (including any 
of these components derived from exosomes) to investigate their association with observed 
clinical outcomes to study drug, and may assist in future development of a liquid biopsy test for 
KRAS.  The samples will be coded with the patient number and stored for up to a maximum 
15 years unless otherwise determined by government or local law.  Details for collecting, 
processing, and storing the samples are similar to those provided in Section 10.4.3.2.
10.4.4. Samples for Drug Concentration Measurements 
Pharmacokinetics
At the visits and times specified in the Pharmacokinetic Sampling Schedule (Attachment 7),
5 venous blood samples of approximately 2 mL each will be collected from patients receiving 
abemaciclib to determine the plasma concentrations of abemaciclib and its metabolites 
LSN2839567, LSN3106726, and LSN3106729.  Patients receiving erlotinib will not have 
samples collected for PK analysis.
Separate blood samples are not required for the parent and its metabolites.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  It is preferred that the 
blood samples be obtained from a peripheral location.  Blood samples will be allowed from 
central access devices but a sample drawn from a central catheter of any type for PK must take 
precautions to prevent obtaining a dilute sample.  If multiple samples are obtained centrally, the 
PK sample should be the last specimen drawn to reduce the potential for a diluted or improperly 
drawn sample.  The actual date and time (24-hour clock time) of each sampling will be recorded.  
A maximum of 5 additional samples may be drawn at other time points during the study if 
warranted and agreed upon between both the investigator and Lilly.
These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemaciclib plus its metabolites LSN2839567, LSN3106726 and 
LSN3106729, will be assayed using a validated liquid chromatography/tandem mass 
spectrometry method.  Bioanalytical samples collected to measure study drug concentration and 
metabolism and/or protein binding, will be retained for a maximum of 1 year following last 
patient visit for the study.  The PK samples will be stored at a facility designated by the sponsor.

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10.5. Appropriateness of Measurements
Efficacy measurements by radiographic imaging are standard, widely used, generally recognized 
as reliable, accurate, and able to discriminate between effective and ineffective agents.
Safety measurements by laboratory monitoring are standard, widely used, generally recognized 
as reliable, accurate, and able to discriminate between agents with acceptable and unacceptable 
safety profiles.

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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.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
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
The primary objective of this study is to compare abemaciclib versus erlotinib with respect to OS 
in patients with Stage IV NSCLC whose tumors have detectable KRAS mutations (specifically, in 
codons 12 and 13 of the KRAS oncogene) and who have progressed after prior platinum-based 
therapy and received 1 other prior therapy or are not eligible for further chemotherapy.
The study will enroll approximately 450 patients in 3:2 randomization (approximately 270
patients in the abemaciclib arm and 180 patients in the erlotinib arm).  The final analysis will 
occur when approximately 304 OS events have been observed.
Assuming an OS HR of 0.72, this sample size yields approximately 80% statistical power to 
detect superiority of the abemaciclib arm over erlotinib arm with the use of a 2-sided log-rank 
test and a type I error of .05.
If the true median OS for the erlotinib arm is 6.5 months, then the HR of 0.72 amounts to an 
approximately 2.5-month improvement in median OS for the abemaciclib arm under an 
additional assumption of exponential survival distribution.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is 
defined as all patients randomized to study treatment.  Patients will be grouped according to 
randomized treatment.
Safety analyses will be based on the Safety Population, defined as all enrolled patients receiving 
at least 1 dose of any study drug.  Patients will be grouped according to treatment received in 
Cycle 1.
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above populations from whom a valid assay result (according to laboratory guideline) 
has been obtained.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise 
stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.
Before unblinding of the aggregate database, minor modifications or clarifications to the data 
analysis methods may be described and justified in the SAP. The assumptions for each statistical 
method will be evaluated.  If there is violation of assumptions, alternative statistical methods 

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may be used. Any other change to the data analysis methods described in the protocol, and the 
justification for making the change, will be described in the CSR.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).
A summary of all important protocol deviations will be provided.
12.2.3. Patient Characteristics
Patient demographics including age, sex, screening height and weight, screening body mass 
index, and smoking status will be reported using descriptive statistics.
Baseline disease characteristics will be summarized by presenting frequency counts and 
percentages for pathological diagnosis (histological or cytological), disease stage, or 
performance status.
Patient preexisting condition, historical illness, and prior chemotherapy (including both cytotoxic 
and targeted agents) will be summarized by treatment arm.
12.2.4. Concomitant Therapy
Concomitant medication will be summarized by treatment arm in a frequency table listing the 
terms recorded on the eCRF.
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, cycles received, and dose intensity will 
be summarized for all treated patients per treatment arm.
Treatment compliance information for abemaciclib or erlotinib will be collected through capsule 
(abemaciclib) or tablet (erlotinib) counts at each tumor assessment visit.  The estimate of percent 
compliance will be given by:
Percent Compliance =
Actual cumulative dose taken
Expected cumulative dose to be taken x 100
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed.  The 

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expected cumulative dose to be taken will be determined based on the assigned dose and taking 
into account any dose reductions or omissions.
12.2.6. Primary Outcome and Methodology
The primary endpoint of this study is OS.Overall survival duration is measured from the date of 
randomization 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 date of last contact prior to the data inclusion cutoff date (contacts considered in 
the determination of last contact date include AE date, lesion assessment date, visit date, and last 
known alive date).
The comparison of each of the OS distributions between treatment groups will be conducted 
using a stratified log-rank test with the following stratification variables: number of prior 
chemotherapy regimens (1 versus 2), ECOG PS (0 versus 1), gender (male versus female), and 
KRAS mutation (G12C versus all others).
The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the OS survival 
curves as well as survival rates at 3, 6, 9, and 12 months for each treatment group. These rates 
will be compared based on a normal approximation for the difference between the arms.
The Cox proportional hazard model (Cox 1972) with treatment as a factor, stratified by the 
stratification factors used in the randomization (as per the primary analysis) will be used to 
estimate the HR and corresponding 95% CI.
12.2.7. Secondary Outcome and Methodology
The secondary objectives for this study are stated in Section 6.2.
Progression-free survival time is measured from the date of randomization to the date of 
investigator-determined objective progression as defined by RECIST v1.1, or death from any 
cause.  Patients who have neither progressed nor died will be censored at the day of their last 
radiographic tumor assessment (if available) or date of randomization if no post initiation (that 
is, postbaseline) radiographic assessment is available. The detailed censoring rules for PFS are 
described in Table JPBK.12.1.

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Table JPBK.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no death 
Date of Randomization
Censored
3
No documented progression and no death (with a 
post-baseline tumor assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew consent 
from study participation) before documented 
progression or death 
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented progression 
Date of death 
Progressed
7
Death or documented progression immediately 
after missed ≥2 consecutive post-baseline tumor 
assessment visits 
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later
Censored
Note:  Progression-free survival and associated outcome is determined by the earliest of the dates above, if more than 
1 situation applies.
The statistical comparison of PFS between treatment groups will be conducted using the same 
methods for OS as described in Section 12.2.6.
The objective response rate of each treatment arm will be calculated as defined by RECIST v1.1.  
All rates will be compared between treatment arms based on a normal approximation for the 
difference between the rates.
Details of the statistical methods for analyzing efficacy outcomes are described in the SAP.
12.2.8. Sensitivity Analysis
Sensitivity analyses may be undertaken for the efficacy endpoints in order to evaluate the 
robustness of the analysis. The following sensitivity analyses may be performed for PFS:
Progression-Free Survival Sensitivity Analysis 1 (censoring for receiving subsequent systemic 
anticancer therapy):  if a patient is initiated on another anticancer therapy prior to objective 
progression, including any postdiscontinuation treatment systemic therapy, radiotherapy, or 
surgical intervention, PFS will be censored at the date of the last complete objective 
progression-free disease assessment before initiation of the new therapy, regardless of whether or 
not this patient subsequently had objective progression or died.
Progression-Free Survival Sensitivity Analysis 2 (nonobjective progression as a PFS event):  if 
a patient is discontinued from study treatment due to investigator determined non-objective 
progression (for example, symptomatic deterioration), then the patient’s PFS time will be 
calculated using the date of non-objective progression as the progression date.

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Progression-Free Survival Sensitivity Analysis 3 (back-dating progressions at unscheduled 
assessments):  if a patient has objective progression at an unscheduled disease assessment, then 
the PFS time for that patient will be back-dated to the prior scheduled disease assessment.
Additional sensitivity analyses may be carried out for patients who are KRAS positive based only 
on central test result. Details are described in the SAP.
12.2.9. Pharmacokinetic Analyses
Pharmacokinetics analyses will be conducted on all patients who have received at least 1 dose of 
abemaciclib and have had samples collected (see PK sampling schedule in Attachment 7).
Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and inter-individual PK variability will be computed using nonlinear 
mixed effect modeling (NONMEM).  The current PK model for abemaciclib, which has been 
developed using plasma concentration data available from the Phase 1 Study JPBA, will be 
updated using the plasma data collected in this study.  Covariate effects (such as age, weight, 
sex, creatinine clearance, and plasma protein levels) on the PK parameters of abemaciclib in 
plasma will also be investigated.
The mean population PK properties of abemaciclib metabolites LSN2839567, LSN3106726, and 
LSN3106729 in plasma may also be analyzed by means of NONMEM.
Finally, pharmacodynamic data (such as neutrophil, lymphocytes, or platelets counts in blood) 
collected in this study may also be analyzed by means of NONMEM and connected to the 
population PK model in a PK/pharmacodynamic model.
The version of software used for the analysis will be documented and will meet the Lilly 
requirements of software validation.
12.2.10.
Biomarker Analyses
12.2.10.1.
KRAS Mutation Assessment
Concordance (agreement) analysis will be performed on samples with valid KRAS status 
(mutation positive and mutation negative) using both the investigational assay and the reference 
method (Sanger sequencing). Measures of agreement between the investigational KRAS assay 
and the reference method, including positive percent agreement, negative percent agreement, and 
overall percent agreement, and their corresponding exact 2-sided 95% CIs, will be estimated for 
the overall mutation status; that is, mutation detected or not detected for the 7 mutations of KRAS
gene. A secondary agreement analysis between the investigational KRAS assay and the reference 
method will be performed for each of the tumor tissue sample types (surgical resection, fine 
needle aspirate and core needle biopsy). The data will also be summarized for each of the 
7 KRAS mutations separately.
12.2.10.2.
Other Biomarkers
For other biomarkers relevant to abemaciclib and the disease state, the distributions of 
biomarkers will be summarized for the patient population for which samples are available. 

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Associations between clinical endpoints and biomarkers will be evaluated using data from 
patients who have an evaluable sample for each biomarker of interest, and such evaluation will 
be done on an individual marker basis.
12.2.11.
Health Outcome/Quality of Life Analyses
Patient-reported outcomes are measured through paper versions of the following:

MDASI-LC (includes additional page with 11 items that will be scored separately)

EQ-5D 5L (EuroQol 5-Dimension 5 Level)
The reason and number of missing and incomplete questionnaires/assessments by visit will be 
summarized for each instrument and study arm.
12.2.11.1.
MDASI-LC
The MDASI-LC population will include all patients who completed at least 1 baseline followed 
by at least 1 MDASI-LC assessment after 1 cycle of study drug (Cycle 2 Day 1 or later).
The MDASI-LC will be summarized for each assessment period and scored as described 
(Mendoza et al. 2011). The instrument will be reported as core symptoms (Items 1-13), 
interference items (Items 14-19) and lung symptoms (Items 14-16), and the 11 additional items 
will be reported as brain tumor symptoms (Items 23 through 30) and additional 3 items (31-33), 
as well as each individual item.
For each patient with data from baseline and at least 1 other visit, the maximum change from 
baseline score will be calculated and summarized for MDASI-LC composite scores, and “worst 
pain”.
Further analysis details will be described in the SAP.
12.2.11.2.
Health State Utility
The EQ-5D 5L population will include all patients who completed at least 1 baseline followed by 
at least 1 EQ-5D 5L assessment after 1 dose of study drug.
The EQ-5D 5L data will be scored based on EuroQol recommendations.  The index score is 
calculated from a set of item weights to derive a score of <0 to 1, with 1 representing the best 
health status.  The visual analogue score (VAS) is scored from 0 (worst imaginable health state) 
through 100 (best imaginable health state) to represent the patient’s self-report for each day.  
EQ-5D 5L responses for each item will be summarized by frequency and corresponding 
percentages.  Descriptive statistics for the index and VAS will be calculated as described in the 
SAP.
12.2.11.3.
Use of Pain Medications
Pain medication will be classified into 1 of 6 categories by the sponsor, using an analgesic ladder 
approach with medication category based on a World Health Organization scale outlined in
Table JPBK.12.2.  A therapy category for each cycle will be assigned according to the maximum 
category of therapy administered based on analgesic data from the Concomitant Form for that 
cycle.  Category of pain medication for each cycle will be determined based on the data collected 

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on analgesic use by Anatomical Therapeutic Chemical code. Change in categories based on 
analgesic ladder compared to baseline will be described by arm.
Table JPBK.12.2.
World Health Organization Pain Scale
Code
Description
0
No analgesia
1
Aspirin (for pain, not cardiovascular prophylaxis), acetaminophen, nonsteroidal anti-inflammatory drugs
2
Codeine, hydrocodone, pentazocine, oxycodone
3
Oral morphine, hydromorphone, methadone, transdermal fentanyl
4
Parenteral opiates
5
Neurosurgical procedures (blocks)
12.2.12.
Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.1.
Overall exposure to study drug, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with dose 
reductions, dose delays, or dose omissions will also be summarized, as will the reasons for dose 
adjustments.
AEs will be reported using a unified CTCAE/MedDRA reporting process:

The CTCAE v4.03 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and System Organ Class (SOC) of the corresponding MedDRA 
Lower Level Term (LLT), unless the reported CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT, and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Preexisting conditions are defined as adverse events that begin prior to the first dose of study 
drug.  A TEAE is defined as an event that first occurred or worsened in severity between the day 
of first dose and 30 days after treatment discontinuation (or up to any time if serious and related 
to study treatment).  Comparisons of preexisting conditions to on-treatment events at the LLT 
level will be used in the treatment-emergent computation.
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to study drug, and repeated for events regardless of study drug causality.  Incidence rates 
of these events will be compared between treatment arms using Chi square test.
The following summaries will be produced by PT within SOC:  preexisting conditions, SAEs, 
TEAEs, drug-related TEAEs, and procedure-related TEAEs.
The following summaries will be produced by PT within SOC and maximum CTCAE grade:  
laboratory-based TEAEs, nonlaboratory-based TEAEs, drug-related laboratory-based TEAEs, 
and drug-related nonlaboratory-based TEAEs.

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Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation.
Hospitalizations and transfusions during the study treatment period or during the 30-day 
short-term follow-up period will be summarized by treatment group.
12.2.13.
Subgroup Analyses
Subgroup analyses of OS will be performed for potential prognostic and predictive subgroup 
variables (for example, patients with or without prior immunotherapy).
12.2.14.
Interim Analyses
12.2.14.1.
Safety Interim Analyses
The DMC is responsible for providing external oversight of patient safety in Study JPBK 
independently of the Lilly study team and Lilly GPS.
During the study, safety interim analyses will be performed approximately every 6 months.  The 
safety interim analyses will be conducted to evaluate the overall safety profile of abemaciclib.  
At the recommendation of the DMC, the frequency of safety interim analyses may be modified.
At each interim analysis, the DMC may recommend the trial continue without modifications, 
continue with specific modifications, or be stopped for safety concerns.  There will be no 
prespecified rules for stopping the trial due to safety concerns.  The DMC members will review 
unblinded safety data at each interim analysis.  If a significant safety signal is identified, the 
DMC may recommend a protocol amendment, termination of enrollment, and/or termination of 
study treatment.  The recommendations of the DMC will be communicated to the Lilly Senior 
Management Designee and, if necessary, an Internal Review Committee.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the treatment group level, members of the DMC can conduct additional analyses of the safety 
data.  Additionally, unblinding of a limited number of Lilly representatives external to the study 
team may be required for evaluation of selected SAEs for determination of regulatory reporting.
12.2.14.2.
Efficacy Interim Analyses
One interim efficacy analysis is planned based on the PFS endpoint. This interim analysis is for 
futility only and will be conducted by the DMC. There is no plan for interim efficacy analysis 
based on the OS endpoint. The DMC may call for additional, unplanned, interim efficacy 
analyses. Details of the DMC communication plan can be found in the DMC charter.
The interim efficacy analysis will be conducted after approximately 100 PFS events have 
occurred.  This analysis will be based on the PFS endpoint and will be for futility only. The 
DMC will be instructed to recommend the study be stopped for futility if the observed hazard 
ratio for PFS (as calculated using a stratified Cox proportional hazards model) is greater than 
0.95.

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Only the DMC is authorized to evaluate unblinded interim efficacy and safety analyses.  Study 
sites will receive information about interim results ONLY if they need to know for the safety of 
their patients.

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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.
There may be 2 ICF used in this study:  pre-screening ICF and study ICF.
The pre-screening ICF will provide relevant information and documents that the patient is 
satisfied with his or her understanding of the genetic testing of the tumor sample for KRAS
mutation status.  No procedures will be conducted or treatment provided to patients after signing 
this pre-screening ICF. Pre-screening is optional; the determination may also be made during 
screening under the study ICF.
The study 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. If determination of KRAS mutation status by the 
Study JPBK central laboratory was not completed during a pre-screening period, then the 
determination will be made during screening under the study ICF. Prior to submitting a request 
for approval for study entry using a local KRAS test result, the study ICF must be signed.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study drug.
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 study site’s ERBs should be provided with the following:

the current IB or package labeling (for example, PI or SmPC) and updates during the 
course of the study

ICF

relevant curricula vitae

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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 

the ICH GCP Guideline (E6)

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 oncology 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 (CSR) coordinating investigator will sign the final CSR 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.
Lilly will select an investigator to serve as the CSR coordinating investigator.
The Lilly responsible medical officer and statistician will sign/approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.

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14.
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Chinnery LW, Chesney MJ, Gralla RJ, Grunberg SM; American Society of Clinical Oncology.
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Attachment 1.Protocol JPBK Study Schedule

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Study Schedule, Protocol I3Y-MC-JPBK
Perform procedure as indicated.
Pre-
Screena
Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
Pre-
screening 
BL
BL
1
2 
3 – n
Short-
Term 
Follow-
Upb
Long-
Term 
Follow
-Up
Visit
PRE0
0
1
2
3 – n
801
802 -
8XX
Duration 
(days)
28 
28
28
28
30
60
Relative 
day within 
a cycle
28
14
1
15
1
15
1
Procedure 
Category
Procedure
Protocol 
Reference
Study Entry 
/Enrollment
Informed Consent 
Form signed (prior to 
performance of any 
protocol-specific 
tests/procedures)
Section 
13.1
X
Xab
Inclusion/Exclusion 
evaluation
Section 7
X
X
Brain scanc
Section 7.1
X
Medical 
Historyz
Initial history/ 
preexisting conditions
X
Historical illnesses
X
Smoking/alcohol 
habits assessment
X
Physical 
Examinationz
Height 
X
Weight
X
X
X
X
Blood pressure/pulse
Section 
10.3.1
X
X
X
X
ECOG performance 
status
Attachment 
4
X
X
X
X
X
Tumor 
Assessment
Tumor measurement 
(palpable or visible)d
Section 
10.1
X
X
X
Xe
Radiologic imaging 
according to RECISTf
Section 
10.1
Attachment 
5
X
X
Xe
Survival information
Section 
10.1
X
Xg
Adverse Event Collection/CTCAE 
Gradingh
Section 
10.3
X
X
X
X
X
X 

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Pre-
Screena
Baseline
Patients on Study Treatment
Postdiscontinuation
Follow-Up
Cycle
Pre-
screening 
BL
BL
1
2 
3 – n
Short-
Term 
Follow-
Upb
Long 
Term 
Follow
-Up
Visit
PRE0
0
1
2 
3 – n
801
802 -
8XX
Duration 
(days)
28 
28
28
28
30
60
Relative day 
within a cycle
28
14
1
15
1
15
1
Procedure 
Category
Procedure
Protocol 
Reference
Concomitant Medication Notation
Section 9.6
X
X
X
X
X
Lab/
Diagnostic 
Tests
Central hematologyi
Attachment 2
X
X
X
X
X
X
X
Central chemistryi
Attachment 2
X
X
X
X
X
X
X
Local serum 
pregnancy testj,k
Attachment 2
X
X
k
X
k
Central 
pharmacokinetic 
sampling l
Attachment 7
X
X
X
Pharmacogenetic 
whole blood sample
Section
10.4.3.2
X
aa
Plasma sample for 
circulating 
biomarkers
Section
10.4.3.3
X
m
X
m
X
m
Local ECG n
Section 
10.3.2.1
X
o
X
p
X
q
X
r
X
s
Archived tumor 
samples
Section 10.4.2
and 10.4.3.1
X
t
X
u
X
v
Health 
Outcomes 
Assessments
MDASI-LC
w
Section 10.2
X
X
X
X
EQ-5D 5L
w
Section 10.2
X
X
X
X
Study Drug
Abemaciclib x
Section 9.1
X
X
X
Erlotinib y
Section 9.1
X
X
X
Abbreviations:  BL = baseline; C1D1 = Cycle 1 Day 1; CNS = central nervous system; CTCAE = Common 
Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EQ-5D 5L = European Quality of Life – 5 Dimensions – 5 Level; FFPE = formalin-fixed
paraffin-embedded; ICF = informed consent form; MDASI-LC = MD Anderson Symptom Inventory;
MRI = magnetic resonance imaging; OS = overall survival; PK = pharmacokinetics; Q12H = every 12 hours; 
RECIST = Response Evaluation Criteria in Solid Tumors; SAEs = serious adverse events; V = Visit.
a
The pre-screening period begins when the pre-screening ICF is signed for evaluation of FFPE tissue by 
Study JPBK central laboratory and ends once the KRAS mutation status of the tissue is determined. This period 
is optional; KRAS mutation status can also be determined during screening under the study ICF.
b
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 (± 7 days).
c
Patients with a history of CNS metastases must have a brain scan (for example, MRI) within 28 days of 
randomization to document stability of their CNS metastases, even if there have been no changes in symptoms.
If a prior brain scan was completed within 45 days of starting C1D1, the brain scan does not need to be repeated 
at baseline.

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Study Schedule, Protocol I3Y-MC-JPBK (continued)
d
Palpable or visual tumor measurement to be performed within 72 hours of start of each cycle if assessed as 
target/non-target lesions. For visible lesions, a digital photograph is required with a ruler. If the skin lesion is a 
target lesion, reassessment is performed at each cycle.  If the skin lesion is non-target, repeat photographs should 
be done at every other cycle.  Photographs must be performed to document any changes to skin lesions and are 
sent to central vendor for review.
e
For patients who discontinue study treatment without objectively measured progressive disease, continue to 
evaluate tumor response approximately every 8 weeks by the same method used at baseline and throughout the 
study until the patient has objective disease progression, or until the study’s final analysis of OS.  After the 
patient has objective disease progression, radiologic tests are no longer required and the patient will be followed
up approximately every 60 days (14 days) until the patient’s death or overall study completion.
f
Imaging studies are performed locally and transmitted for central review. Radiological assessment of the chest 
and abdominal region is performed at baseline (within 28 days of treatment start), then on Day 1 7 days of the 
scheduled Day 1) of every other cycle beginning with Cycle 3 until progressive disease or the start of the next 
line of anti-tumor treatment. A scan performed up to 30 days prior to the first dose of treatment is permitted as 
the baseline scan, therefore omitting the baseline scan. If a cycle is delayed, tumor assessment should be 
concurrent with Day 1 of the new cycle. If the assessment was completed before Day 1 of the next cycle and the 
patient has a delay in starting the next cycle, the radiological scan does not need to be repeated again when Day 1 
of the next cycle is resumed.
g
Collection of survival data and subsequent antitumor therapies.  Every 60 days (±14 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 phone.
h
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly Safety 
System.  During long-term follow-up, only SAEs that are related to protocol procedures or study drug will be 
collected. All drug- or procedure-related adverse events and serious adverse events should be followed until they 
resolve, are no longer considered to be drug- or procedure-related, become stable or return to baseline, the patient 
starts a new therapy, the patient dies, or the patient becomes lost to follow-up.  Frequency of evaluation is left to 
the judgment of the investigator.
i
Laboratory assessments should occur on Day 1 (±3 days) of each cycle and Day 15 (+ 3 days) of Cycles 1 and 2.  
If the baseline laboratory assessment was conducted ≤3 days prior to Cycle 1 Day 1, reassessment is not required 
at Cycle 1 Day 1.  For central versus local labs, refer to Attachment 2.
j
Perform pregnancy tests for woman of child-bearing potential.
k
Perform pregnancy tests once every 28 days (±7 days) prior to administration of study drug, where required by 
local regulations.
l
Sparse PK samples will be collected on Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 3 Day 1 (only for patients 
receiving abemaciclib).
m A plasma sample should be collected at baseline at the time FFPE tissue is requested for testing at the 
Study JPBK central laboratory. Patients who enter the study with a local KRAS test result may omit this baseline 
sample.  Patients that have submitted FFPE tissue during pre-screening may have this baseline sample collected 
at the time of other blood laboratory samples.  Additional samples are collected on all randomized patients at 
Cycle 1 Day 1 and Cycle 2 Day 1.
n
Local ECG (no replicates required).
o
A baseline ECG will be collected from all patients.
p
ECG will be collected from patients receiving abemaciclib only.  Two ECG will be collected on Cycle 1 Day 1.  
The first ECG will be collected predose; the second will be collected 4 to 6 hours postdose. If the patient had a 
baseline ECG performed within 24 hours of the predose ECG at Cycle 1 Day 1, the scheduled predose ECG may 
be omitted.
q
ECG will be collected from patients receiving abemaciclib only.  An ECG will be collected 4 to 6 hours postdose 
on Cycle 2 Day 1.
r
If the patient received abemaciclib for 6 months, an additional ECG will be collected 4 to 6 hours postdose 
Cycle 7 Day 1.

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Study Schedule, Protocol I3Y-MC-JPBK (concluded)
s
ECG will be collected from patients receiving abemaciclib only.
t
Formalin-fixed paraffin-embedded tumor tissue requested after patient signs pre-screening ICF.  Eight slides are 
mandatory for KRAS testing by the Study JPBK central laboratory prior to enrollment. If testing did not occur 
during pre-screening, sample collection and testing is required during baseline visit.
u
If the patient was not pre-screened, FFPE tumor tissue is requested after patient signs the study ICF.  Eight slides 
are mandatory for KRAS testing by the Study JPBK central laboratory prior to enrollment. If enrollment using a 
local KRAS result is approved, no further tissue should be submitted to the Study JPBK central laboratory for 
analysis.  Approval for local KRAS result is required from the sponsor prior to randomization. Local KRAS
testing is not a required study procedure.
v
An additional 20 slides or FFPE tumor tissue block requested for biomarker research. If enrollment using a local 
KRAS result is approved, no further tissue should be submitted to the Study JPBK central laboratory for analysis.
w MDASI-LC and EQ-5D 5L should be administered at baseline (within 14 days of treatment start), on Day 1 of 
every cycle beginning with Cycle 2, and at the 30-day follow up visit (V801). The preferred order of collection 
is MDASI-LC and then EQ-5D 5L.  Patients should complete before interaction with site staff.
x
Abemaciclib is to be administered every 12 hours (± approximately 2 hours) on Days 1 through 28 of each cycle.
On Cycle 1 Day 1 only, patients should take 1 single dose of abemaciclib at clinic and initiate subsequent Q12H 
dosing from Cycle 1 Day 2 moving forward.
y
Erlotinib is to be administered every 24 hours (± approximately 2 hours) on Days 1 through 28 of each cycle.
Z
The medical history and physical examination will be performed by a qualified healthcare provider with 
assessments that include general appearance, skin, head and neck, respiratory, cardiovascular, abdomen, lymph 
nodes, thyroid, and musculoskeletal and neurological systems.
aa Pharmacogenetic whole blood sample should be collected. This may be collected either predose or postdose.
ab The study ICF must be signed at baseline before any study screening procedures are performed, but this does not 
have to be within 28 days of treatment start (Cycle 1 Day 1).  No window is defined; however, the patient will 
have to re-sign the study ICF in case it has been updated/revised. The study ICF needs to be signed prior to 
requesting approval by the sponsor for study entry for those with a local KRAS result.

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Study Schedule for the extension period only, Protocol I3Y-MC-JPBK]
Patients experiencing ongoing clinical benefit may continue to receive abemaciclib or erlotinib in 
the extension period. There is no cross-over between the 2 study treatment arms.
Perform procedure as indicated.
Patients on Study Treatment
Extension Period Follow-Up
Cycle
2 – n
Follow-Upa
Visit
501-5XX
901
Duration
(days)
28
30
Relative day 
within a 
cycle
1
Procedure 
Category
Procedure
Protocol 
Reference
Adverse Events Collection/CTCAE 
Gradingb
Section 
10.3.1
X
X
Study Drug
Abemaciclib or 
Erlotinib c
Section 9.1
X
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; PK = pharmacokinetics; 
SAEs = serious adverse events.
a
The extension period begins after study completion and ends at the end of trial.
b
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly safety 
system.
c
Abemaciclib is to be administered every 12 hours (± approximately 2 hours) on Days 1 through 28 of each cycle.
Erlotinib is to be administered every 24 hours (± approximately 2 hours) on Days 1 through 28 of each cycle.
Note:  Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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Attachment 2.Protocol JPBK Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume (MCV)
Chloride
Mean cell hemoglobin concentration (MCHC)
Total bilirubin
Leukocytes (WBC)
Direct bilirubin
Neutrophils
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Blood urea nitrogen (BUN)
Basophils
Creatinine
Platelets
Calcium
Albumin
Total Protein
Pregnancy Test (females only)b
Serum
Abbreviations:  RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Local or investigator-designated laboratory.
Other Laboratory Tests
KRASa
Sanger Sequencingb
a
Assayed by Lilly-designated central laboratory or with sponsor approval by local or investigator-designated 
laboratory.
b
To be performed on the same samples used for KRAS central laboratory testing.

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Attachment 3.Protocol JPBK Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 4.Protocol JPBK ECOG 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 5.Protocol JPBK RECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm)

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:  

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.

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Cystic lesions:

Simple cysts should not be considered as malignant lesions (neither measurable 
nor nonmeasurable)

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability.  If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated at a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion.
Baseline Documentation of Target and Non-Target Lesion
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Non-nodal 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements..  
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of 15 mm by 
CT scan.  All measurements are to be recorded in the case record form (CRF) in millimeters (or 
decimal fractions of centimeters [cm]).
Nontarget Lesions
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline.  Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’  In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as 1 liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 

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should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient.  If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and follow-
up should be guided by the tumor type under investigation and the anatomic location of the 
disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion is recommended.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may be reviewed at the 
end of the study.
Chest X-ray:  Chest CT is preferred over chest X-ray when progression is an important endpoint.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
CT and MRI:  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm.  When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (for example, for body scans).  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.
Ultrasound:  Ultrasound should not be used to measure lesion size.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  Specific guidelines for both prostate-specific antigen (PSA) response 
(in recurrent prostate cancer) and CA-125 response (in recurrent ovarian cancer) have been 
published.

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Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete response (CR) in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or SD in order to differentiate between
response (or SD) and progressive disease (PD).
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan.
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected.
Response Criteria
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of 1 or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response.
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).

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Non-CR/ non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response (BOR) is the best response recorded from the start of the study 
treatment until the earliest of objective progression or start of new anticancer therapy, taking into 
account any requirement for confirmation.  The patient’s best overall response assignment will 
depend on the findings of both target and nontarget disease and will also take into consideration 
the appearance of new lesions.  The BOR will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline.
Table 1.
Time Point Response: Patients with Target (Nontarget) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease.; PD = progressive disease; 
NE = inevaluable. 
Table 2 is to be used when patients have nonmeasurable disease only.

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Table 2.
Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations:  CR = complete response; PD = progressive disease ; NE = inevaluable.
a
non-CR/non-PD is preferred over SD for nontarget disease. 
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6-8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur;  assessment of 
nontargets is not required.
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required.  But, elimination of the requirement may 
increase the importance of central review to protect against bias, in particular of studies which 
are not blinded.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from first dose.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study).

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD).
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.

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Attachment 6.Protocol JPBK Sampling Summary
This table summarizes the maximum number of samples (venipunctures, biopsies), volumes for
all sampling, and tests (study qualification, health monitoring, drug concentration, 
pharmacodynamics/tailoring biomarkers) during the study.  The summary below provides 
estimates. More samples could be required in the case of retests, additional health monitoring (if 
needed), or for patients continuing treatment beyond the protocol-specified number of cycles in 
the study. Fewer samples may actually be taken (for example, patients who discontinue from the 
study).
Protocol I3Y-MC-JPBK Sampling Summarya
Purpose
Sample 
Type
Maximum Amount 
per Sample 
Maximum Number 
Samples
Maximum 
Total Amount
Study qualificationb
Blood
6 mL
1
6 mL
KRAS mutant statusb
FFPE tumor 
tissue slides 
or block
FFPE tumor tissue
slides
OR
FFPE tumor tissue
block
8 slides 
OR
1 tumor tissue block
FFPE tumor
tissue slides or 
block
Tissue for biomarker 
research 
FFPE tumor 
tissue slides 
or block
FFPE tumor tissue 
slides
OR
FFPE tumor tissue
block
20 slides 5 micron 
thickness
OR
1 tumor tissue block
FFPE tumor
tissue slides or 
block
Health monitoringa
Blood for 
chemistry
3 mL
15
45 mL
Blood for 
Hematology
3 mL
15
45 mL
Drug concentration
Blood
2 mL
5
10 mL
Pharmacodynamics and/or 
circulating biomarkers
Plasma
6 mL
3
18 mL
Pharmacogenetic 
evaluations
Whole blood
10 mL
1
10 mL
Hepatic monitoringc
Blood
3 - 30 mL
-
-
Total: Blood
134 mL
Abbreviation:  FFPE = formalin-fixed paraffin-embedded.
a
Covers 12 cycles and Visit 801.
b This sample is required for initial qualification unless sponsor approves enrollment per local KRAS mutation 
result.  The remaining samples are for those patients enrolled in the study.
c
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with the designated medical monitor.

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Attachment 7.Protocol JPBK Pharmacokinetic
Sampling Schedule
Pharmacokinetic Sampling Schedule
PK Sample 
Number
Cycle (C) 
and Day (D)
Dosing of 
Abemaciclib
Sampling Time for PK from Blooda
1
C1D1
Xb
4-6 hrs after abemaciclib dose
2
C2D1
Xc
At least 4 hrs after taking abemaciclib dose at 
home (that is, upon arrival at site)
3
C2D1
At least 7 ± 0.5 hrs after taking abemaciclib dose 
at home (that is, 3 ± 0.5 hrs after arrival at site)
4
C3D1
X
Prior to abemaciclib dose
5
C3D1
3 ± 0.5 hrs after abemaciclib dose
Abbreviations: C = Cycle; D = Day; hr = hour; PK = pharmacokinetic; Q12H = every 12 hours.
a
Samples of approximately 2 mL of whole blood will be drawn, for measurement of abemaciclib and its 
metabolites concentrations in plasma.
b On Cycle 1 Day 1 only, patients should take 1 single dose of abemaciclib and initiate chronic Q12H dosing on 
Cycle 1 Day 2.
c
On Cycle 2 Day 1 only, patient should take abemaciclib dose at home at approximately 4 hours before arrival at 
site. The time of abemaciclib dose intake must be recorded that day.

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Attachment 8.Protocol JPBK Inducers and Strong Inhibitors 
of CYP3A4 or Substrates of CYPs with Narrow Therapeutic 
Range
The information in this attachment is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated.
Inducers of CYP3A4
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A4
All HIV protease inhibitors
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 
days, if clinically indicated.  A patient who develops brain metastases may receive acute or chronic 
therapy with dexamethasone if clinically indicated.  Development of brain metastases is considered 
progressive disease and the patient should discontinue study treatment.
Cytochrome P450 Substrates with Narrow Therapeutic Range
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel
CYP2C9
Warfarina
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenidine
a Important note:  For patients who receive concomitant warfarin, appropriate monitoring of the International Normalized Ratio 
(INR) must be performed.

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Attachment 9.Protocol JPBK CTCAE 4.03 Diarrhea Definition
Diarrhea will be evaluated in this study using the criteria proposed by Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 revised:  CTCAE 4.03-June 14, 2010: Gastrointestinal disorders.
Gastrointestinal Disorders
Grade
Adverse Event
1
2
3
4
5
Diarrhea
Increase of <4 stools 
per day over baseline; 
mild increase in 
ostomy output 
compared to baseline.
Increase of 4-6 stools 
per day over baseline; 
moderate increase in 
ostomy output 
compared to baseline
Increase >= 7 stools per 
day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self-care 
ADL
Life-threatening 
consequences; urgent 
intervention indicated
Death
Definition:  a disorder characterized by frequent and watery bowel movements
Abbreviation:  ADL = Activities of Daily Living.

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Attachment 10.
Protocol JPBK Amendment(e) Summary
JUNIPER:  A Randomized Phase 3 Study of Abemaciclib
plus Best Supportive Care versus Erlotinib plus Best 
Supportive Care in Patients with Stage IV NSCLC with a 
Detectable KRAS Mutation Who Have Progressed After 
Platinum-Based Chemotherapy
Study I3Y-MC-JPBK(d), A Randomized Phase 3 Study of Abemaciclib plus Best Supportive 
Care versus Erlotinib plus Best Supportive Care in Patients with Stage IV NSCLC with a 
Detectable KRAS Mutation Who Have Progressed After Platinum-Based Chemotherapy, has 
been amended.  The new protocol is indicated by Amendment (e) and will be used to conduct the 
study in place of any preceding version.
The overall changes made to this protocol are as follows:

Synopsis updated the following: number of planned patients and interim analysis, length 
of study, PFS as a secondary objective and statistical method information

Section 5 updated erlotinib background information to align with erlotinib label

Section 5.5 incorporated amendment (e) rationale

Sections 6.1 and 6.2 deleted co-primary objective of PFS and added it as a secondary 
objective

Section 8.1 updated study design illustration number of patients

Section 9.5 removed DMC information for OS interim analysis

Sections 10.1.3 and 10.1.4 moved PFS efficacy measure information from primary to 
secondary efficacy measure

Section 12.1 updated study enrollment patient numbers; OS number of events, HR and 
median OS information; and removed PFS information.

Section 12.2.1 clarified assumptions for statistical methods

Section 12.2.6 and 12.2.7 moved PFS outcome and methodology analysis and endpoint 
information from primary to secondary outcome

Section 12.2.8 provided clarity for sensitivity analyses for efficacy endpoints

Section 12.2.12 clarified TEAE definition as an event

Section 12.2.13 clarified subgroup analyses

Section 12.2.14.2 updated interim efficacy analysis and reference to DMC plan
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1. Protocol I3Y-MC-JPBK(de)
JUNIPER:  A Randomized Phase 3 Study of Abemaciclib plus Best 
Supportive Care versus Erlotinib plus Best Supportive Care in 
Patients with Stage IV NSCLC with a Detectable KRAS Mutation 
Who Have Progressed After Platinum-Based Chemotherapy
2. Synopsis
Clinical Protocol Synopsis:  Study I3Y-MC-JPBK
Name of Investigational Product:  Abemaciclib
Title of Study:  JUNIPER:  A Randomized Phase 3 Study of Abemaciclib plus Best Supportive Care versus 
Erlotinib plus Best Supportive Care in Patients with Stage IV NSCLC with a Detectable KRAS Mutation Who Have 
Progressed after Platinum-Based Chemotherapy.
Number of Planned Patients:
Entered:  2500
Enrolled/Randomized:  approximately 450550
Completed:  550approximately 450
Phase of Development:  3
Length of Study:  Approximately 47 months
Planned first patient visit:  September 2014
Planned last patient visit:  excluding the extension period:  August 2018November 2017
Planned interim analysis:  Analysis for safety will occur every 6 months.  One futility analysis will occur after 
approximately 100 progression-free survival (PFS) events have been observed.  One 
efficacy analysis will occur after approximately 338 PFS events have been observed, or 
approximately 1 month after study enrollment completion, whichever comes later.
Objectives:  The co-primary objectives of this study isare to compare abemaciclib plus BSC versus erlotinib plus 
BSC in patients with Stage IV NSCLC whose tumors have detectable KRAS mutations and who have progressed 
after prior platinum-based therapy and 1 other prior therapy or are not eligible for further chemotherapy with respect 
to:

PFS

overall survival (OS)
The secondary objectives of the study are to compare abemaciclib plus BSC to erlotinib plus BSC with respect to:

overall response rate (complete response + partial response)

progression-free survival (PFS)

changes in patient-reported pain and disease-related symptoms collected via the MD Anderson Symptom 
Inventory (MDASI-LC) and changes in health status via European Quality of Life – 5 Dimensions –
5 Level (EQ-5D 5L)

safety and tolerability

resource utilization (for example, analgesic type, hospitalization, transfusion)
An additional secondary objective is to examine the pharmacokinetic (PK)/pharmacodynamic (PD) properties of 
abemaciclib.
Statistical Methods:
Statistical:  The study will enroll approximately 550 450 patients in 3:2 randomization (330 approximately 270
patients in the abemaciclib arm and 220 180 patients in the erlotinib arm).  The primary PFS analysis will be 
performed after approximately 338 PFS events have occurred or approximately 1 month after the last patient is 

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enrolled, whichever is later.  An interim OS analysis will be conducted at the time of primary PFS analysis.  The
final OS analysis will occur when approximately 304407 OS events have been observed.The study-wise alpha of .05 
will be split between the endpoints:  .005 for PFS and .045 for OS.  The test on PFS will occur first; if the test on 
PFS is significant, the alpha used for this test will be added to the .045 originally allocated to OS for a total of .05.  
If the primary PFS analysis is significant, two-sided alpha=0.0112 will be spent in the interim OS analysis and 
alpha=0.0466 will be used in the final OS analysis based on O’Brien and Fleming alpha-spending approach using 
East® 6.3 (Lan and DeMets 1983). If the primary PFS is not significant, two-sided alpha=0.0096 will be spent in 
the interim OS analysis and alpha= 0.0420 will be used in the final OS analysis.  A fallback procedure (Wiens 2003) 
will be used to maintain a study-wise alpha level of .05.
Assuming a PFS hazard ratio (HR) of 0.67, this sample size yields approximately 80% statistical power to detect 
superiority of the abemaciclib arm over erlotinib arm with the use of a 2-sided log-rank test and a type I error of 
.005.  If the true median PFS for the erlotinib arm is 2 months, then the HR of 0.67 amounts to an approximately 1-
month improvement in median PFS for the abemaciclib arm under an additional assumption of exponential survival 
distribution.  Assuming an OS HR of 0.725, this sample size yields approximately 80% statistical power to detect 
superiority of the abemaciclib arm over erlotinib arm with the use of a 2-sided log-rank test and a type I error of 
.045.  If the true median OS for the erlotinib arm is 6.5 months, then the HR of 0.725 amounts to an approximately 
2.52-month improvement in median OS for the abemaciclib arm under an additional assumption of exponential 
survival distribution.
Efficacy:   Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is defined as 
all patients randomized to study treatment.  For the co-primary endpoints of PFS and OS and PFS, the comparison 
of the survival curves between treatment groups will be conducted by a stratified log-rank test with the following 
stratification variables:  number of prior chemotherapy regimens (1 versus 2), ECOG PS (0 versus 1), gender (male 
versus female), and KRAS mutation (GLY12CYS [G12C] vs. all others).  In addition, the Kaplan-Meier method 
(Kaplan and Meier 1958) will be used to estimate the survival curves as well as survival rates at 3, 6, 9, and 12 
months for each treatment group.  As supportive analysis of OS and PFS, the Cox proportional hazard model will be 
used to estimate treatment HR and corresponding 95% confidence interval (CI) with Wald’s test p-value after 
adjusting for the same randomization variables specified for the primary analysis.  All randomized patients, 
according to the ITT principle, will be included in the analysis of this endpoint.
5. Introduction
Erlotinib is indicated for the treatment of patients with locally advanced or metastatic NSCLC 
after failure of at least 1 prior chemotherapy regimen (Tarceva United States [US] package insert 
[USPI], 2010).  Until recently, uUnlike the use of erlotinib for first-line treatment of patients 
with NSCLC, second- and third-line treatment has no limitation with regard to epidermal growth 
factor receptor (EGFR) or KRAS mutation status.  In October 2016 the FDA modified the 
erlotinib label to include only those patients with tumors with common EGFR mutations, del 19 
and exon 21 L858R substitutions.  Before this action, there has had been some concern regarding 
the activity of erlotinib in treating NSCLC with KRAS mutations due to results from 3 studies.  
First, in the original BR-21 study, a subgroup evaluation of 30 patients with KRAS mutant 
tumors randomized between placebo and erlotinib demonstrated a nonsignificant better survival 
outcome in the placebo group (Zhu et al. 2008).  Second, in TITAN, a second-line study of 
erlotinib versus chemotherapy, 35 patients with KRAS mutant tumors had inferior outcome on 
erlotinib compared to chemotherapy (Ciuleanu et al. 2012).  Lastly, a meta-analysis of response 

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rate showed numerically inferior response rate in patients with KRAS mutant tumors treated with 
EGFR tyrosine kinase inhibitors (TKIs, such as erlotinib and gefitinib) (Linardou et al. 2008).  In 
the TAILOR study comparing docetaxel to erlotinib as second-line therapy, overall survival (OS) 
favored docetaxel treatment in patients with both KRAS wild-type and KRAS mutant tumors 
(hazard ratio [HR] = 0.79 and 0.81, respectively); similarly, progression-free survival (PFS)
favored docetaxel (HR = 0.68 and 0.89) for KRAS wild-type and KRAS mutant, respectively 
(Garassino et al. 2013).  There was not a significant treatment interaction based on KRAS status.  
However, the SATURN study of erlotinib maintenance therapy demonstrated that improved PFS
was preserved in a subset of 90 patients with KRAS mutant tumors (HR = 0.77 erlotinib 
compared to placebo) (Brugger et al. 2011).  Overall, the data remain conflicting and after 
extensive review of the literature, Langer stated, “KRAS mutation cannot be used at this time to 
preclude NSCLC patients from receiving anti-EGFR TKI’s” (Langer 2011).  A more recent 
evaluation of pooled results from four Phase 3 studies of erlotinib showed that KRAS mutation 
was not predictive of treatment outcome with tyrosine kinase inhibitors (Zer et al. 2015).  The 
selection of treatment depends on the overall benefit/risk for the patient.  Given the differences in 
toxicity profile for available treatments, and the limited treatment options for patients, erlotinib is 
an acceptable control arm as the only oral drug available for patients with lung cancer, and only 
approved drug for treatment of third-line patients in selected geographies.
5.5. Rationale for Amendment (e)
Due to recent changes in the FDA ertlotinib label and National Comprehensive Cancer Network 
(NCCN) Guidelines, the Sponsor amended the protocol to address the impact on study 
enrollment completion, and the need for a larger improvement in OS than that historically 
targeted for NSCLC patients.  The amendment updates include the followings:

PFS is removed as a co-primary endpoint and changed to a secondary endpoint.  With 
this change OS becomes the sole primary endpoint. 

The final OS analysis will occur when approximately 304 OS events have been 
observed, a reduction from the current protocol requirement of 407 OS events.  With this 
change, the study will provide 80% statistical power for a new targeted hazard ratio of 
0.72. 

Due to the reduced number of targeted OS events, a smaller sample size of 
approximately 450 patients will be sufficient to reach the 304 OS events for the final 
analysis (note that current protocol requires 550 patients). 
While amending the protocol, the Lilly study team remains blinded to aggregate data and will not 
be unblinded until the final OS analysis.
Previously, erlotinib was indicated for the treatment of patients with locally advanced or 
metastatic NSCLC after failure of at least 1 prior chemotherapy regimen (Tarceva® United States 
[US] package insert [USPI], 2010) based upon the BR-21 study.  In addition, NCCN Guidelines 
(April 2015) supported erlotinib use as an option for subsequent second line or third line 
treatment in NSCLC patients (all histologies) for PS 0-3. 

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On 18 October 2016, the FDA modified the indication for erlotinib (Tarceva®) for treatment of 
NSCLC, limiting the use to patients whose tumors have specific EGFR mutations (exon 19 
deletions or exon 21 L858R substitutions).  This labeling supplement occurred based on study 
results of the IUNO Study (a randomize, double-blind, placebo controlled, trial of erlotnib 
administered as maintenance therapy in advanced NSCLC patients who had not experienced 
disease progression or unacceptable toxicity during four cycles of platinum-based first-line 
chemotherapy).  The results showed no observed benefits in PFS, ORR, DCR or OS ( median OS 
was 9.7 and 9.5 months with ‘early’ and ‘late erlotinib’, respectively (HR, 1.02, 95% CI:  
0.85−1.22; log-rank p = 0.82) in patients receiving erlotinib as maintenance therapy (“early 
erlotinib”) compared to second-line treatment (“late erlotinib”) in patients whose tumor did not 
harbor an EGFR-activating mutation.  However, safety results were consistent with the 
established safety profile of erlotinib.  Furthermore, in lieu of the FDA labeling supplement, the 
NCCN Guidelines removed erlotinib from recommended therapies in patients who progress on 
platinum therapy and who do not have EGFR mutations (NCCN Guidelines October 2016). 
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
6.1. Primary Objective
The co-primary objectives of this study isare to compare abemaciclib plus BSC versus erlotinib 
plus BSC in patients with Stage IV NSCLC whose tumors have detectable KRAS mutations and 
who have progressed after prior platinum-based therapy and 1 additional therapy which may 
include an immune checkpoint inhibitor and/or other anti-cancer treatment; or are not eligible for 
further chemotherapy with respect to:progression-free survival (PFS)

overall survival (OS)
6.2. Secondary Objectives
The secondary objectives of the study are to compare abemaciclib plus BSC to erlotinib plus 
BSC with respect to:

overall response rate (complete response [CR] + partial response [PR])

progression-free survival (PFS)

changes in patient-reported pain and disease-related symptoms collected via the MD 
Anderson Symptom Inventory (MDASI-LC) and changes in health status via European 
Quality of Life – 5 Dimensions – 5 Level (EQ-5D 5L).

safety and tolerability

resource utilization (for example, analgesic type, hospitalization, transfusion)
7. Study Population
If a KRAS mutation positive result was obtained for an individual under their first patient 
number, this result can be linked to their new number in an effort to preserve patient tissue.  If a 
KRAS mutation result was not successfully obtained for an individual under their first patient 

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number, then the investigator can submit a new sample for this individual (as well as one repeat 
if needed) can be submitted to the central lab with the new patient number.
8.1. Summary of Study Design
Figure JPBK.8.1 illustrates the study design.

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Abbreviations:  ECOG = Eastern Cooperative Oncology Group; N = number of patients; NSCLC = non-small cell 
lung cancer; PD = progressive disease; PO = orally; PS = performance status; Q12H = every 12 hours; 
Q24H = every 24 hours.
Figure JPBK.8.1.
Illustration of study design.
8.1.1. Study Completion and End of Trial

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Abbreviations:  OS = overall survival; PFS = progression-free survival.
a
Lilly will notify sites when this begins and ends.
Figure JPBK.8.2.
Study period and extension period diagram.
8.2. Discussion of Design and Control
A randomized, controlled design is being used in this study.  Randomization minimizes 
systematic bias in the selection and assignment of patients to study therapy and provides 
justification for inferential statistical methods to be used on data from this study.  It is expected 
that abemaciclib will produce better efficacy outcomes than the control; therefore, this study uses
a 3:2 randomization has been used in this study.  Using an appropriate concurrent control arm 
enables direct statistical estimation of benefits and harms due to study therapy and minimizes 
bias in the assessment and interpretation of observed treatment effects. Patients will be stratified 
for differences in factors thought to be associated with clinical outcomes to further reduce the 
potential for bias and improve the power of the analyses.
9.5. Blinding
In order to maintain the scientific integrity of this trial, access to study data will be strictly 
controlled prior to the interim and final analyses. For the accumulated group-level data, 
treatment assignment will not be included, and other parameters that can disclose treatment 
assignment will be scrambled.  Therefore, the sponsor and all investigative sites will remain 
blinded to treatment group assignments for the summary statistics and reports until the database 
lock for the final analysis. Scrambled treatment assignments will be used in the reporting 
database for Lilly trial-level safety review until the final database lock.  Interim analyses will be 
carried out approximately every 6 months by an independent DMC (external to Lilly) to monitor 
safety and efficacy.  The DMC is unblinded and the Statistical Analysis Center (SAC), which is 
also external to Lilly, will carry out analyses for the DMC.  Until the primary analyses, only the
SAC and the DMC will be unblinded to the summary statistics and reports.  If the DMC 
recommends to stop the trial based on positive outcome of OS interim analysis, in light of the 
critical importance of obtaining unbiased results of final OS analysis in the study, the unblinded 
database will be accessible to a limited number of individuals who need to have such access to 
perform analyses and make critical decisions (for example, regulatory submission).  This group 
of individuals will be identified and documented prior to the database lock for the final analysis.
10.1.3. Primary Efficacy Measure
This study has co-primary efficacy measures of the study is PFS and OS.
Progression-free survival will be defined as the time from randomization until the first evidence 
of objective progression as defined by RECIST v1.1 (Eisenhauer et al. 2009), or death from any 
cause, whichever is earlier.  Patients who are not known to have either progressed or died at the 
time of analysis will be censored at the day of their last radiographic tumor assessment, if 
available, or the date of randomization if no postbaseline radiographic assessment is available.  
The detailed censoring rules are described in Table JPBK.12.2.

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The primary PFS analysis will be based on the local investigator’s tumor assessments.
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  A central review of imaging scans may be performed by Lilly or its 
designee.
10.1.4. Secondary Efficacy Measures
The secondary efficacy measure isTumor response isas defined by RECIST v1.1 (Eisenhauer et 
al. 2009) provided in Attachment 5.  ATo derive the overall response rate, a responder is defined 
as any patient who exhibits a confirmed CR or PR. Best response is determined from the 
sequence of responses assessed.
Progression-free survival will be defined as the time from randomization until the first evidence 
of objective progression as defined by RECIST v1.1 (Eisenhauer et al. 2009), or death from any 
cause, whichever is earlier.  Patients who are not known to have either progressed or died at the 
time of analysis will be censored at the day of their last radiographic tumor assessment, if 
available, or the date of randomization if no postbaseline radiographic assessment is available.  
The detailed censoring rules are described in Table JPBK.12.2.
The PFS analysis will be based on the local investigator’s tumor assessments.
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.  Lilly or its designee will collect and store all 
tumor measurement images on all enrolled patients throughout the study.  A central review of 
imaging scans may be performed by Lilly or its designee.
12.1. Determination of Sample Size
The co-primary objectives of this study isare to compare abemaciclib versus erlotinib with 
respect to PFS and OS in patients with Stage IV NSCLC whose tumors have detectable KRAS
mutations (specifically, in codons 12 and 13 of the KRAS oncogene) and who have progressed 
after prior platinum-based therapy and received 1 other prior therapy or are not eligible for 
further chemotherapy.
The study will enroll approximately 550 450 patients in 3:2 randomization (approximately 
270330 patients in the abemaciclib arm and 180220 patients in the erlotinib arm).  The primary 
PFS analysis will be performed after 338 PFS events have occurred.  The final OS analysis will 
occur when approximately 304407 OS events have been observed.
Assuming an OS HR of 0.725, this sample size yields approximately 80% statistical power to 
detect superiority of the abemaciclib arm over erlotinib arm with the use of a 2-sided log-rank 
test and a type I error of .045.
If the true median OS for the erlotinib arm is 6.5 months, then the HR of 0.725 amounts to an 
approximately 2.52-month improvement in median OS for the abemaciclib arm under an 
additional assumption of exponential survival distribution.

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12.2.1. General Considerations
Before unblinding of the aggregate database, minor modifications or clarifications to the data 
analysis methods may be described and justified in the SAP.  The assumptions for each statistical 
method will be evaluated.  If there is violation of assumptions, alternative statistical methods 
may be used.  Any other change to the data analysis methods described in the protocol, and the 
justification for making the change, will be described in the CSR.
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.6. Primary Outcome and Methodology
The co-primary endpoints of this study isare PFS and OS.The study-wise alpha of .05 will be 
split between the endpoints: .005 for PFS and .045 for OS. There is 1 planned interim analysis 
and 1 primary analysis for the PFS endpoint.  The interim PFS analysis will occur after 
approximately 100 PFS events have been observed and will be for futility only.  The primary 
PFS analysis will be performed after approximately 338 PFS events have occurred, or 
approximately 1 month after study enrollment completion, whichever comes later.  There is 1 
interim analysis and 1 final analysis planned for the OS endpoint.  The interim OS analysis will 
be conducted at the time of primary PFS analysis.  The final OS analysis will be conducted after 
at least approximately 407 OS events have been observed.  Two-sided alpha of  0.0112 (if PFS 
analysis is significant) or 0.0096 (if PFS analysis is not significant) will be spent in the interim 
OS analysis based on O’Brien and Fleming alpha-spending approach using East® 6.3 (Lan and 
DeMets 1983).  A fallback procedure (Wiens 2003) will be used to maintain a study-wise alpha 
level of .05.  Specifically:
If the primary PFS analysis is significant, the final OS analysis will be conducted at 2-sided 
alpha level of .0466.
If the primary PFS analysis is not significant, the final OS analysis will be conducted at 2-sided 
alpha level of 0.0420.
The alpha level used for each test at each analysis is described in Table JPBK.12.1.  The alpha 
levels for OS analyses are approximate based on projected 266 OS events at interim; the actual 
levels will depend on the exact accrued OS events at the time of interim OS analysis.
Table JPBK.12.1.
Alpha Allocation (2-Sided) for Progression-Free Survival and Overall 
Survival
Endpoint
Alpha at PFS Analysis
(338 PFS events)
Alpha at OS Analysis
(407 OS events)
PFS
0.005
----
OS (If PFS is significant)
0.0112
0.0466

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OS (If PFS is not significant)
0.0096
0.0420
Abbreviations:  OS = overall survival; PFS = progression-free survival.PFS time is measured 
from the date of randomization to the date of investigator-determined objective progression as 
defined by RECIST v1.1, or death from any cause.  Patients who have neither progressed nor 
died will be censored at the day of their last radiographic tumor assessment (if available) or date 
of randomization if no post initiation (that is, postbaseline) radiographic assessment is available.  
All randomized patients, according to the ITT principle, will be included in the analysis of both 
endpoints.  The detailed censoring rules for PFS are described in Table JPBK.12.2.
Table JPBK.12.2.
Rules for Determining Date of Progression or Censor for Progression-Free 
Survival
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no 
death 
Date of Randomization
Censored
3
No documented progression and no death 
(with a post-baseline tumor assessment)
Date of last adequate tumor 
assessment
Censored
4
Patient lost to follow-up (or withdrew 
consent from study participation) before 
documented progression or death 
Date of last adequate tumor 
assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done 
on multiple days, use the earliest 
date for that visit.
Progressed
6
Death without documented progression 
Date of death 
Progressed
7
Death or documented progression 
immediately after missed ≥2 consecutive 
post-baseline tumor assessment visits 
Date of last adequate tumor 
assessment before missed 
assessments or date of 
randomization, whichever is later
Censored
Note:  Progression-free survival and associated outcome is determined by the earliest of the dates 
above, if more than 1 situation applies. 
Overall survival duration is measured from the date of randomization 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 date of last contact prior to 

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the data inclusion cutoff date (contacts considered in the determination of last contact date 
include AE date, lesion assessment date, visit date, and last known alive date).
The comparison of each of the PFS and OS distributions between treatment groups will be 
conducted using a stratified log-rank test with the following stratification variables: number of 
prior chemotherapy regimens (1 versus 2), ECOG PS (0 versus 1), gender (male versus female), 
and KRAS mutation (G12C versus all others).
The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the PFS and OS 
survival curves as well as survival rates at 3, 6, 9, and 12 months for each treatment group.  
These rates will be compared based on a normal approximation for the difference between the 
arms.
12.2.7. Secondary Outcome and Methodology
The secondary objectives for this study are stated in Section 6.2.
Progression-free survival time is measured from the date of randomization to the date of 
investigator-determined objective progression as defined by RECIST v1.1, or death from any 
cause.  Patients who have neither progressed nor died will be censored at the day of their last 
radiographic tumor assessment (if available) or date of randomization if no post initiation (that 
is, postbaseline) radiographic assessment is available.  The detailed censoring rules for PFS are 
described in Table JPBK.12.2.
Table JPBK.12.2.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no death 
Date of Randomization
Censored
3
No documented progression and no death (with a 
post-baseline tumor assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew consent 
from study participation) before documented 
progression or death 
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented progression 
Date of death 
Progressed
7
Death or documented progression immediately 
after missed ≥2 consecutive post-baseline tumor 
assessment visits 
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later
Censored
Note:  Progression-free survival and associated outcome is determined by the earliest of the dates above, if more than 
1 situation applies.
The statistical comparison of PFS between treatment groups will be conducted using the same 
methods for OS as described in Section 12.2.6.

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The objective response rate of each treatment arm will be calculated as defined by RECIST v1.1.  
All rates will be compared between treatment arms based on a normal approximation for the 
difference between the rates.
Details of the statistical methods for analyzing efficacy outcomes are described in the SAP.
12.2.8. Sensitivity Analysis
Sensitivity analyses maywill be undertaken for calculation of the primary endpointthe efficacy 
endpoints in order to evaluate the robustness of the analysis. The following sensitivity analyses 
maywill be performed for PFS:
12.2.12. Safety Analysis
Preexisting conditions are defined as adverse events that begin prior to the first dose of study 
drug.  A TEAE is defined as an event that first occurred or worsened in severity between the day 
of first dose and 30 days after treatment discontinuation (or up to any time if serious and related 
to study treatment)after baseline.  Comparisons of preexisting conditions to on-treatment events 
at the LLT level will be used in the treatment-emergent computation.
12.2.13. Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for potential prognostic and predictive 
subgroup variables (for example, patients with or without prior immunotherapy).
12.2.14.2. Efficacy Interim Analyses
OneTwo interim efficacy analysies isare planned based on the PFS endpointco-primary 
endpoints, as described in Section 12.2.6. BothThis interim analysies is for futility only and will 
be conducted by the DMC.  There is no plan for interim efficacy analysis based on the OS 
endpoint.  The DMC may also call for additional, unplanned, interim efficacy analyses. Details 
of the DMC communication plan can be found in the DMC charter.
The first interim efficacy analysis will be conducted after approximately 100 PFS events have 
occurred.  This analysis will be based on the PFS endpoint and will be for futility only.  The 
DMC will be instructed to recommend the study be stopped for futility if the observed hazard 
ratio for PFS (as calculated using a stratified Cox proportional hazards model) is greater than 
0.95.The second interim efficacy analysis will be conducted after at least 338 PFS events have 
occurred, or approximately 1 month after study enrollment completion, whichever comes later.  
This analysis will include both the primary PFS and an interim OS analyses.  For both the PFS 
and OS endpoints, a stratified log-rank test will be conducted to compare the survival 
distribution between treatment groups.  The DMC will review unblinded efficacy and safety 
data.  If the efficacy result meets the prespecified threshold and is supported by safety data, the 
DMC will be instructed to engage the Senior Management Designee, who may subsequently 
convene an Internal Review Committee to propose actions based upon the DMC’s 
recommendation.  Details of the DMC communication plan can be found in the DMC charter.

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14. References
Zer A, Ding, K, Lee SM, Goss GD, Seymour L, Ellis PM, Hackshaw A, Bradbury PA, Han L, 
O’Callaghan CJ, Tsa MS, Shepherd FA. Pooled analysis of the prognostic and predictive value 
of KRAS mutation status and mutation subtype in patients with non–small cell lung cancer 
treated with epidermal growth factor receptor tyrosine kinase inhibitors. J Thor Onc.
2015;11(3):312-323.
Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. Pharma Stat.
2003;2(3):211–215.

Approver: 
Approval Date & Time: 19-Dec-2016 21:46:58 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 20-Dec-2016 10:13:26 GMT
Signature meaning: Approved
PPD
PPD
CCI

Leo Document ID = 7b74a75c-7d81-4e39-81d6-f2cb16df3fbf
Approver: 
Approval Date & Time: 11-Jul-2018 20:06:14 GMT
Signature meaning: Approved
PPD

Leo Document ID = 94fad105-f5d6-40d5-973e-cae5019ce9d7
Approver: 
Approval Date & Time: 23-Aug-2018 14:44:33 GMT
Signature meaning: Approved
PPD