A Study to Determine the Concordance of Key Actionable Genomic Alterations as Assessed in Tumor Tissue and Plasma From Patients With Non Small Cell Lung Carcinoma (NSCLC)
Conditions: Non Small Cell Lung Carcinoma
Sponsor: Genomic Health®, Inc.

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Study Protocol 
 
 
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Page 1 of 41 Genomic Health DSP-DE-MS 14-009 Study Protocol Version 3.0  
 
 
A STUDY TO DETERMINE THE CONCORDANCE OF KEY 
ACTIONABLE GENOMIC ALTERATIONS AS ASSESSED IN TUMOR 
TISSUE AND PLASMA FROM PATIENTS WITH NON SMALL CELL 
LUNG CARCINOMA (NSCLC) 
 
 
 
Study Protocol Number: 
DSP-DE-MS 14-009 
 
 
Protocol Version: 
Version 3.0 
 
Protocol Issue Date: 
  
 
 
Sponsor and Study Laboratory: 
Genomic Health, Inc. 
 
 
301 Penobscot Drive 
 
 
Redwood City, CA 94063 
 
 
Phone: 650-556-9300 
 
 
IDE Number: 
Not Applicable 
 
 
Study Sites: 
Approximately 25 USA and International 
centers including centers in France, Germany, 
Ireland, Spain, United Kingdom, Japan, Chile 
and Mexico. 
 
 
 
  
 
 
 
 
 
Confidentiality Statement 
The concepts and information contained herein are considered confidential and proprietary information of 
Genomic Health, Inc. Except as may be required by Federal, State, or local laws or regulations, this 
document may not be disclosed to others without written permission of Genomic Health. 
 

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PROTOCOL APPROVAL FORM 
Protocol Number: 
DSP-DE-MS 14-009 
Version Number and Date: 
Version 3.0  
Study Title: 
A study to determine the concordance of key actionable 
genomic alterations as assessed in tumor tissue and plasma 
from patients with non small cell lung carcinoma (NSCLC) 
 
This study protocol was subjected to critical review. The information presented in this document 
is consistent with Genomic Health’s current knowledge of the risks and benefits of the 
developmental genomic sequencing test system/technology, as well as with the moral, ethical 
and scientific principles governing clinical research as set out in the Declaration of Helsinki, as 
amended in 2002 and clarified in 2004. 
 
 
 
Genomic Health approvals: 
 
 
 
_________________________________________  
____________________ 
Steve Shak, MD 
 
 
 
 
 
Date 
Chief Medical Officer 
Genomic Health, Inc. 
 
 
 
_________________________________________  
____________________ 
Jim Whitmore, PhD  
 
 
 
 
Date 
VP, Biostatistics and Data Management 
Genomic Health, Inc. 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Number: 
DSP-DE-MS 14-009 
Version Number and Date: 
Version 3.0 
Study Title: 
A study to determine the concordance of key actionable 
genomic alterations as assessed in tumor tissue and plasma 
from patients with non small cell lung carcinoma (NSCLC) 
 
 
 
 
The study protocol has been reviewed and approved by the following Genomic Health 
Representatives: 
 
 
____________________________________________        ____________________ 
Rick Baehner, MD 
 
 
 
 
 
Date 
VP, Pathology 
Genomic Health, Inc. 
 
 
 
____________________________________________        ____________________ 
John Bennett, MPH 
Date 
Lead Statistical Programmer 
Genomic Health, Inc. 
 
 
 
____________________________________________        ____________________ 
Keith Gran, DPT 
Date 
Director, Clinical Operations  
Genomic Health, Inc. 
 
 
 
 
 
 
 
 
 
 
 

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RESPONSIBLE PERSONNEL 
 
 
Medical Monitor & Pathologist 
Genomic Health Laboratory  
Rick Baehner, MD 
Kim Langone, PhD  
VP, Pathology 
Director, Product Science, Genomic Sciences  
Genomic Health, Inc. 
Genomic Health, Inc. 
301 Penobscot Drive 
301 Penobscot Drive  
Redwood City, CA 94063 
Redwood City, CA 94063 
Phone: +1 650-569-2430 
Phone: +1 650-569-223
E-mail Address:  
klangone@genomichealth.com 
Clinical Project Manager 
 
Keith Gran, DPT 
 
Director, Clinical Operations 
 
Genomic Health, Inc. 
 
301 Penobscot Drive 
 
Redwood City, CA 94063 
 
Phone: +1 650-569-2042 
 
E-mail Address: kgran@genomichealth.com 
 
 
 
Clinical Biostatistician 
 
 
John Bennett, MPH  
  
 
Lead Statistical Programmer 
   
Genomic Health, Inc. 
 
301 Penobscot Drive 
 
Redwood City, CA 94063 
 
  
Phone: +1 650-569-5681 
  
E-mail Address: jbennett@genomichealth.com                          
 
  
Data Management 
Marina Pavlova, MS 
Sr Biomedical Data Manager 
Genomic Health, Inc. 
301 Penobscot Drive 
 
Redwood City, CA 94063 
Phone: +1 650-569-2044 
E-mail Address: mpavlova@genomichealth.com  
 
 
 

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DOCUMENT HISTORY 
Version 
Date 
Replaces 
Description of Change 
1.0 
 
N/A 
New issue 
2.0 
 
1.0 
Change in exclusion criterion: 
5.2.3 Increase interval between tissue and 
blood samples from 6 to 8 weeks  
Added an exclusion criterion 
5.2.5  Patients progressing on Osimertinib 
treatment (clarification) 
Sample size of the all comer phase increased 
from 79 to 200 patients 
Changed the trigger for an interim analysis 
Other administrative changes throughout 
2.5 
 
2.0 
Update with corrections made in Letter of 
Clarification – Exclusion Criteria 5.2.3 dated 
08Aug2017. 
3.0 
 
2.5 
Replace Dr. Christer Svedman with Dr. Rick 
Baehner as Medical Monitor 
Remove central CLIA lab / Foundation 
Medicine study procedures 
Change follow up data collection procedures to 
permit outcome analysis of the interim analysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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DEFINITIONS AND ACRONYMS 
 
 
ALK 
Anaplastic Lymphoma Kinase 
CAP 
College of American Pathologists 
CLIA 
Clinical Laboratory Improvement Amendments 
CNV 
Copy Number Variation 
cfDNA 
Cell Free DNA 
DNA 
Deoxyribonucleic Acid 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
FPE 
Fixed Paraffin-embedded 
HIPAA 
Health Insurance Portability and Accountability Act  
InDels 
Insertion or Deletion  
IRB/EC 
Institutional Review Board, independent Ethics committee, or 
equivalent 
LBMP 
Liquid Biopsy Mutation Panel 
LDT 
Laboratory Developed Test 
NCCN  
National Comprehensive Cancer Network 
NGS 
Next Generation Sequencing 
NPA 
Negative Percent Agreement 
NSCLC 
Non-Small Cell Lung Cancer 
PCR 
Polymerase Chain Reaction  
PPA 
Positive Percent Agreement 
SNV 
Single Nucleotide Variant 
SOP 
Standard Operating Procedure 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS  
1. 
PROTOCOL SYNOPSIS 
 
 
 
 
 
 
 
9 
2. 
INTRODUCTION AND BACKGROUND  
 
 
 
 
12 
3.  
ABOUT THE GENOMIC HEALTH LIQUID BIOPSY MUTATION PANEL 
14 
4. 
STUDY DESIGN 
 
 
 
 
 
 
 
 
15 
 
4.1  
Required Procedures at clinical sites  
 
 
 
 
17 
 
4.2 
Processing of samples and analysis  
 
 
 
 
18 
5. 
STUDY POPULATION 
 
 
 
 
 
 
 
19 
5.1 
Inclusion Criteria  
 
 
 
 
 
 
 
19 
5.2 
Exclusion Criteria 
 
 
 
 
 
 
 
19 
5.3 
Study duration and withdrawal 
 
 
 
 
 
20 
6. 
STUDY OBJECTIVES 
 
 
 
 
 
 
 
20 
6.1 
Primary Objective 
 
 
 
 
 
 
 
20 
6.2 
Secondary Objectives  
 
 
 
 
 
 
20 
6.3 
Exploratory Objective 
 
 
 
 
 
 
21 
6.4 
Measures to Minimize Bias  
 
 
 
 
 
21 
7. 
STUDY PROCEDURES 
 
 
 
 
 
 
 
21 
7.1 
Subject screening 
 
 
 
 
 
 
 
21 
7.2 
Obtaining informed consent  
 
 
 
 
 
21 
7.3 
Clinical Assessment and Data Capture 
 
 
 
 
22 
7.4 
Collection, Shipment and Processing of Blood Samples 
 
 
23 
7.5 
Collection, and Processing of Pathology Samples 
 
 
 
24 
8.  
STATISTICAL METHODS  
 
 
 
 
 
 
25 
8.1 
General methods 
 
 
 
 
 
 
 
25 
8.2 
Analysis populations  
 
 
 
 
 
 
25 
8.3 
Primary analysis 
 
 
 
 
 
 
 
26 
 
8.4 
Secondary analysis 
 
 
 
 
 
 
 
27 
 
8.5  
Exploratory analysis  
 
 
 
 
 
 
28 
 
8.6 
Interim analysis 
 
 
 
 
 
 
 
29 
 
8.7 
Sample size 
 
 
 
 
 
 
 
 
29 
9. 
DATA MANAGEMENT 
 
 
 
 
 
 
 
31 
10.  
ADVERSE EVENT REPORTING  
 
 
 
 
 
32 
11. 
RISK VERSUS BENEFIT ANALYSIS 
 
 
 
 
 
32 
 
11.1 
Risk analysis  
 
 
 
 
 
 
 
32 
 
11.2 
Risk Management 
 
 
 
 
 
 
 
32 
 
11.3 
Study benefits  
 
 
 
 
 
 
 
33 
12.  
ETHICAL AND REGULATORY CONSIDERATIONS 
 
 
 
33 
 
12.1 
Study conduct  
 
 
 
 
 
 
 
33 
 
12.2 
Subject Confidentiality 
 
 
 
 
 
 
33 
 
12.3 
Institutional Review Board / Independent Ethics Committee 
 
34 
 
12.4 
Site Monitoring, Audits, Reviews, and Inspections  
 
 
34 

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12.5 
Financial Disclosure  
 
 
 
 
 
 
36 
13. 
MODIFICATIONS TO THE PROTOCOL  
 
 
 
 
36 
14.  
STUDY DOCUMENTS ACCESS AND AVAILABILITY  
 
 
36 
14.1 
Recordkeeping and Retention  
 
 
 
 
 
36 
14.2 
Inspection of Records  
 
 
 
 
 
 
37 
15. 
PUBLICATION 
 
 
 
 
 
 
 
 
37 
16.  
APPENDICES: Study requirements for different patient categories  
 
38 
17. 
REFERENCES 
 
 
 
 
 
 
 
 
40 
 
 

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1. PROTOCOL SYNOPSIS 
 
Protocol Title 
A Study to Determine the Concordance of Key Actionable 
Genomic Alterations as Assessed in Tumor Tissue and Plasma 
from patients with non small cell lung carcinoma (NSCLC) 
Protocol Number 
DSP-DE-MS-14-009 
Investigational Product and 
Intended Use Statement 
The Genomic Health Next Generation Sequencing Liquid 
Biopsy Mutation Panel (LBMP) is currently classified as a 
Laboratory Developed Test (LDT) System. Genomic Health 
LBMP has been developed to detect clinically relevant genomic 
alterations in blood (plasma). The present study aims to 
characterize the concordance of key actionable alterations in 
patients with stage IV NSCLC. This clinical concordance study 
is designed to yield results that support clinical use of the 
LBMP.  
Study Objectives 
Primary Objective 
Assess concordance of genomic alterations of clinical relevance 
in EGFR detected in plasma versus tumor tissue in patients with 
stage IV non squamous NSCLC who are newly diagnosed or 
progressing on treatment. 
Secondary Objectives 
1. Assess concordance of genomic alterations in ALK 
(EML4-ALK fusions) detected in plasma versus tumor 
tissue. 
2. Assess concordance of all detected alterations in plasma 
versus tumor tissue  
3. Assess concordance of mutation-specific NCCN 
guideline-based clinical actions based on alterations 
found in plasma versus tumor tissue and versus 
treatment received based on findings in tumor tissue.  
4. Assess concordance of detected genomic alterations 
separately in patients with newly diagnosed metastatic 
disease and patients progressing on treatment 
5. Summarize the overall distribution of genomic 
alterations present in plasma, tumor tissue or both  
6. Characterize the detection of EGFR T790M alterations 
in plasma in patients progressing on EGFR targeting 
therapy (erlotinib, gefitinib, afatinib). 

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Exploratory Objectives 
Explore the association of genomic alterations detected 
in plasma or tumor tissue and time to progression and 
response to therapy initiated after the liquid biopsy test 
Study Design and Study 
Population 
This is a prospective clinical study to characterize the 
concordance of key clinically relevant genomic alterations in 
tumor tissue and liquid biopsy (blood) using the Genomic 
Health LBMP in patients with stage IV non squamous NSCLC 
that are either newly diagnosed with metastatic disease or 
progressing on therapy (any line). Tissue biopsy of a metastatic 
lesion or primary lesion with stage IV presentation at diagnosis 
and blood collection (liquid biopsy) should be less than eight 
weeks apart and with no new systemic antitumoral treatment 
given in the interval between the tissue and liquid biopsies. 
Tumor tissue material will be assessed at each participating 
institution as per their clinical standard of care practices. 
For patients progressing on EGFR targeted therapy (erlotinib, 
gefitinib, afatinib), liquid biopsy will be collected to assess 
detection of T790M alterations in this population. Participation 
in the study does not alter clinical care. The only procedure 
required by the Protocol is collection of a research blood sample 
by peripheral venipuncture. All other clinical procedures 
performed and collection of non-study data will be in 
accordance with each participating institution’s standard of 
care.  
Sample Size 
The study will enroll approximately 310 patients with stage IV 
non squamous NSCLC including: 
• approximately 260 patients with plasma and tissue 
samples will be enrolled. Initially, approximately 200 
patients will be enrolled (First Enrollment Phase) 
regardless of genomic alteration status in tumor tissue. 
In order to enroll approximately 69 patients with 
alterations in EGFR and approximately 31 patients with 
alterations in ALK (EML4-ALK fusions) this First 
Enrollment Phase will be followed by enrollment of 
patients with genomic alterations in EGFR and ALK 
(Second Enrollment Phase) as described in Table 2. 
• approximately 50 patients with plasma samples 
(concurrent tumor tissue biopsy not mandatory) who are 
progressing on EGFR targeted therapy (erlotinib, 

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gefitinib, afatinib) will be enrolled across the enrollment 
phases. 
The sample size considerations are based on the probability of 
observing PPA/NPA estimates in the desired range as well as 
the size of the confidence intervals around these estimates. The 
results of the central tissue assessments will be used in analysis 
where available. In patients without central CLIA laboratory 
results, local assessments of genomic alterations in tissue will 
be utilized. We anticipate that ~20% of samples may be 
excluded from analysis due to insufficient DNA yield and/or 
pre-specified QC criteria.  
Clinical Sites 
 
Approximately 25 USA and International centers including 
centers in France, Germany, Ireland, Spain, United Kingdom, 
Japan, Chile and Mexico.  
Inclusion/Exclusion Criteria 
Initially, approximately 200 patients will be enrolled regardless 
of genomic alteration status in tumor tissue (First Enrollment 
Phase). This will be followed by a Second Enrollment Phase 
including approximately 39 patients with clinically relevant 
alterations in EGFR and approximately 21 patients with 
alterations in ALK (EML4-ALK fusions) (as assessed in tumor 
tissue. In addition, approximately 50 patients progressing on 
erlotinib, gefitinib, or afatinib will be included across the 
enrollment phases (see Section 4, Figure 1). 
Inclusion Criteria (all of the below) 
• 
Patients must be 18 years or older. 
• 
Patients with stage IV non squamous NSCLC who are 
either newly diagnosed or progressing on any treatment 
(progression defined as increasing tumor size or new 
metastatic lesions on clinical or imaging assessment). 
Patients with available tissue sample from a metastatic site 
or, if the patient presents with stage IV disease at 
diagnosis, from the primary tumor or a metastatic site. If a 
patient is progressing on EGFR targeted therapy 
(erlotinib, gefitinib, afatinib), tumor tissue sample is 
required only if available. 
• 
No new systemic anti-tumor therapy administered in the 
interval between the tissue biopsy and collection of the 
blood sample (interval not to exceed eight weeks). Local 
radiation therapy is permitted. 

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• 
Able and willing to read, understand and sign an informed 
consent and Health Insurance Portability and 
Accountability Act (HIPAA) authorization where this is 
applicable, or equivalent in other geographies as required. 
Exclusion Criteria: 
• 
Patients who are currently receiving therapy (targeted, 
immune therapy or chemotherapy) without sign of 
progression. 
• 
Patients with squamous NSCLC. 
• 
Patients with more than 8 weeks between collection of 
tumor specimen and collection of blood sample for 
analysis. (Not applicable for patients progressing on 
EGFR targeted therapy with no biopsy at progression) 
• 
Patients changing EGFR therapy due to toxicity or 
preference without documented disease progression.  
• 
Patients progressing on Osimertinib. 
• 
Patients with brain metastases only. 
• 
Patients who are unable to comply with study and/or 
follow-up procedures. 
• 
Patients who are unable or unwilling to provide written 
informed consent. 
Risk versus Benefit 
Analysis 
Participants will undergo a single venous blood draw and they 
will not receive any diagnostic information or treatment 
recommendations based on the Genomic Health liquid biopsy 
mutation panel. Therefore, the risks and discomforts in this 
study are those associated with a single venous blood draw. 
These risks include temporary discomfort, bruising, 
lightheadedness, and in rare occasions infection or fainting.  
If successful, results of this study may benefit future cancer 
patients by providing a method to assess genomic alteration 
status with less discomfort and risk than a tissue biopsy 
procedure. A liquid biopsy may also overcome heterogeneity 
issues associated with single biopsies of tumors. 
 
 
2. INTRODUCTION AND BACKGROUND 
 
Molecular understanding of cancer has enabled personalized treatment of patients with 
agents targeting cancer specific alterations. For example, in non small cell lung cancer 
(NSCLC), agents are currently approved for patients with sensitizing EGFR mutations (i.e., 
erlotinib1, afatinib2, gefitinib3) and ALK gene rearrangements (crizotinib4, ceritinib5, 

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alectinib6 [Japan]) and the recent approval of osimertinib7 with efficacy in EGFR T790M 
tumors is evidence of the rapidly increasing understanding of the importance of assessing and 
targeting emerging mutations associated with sensitivity or resistance. In addition, the 
assessment of alterations associated with agents currently in clinical trials that have 
demonstrated efficacy is important: EGFR T790M (rociletinib8), ROS1 re-arrangements 
(crizotinib9), MET amplification (crizotinib10), ERBB2 mutations (trastuzumab11, afatinib12) 
and RET re-arrangements (cabozantinib13). There are also genomic alterations associated 
with either sensitivity or resistance to approved targeted therapies in other solid tumor types: 
BRAF V600 mutations in melanoma (vemurafenib14,15, dabrafenib/trametenib16), KRAS 
mutations in colon cancer (cetuximab17, panitumumab18) and KIT (imatinib19, sunitinib20) and 
PDGFRA (imatinib, sunitinib20) in Gastrointestinal Stromal Tumors. 
 
To optimize selection of therapy, a clinical need to assess the genomic alterations of a 
patient’s disease not just at diagnosis but at various times over the course of their metastatic 
disease is leading to repeated tissue sampling becoming a part of the standard of care. 
Performing biopsies in the metastatic setting is sometimes challenging due to the location of 
the lesions with risk of procedure related complications such as infection, bleeding and 
perforation. Even in patients where it is possible to perform biopsy and/or cytology, the 
amount of material obtained is in some situations scarce and the procedure is not without risk 
and discomfort for the patient. The representativeness of a biopsy from a single metastatic 
site is also being questioned due to an increasing body of evidence indicating that substantial 
tumor heterogeneity exists21,22. Thus, alternative, less invasive methods to assess the genomic 
alterations of patient’s tumors are warranted. 
 
It has been demonstrated that circulating cell-free DNA from blood can be used to detect 
tumor-specific genomic alterations in the metastatic setting in various tumor types and that 
current sequencing technologies allow for rapid identification of a large number of genomic 
alterations from a modest volume of blood23-5. In addition to causing less discomfort for the 
patient, assessing the genomic alterations in blood likely reflects the mutational landscape of 
metastatic lesions at different sites and may overcome molecular heterogeneity between 
various tumor sites and regions. Recent data also indicate that liquid biopsy may be useful for 
monitoring the development of alterations associated with acquired resistance26, 27.  
 
Genomic Health is developing a next generation sequencing LBMP that assesses genomic 
alterations in plasma including both established alterations where the benefit of treatment 
with a targeted agent is supported by level I evidence (if present in the tumor). In addition, 
the LBMP will assess genes that are targets of therapies in late stage clinical trials and 
genomic alterations that may be relevant for treatment selection but which are supported by 
only preliminary or preclinical evidence so far.  
 
The reported concordance for assessing genomic alterations in blood versus tumor tissue 
varies relatively widely due to multiple factors such as methods used, varying tumor burden 

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(with lower sensitivity in patients with lower tumor burden and earlier stages of disease) and 
coverage of the regions of interest. It is of clinical importance to characterize the 
performance of the Genomic Health LBMP in the intended use population by assessing the 
concordance of key actionable genomic alterations detected in plasma with those found in 
tissue, the current standard of care (biopsy/cytology/excision).  
 
This study focuses on assessing the concordance between LBMP and tissue biopsy in 
patients with non squamous NSCLC where the clinical utility of a liquid biopsy based 
mutation assessment is the highest. In NSCLC, many patients are difficult to biopsy and/or 
have poor quality tumor material and knowing the status of genomic alterations is necessary 
to select optimal therapy for patients.  
 
The primary objective of this study is to assess concordance for the detection of clinically 
relevant genomic alterations in EGFR, between tumor tissue and blood in patients with stage 
IV non squamous NSCLC. In addition, we will perform descriptive analysis of other 
genomic alterations in tissue and liquid biopsy that may have clinical relevance. An extended 
number of patients with ALK alterations will also be included in order to generate robust 
data for this alteration which is difficult to assess in liquid using other technologies.  
 
 
3. ABOUT THE GENOMIC HEALTH LIQUID MUTATION PANEL 
 
The Genomic Health LBMP is a laboratory developed test that will be performed in a single 
CLIA-certified laboratory at Genomic Health, Inc. The test assesses selected genomic 
alterations in cfDNA in plasma and reports whether an alteration is detected or not.  
 
The Genomic Health liquid biopsy test involves a blood collection (2 tubes X 10 mL blood), 
followed by the isolation of circulating DNA from plasma. Detection of genomic alterations 
will be performed by an NGS approach following operating procedures specified in a 
separate laboratory protocol that will be finalized prior to sample processing. The 
genes/alterations covered in the panel are detailed in Table 1. 
 
 
 
Table 1. Genes/alterations covered by the Genomic Health LBMP. The panel includes 
detection of single nucleotide variants, copy number variation (gain or loss), targeted 
insertion/deletion and targeted translocations. 
 
Gene 
Variant Type(s) Reported 
ALK 
Targeted and De Novo SNVs, Targeted and De Novo SVs 
AR 
Targeted and De Novo SNVs 
BRAF 
Targeted and De Novo SNVs, Targeted and De Novo InDels 

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BRCA1 
Targeted and De Novo SNVs, Targeted and De Novo InDels 
BRCA2 
Targeted and De Novo SNVs, Targeted and De Novo InDels 
EGFR 
Targeted and De Novo SNVs, CNV gains, Targeted and De Novo InDels 
ERBB2 
Targeted and De Novo SNVs, CNV gains, Targeted and De Novo InDels 
ESR1 
Targeted and De Novo SNVs, CNV gains 
KIT 
Targeted and De Novo SNVs, CNV gains, Targeted and De Novo InDels 
KRAS 
Targeted and De Novo SNVs, Targeted and De Novo InDels 
MET 
Targeted and De Novo SNVs, CNV gains, Targeted and De Novo InDels 
NRAS 
Targeted and De Novo SNVs  
PDGFRA 
Targeted and De Novo SNVs, CNV gains, Targeted and De Novo InDels 
PIK3CA 
Targeted and De Novo SNVs, CNV gains, Targeted and De Novo InDels 
PTEN 
Targeted and De Novo InDels 
RET 
Targeted and De Novo SNVs, Targeted and De Novo InDels, Targeted and De Novo SVs 
ROS1 
Targeted and De Novo SNVs, Targeted and De Novo SVs 
 
Prior to initiation of the investigational laboratory test procedure, using the Genomic Health 
LBMP as described in this protocol, the assay will be analytically validated by Genomic 
Health. The analytical validation study will be documented under other protocols, and will be 
conducted in accordance with the requirements of CLIA (Clinical Laboratory Improvement 
Amendments of 1988). 
 
4. STUDY DESIGN 
This is a prospective clinical study to characterize the concordance of key clinically relevant 
genomic alterations in tumor tissue (biopsy/excision/cytology) and liquid biopsy (blood) 
using the Genomic Health LBMP in patients with stage IV non squamous NSCLC, that are 
either newly diagnosed with metastatic disease or progressing on therapy (any line). Tissue 
biopsy and blood collection (liquid biopsy) should be less than eight weeks apart and with no 
new systemic antitumoral treatment given in the interval between the tissue biopsy and blood 
collection. Local assessment of tumor tissue samples will be performed at each participating 
institution as per their clinical standard of care practices and results from the local assessment 
of genomic alteration status will be used. 
Additionally, detection of EGFR T790M alterations in plasma samples will be characterized 
in patients progressing on EGFR targeted therapy (erlotinib, gefinitib, afatinib). 
 
The study will enroll a total of approximately 310 patients (Figure 1): 
• approximately 260 patients with plasma and tissue samples will be enrolled. Initially, 
approximately 200 patients will be enrolled (First Enrollment Phase) regardless of 
genomic alteration status in tumor tissue. In order to enroll approximately 69 patients 
with alterations in EGFR and 31 patients with alterations in ALK this First Enrollment 

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Phase will be followed by enrollment of patients in a with genomic alterations in EGFR 
and ALK (Second Enrollment Phase) as described in Table 2. Patients in both 
enrollment phases may be either newly diagnosed or progressing on therapy.  
• approximately 50 patients with plasma samples (concurrent tumor tissue sample not 
mandatory) who are progressing on EGFR targeted therapy (erlotinib, gefitinib, 
afatinib) will be enrolled across the enrollment phases. We expect that approximately 
25 of these patients will have T790M alteration. 
 
We anticipate that ~20% of samples may be excluded from analysis due to insufficient DNA 
yield and/or pre-specified QC criteria. 
 
Table 2: Patient enrollment targets for patients with plasma and tissue samples 
 
All 
patients 
Patients 
with EGFR 
alterations* 
Patients 
with ALK 
alterations* 
Patients without 
EGFR or ALK 
alterations* 
First Enrollment Phase: 
Approximate number of 
patients enrolled regardless 
of presence or absence of 
genomic alterations 
200 
30 
10 
160 
Second Enrollment Phase: 
Approximate number of 
patients enrolled based on 
known gene alterations of 
interest 
60 
39 
21 
NA 
Total 
260 
69 
31 
160 
*Expected prevalence: 15% for EGFR alterations, 5% for ALK alterations, 80% without EGFR or ALK as 
these alterations are expected to be mutually exclusive. 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1. Schematic view of the patient categories to be included in the study  
 
 
 
 
 
A 
 
 
 
 
B 
 
 
4.1 Required Procedures at Clinical Sites 
 
Participants who are eligible and consent to participate in the study will provide a 
venous blood sample (2X 10 mL Streck tubes) at a single study related visit. 
Participants will have no further visits as part of this study. Participants data will be 
collected at time of progression or at 12 months after blood sample collection, 
whichever occurs first and in addition, data will be collected to permit outcome analysis 
of the interim analysis.. Participation in the study will not alter clinical care. All other 
clinical procedures performed and collection of non-study data will be in accordance 
with each participating institution’s standard of care. Local assessment of tumor tissue 
samples will be performed at each participating institution as per their clinical standard 
of care practices and results from the local assessment of genomic alteration status will 
be used. Each site will need to provide a single H&E slide to Genomic Health for an 
independent pathology review. 
 
 
 
 
 
 
 
 
 
 
 
~50 patients with progressing on erlotinib, gefitinib, or afatinib 
(Patients included during both enrollment phases) 
~200 patients with non-squamous NSCLC regardless of 
genomic alteration status (newly diagnosed or 
progressing on therapy) 
~21 patients with ALK (EML4-ALK fusions) 
alterations (newly diagnosed or progressing 
on therapy 
~39 patients with EGFR alterations (newly 
diagnosed or progressing on non EGFR 
targeted therapy) 
First Enrollment Phase 
Second Enrollment Phase 

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Table 3. Requirements by patient category to help identify correct patients and required 
materials at the single required patient visit. Detailed overview in Table 6 (page 39). 
 
 
 
 
Requirements 
Patient Category (see Figure 1) 
A:  
Newly diagnosed with 
stage IV disease 
A:  
Patient progressing on 
treatment (except if 
progressing on erlotinib, 
gefitinib, or afatinib) 
B: 
Patient progressing on 
erlotinib, gefitinib, or 
afatinib 
Biopsy/cytology/excision 
performed on primary or 
metastatic lesion 
X 
 
 
Biopsy/cytology/excision 
performed on metastatic lesion 
 
X 
Only if available 
Local pathology report 
X 
X 
X (original diagnosis) 
Local mutation report 
X  
 
X  
 
X (original diagnosis) 
Provide H&E slide from 
biopsy/cytology/excision to 
Genomic Health for independent 
review 
X 
X 
X 
Blood sample (2X 10 mL) 
collected in Streck tubes 
X 
Prior to initiating new 
systemic anti-tumor 
treatment AND no more 
than 8 weeks after tissue 
biopsy 
X 
Prior to initiating new 
systemic anti-tumor 
treatment AND no more 
than 8 weeks after tissue 
biopsy 
X 
Prior to initiating new 
systemic anti-tumor 
treatment AND no more 
than 8 weeks after tissue 
biopsy only in cases where 
a biopsy was performed 
 
4.2 Processing of Samples and Data Management 
 
The Genomic Health staff involved in the processing of liquid biopsy samples will 
remain blinded to the central assessment of FPE tissue, Pathology and Clinical data. 
The laboratory performing central assessment of FPE tissue will be blinded to the 
results of the liquid biopsy. The liquid biopsy, central FPE tissue assessment, Pathology 
and Clinical data will be independently processed and reviewed for quality. Once all 
data QC review and reconciliation are completed and data are locked, Genomic Health 
Data Management will merge the liquid biopsy, FPE tissue assessment, Pathology and 
Clinical data and prepare the SAS analysis dataset, following standard Genomic Health 
procedures. There will be only one, unique Specimen Identifier, and this number will 
not provide Genomic Health staff a direct link to private patient information. The direct 
link to private patient information is maintained and secured by study sites and 
Genomic Health will have no access to this information. 
 
Please see section 8.6 for additional information regarding the planned Interim 
Analysis. 

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Sample specimens will not be used to develop genetic lines or nucleic acid banks. 
Archived samples and/or left over specimens may be used for quality control and/or for 
exploratory analysis of test result concordance specific to relevant cancer gene 
alterations that are not currently included in the Genomic Health mutation panel.  
 
5. STUDY POPULATION 
Initially, 200 patients will be enrolled regardless of genomic alteration status in tumor tissue 
(First Enrollment Phase). This will be followed by a Second Enrollment Phase including 
approximately 39 patients with clinically relevant alterations in EGFR and 21 patients with 
alterations in ALK (EML4-ALK fusions) (as assessed in tumor tissue). In addition, 50 
patients progressing on erlotinib, gefitinib, or afatinib will be included across the enrollment 
phases (see Table 2 and Figure 1). 
 
Participants may be included in the study only if they meet all the criteria listed below in 
Section 5.1 and if they are not excluded by any of the criteria listed below in section 5.2. 
5.1 Inclusion Criteria 
5.1.1 Subjects must be 18 years or older. 
5.1.2 Patients with stage IV non squamous NSCLC who are either newly diagnosed 
or progressing on any treatment (progression defined as increasing tumor size 
or new metastatic lesions on clinical or imaging assessment). 
5.1.3 Patients with available tissue sample from a metastatic site or, if the patient 
presents with stage IV disease at diagnosis, from the primary tumor or a 
metastatic site. If a patient is progressing on EGFR targeted therapy (erlotinib, 
gefitinib, afatinib), tumor tissue sample is required only if available. 
5.1.4 No new systemic anti-tumor therapy administered in the interval between the 
tissue biopsy and collection of the blood sample. (interval not to exceed eight 
weeks). Local radiation therapy is permitted. 
5.1.5 Able and willing to read, understand and sign an informed consent and Health 
Insurance Portability and Accountability Act (HIPAA) authorization, or 
equivalent privacy law, where this is applicable. 
5.2 Exclusion Criteria 
5.2.1 Patients who are currently receiving therapy (targeted, immune- or 
chemotherapy) without sign of progression. 
5.2.2 Patients with squamous NSCLC. 
5.2.3 Patients with more than 8 weeks between collection of tumor specimen and 
collection of blood sample for analysis. (Not applicable for patients 
progressing on EGFR targeted therapy with no biopsy at progression) 

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5.2.4 Patients changing EGFR therapy due to toxicity or preference without 
documented disease progression. 
5.2.5 Patients progressing on Osimertinib treatment. 
5.2.6 Patients with brain metastases only. 
5.2.7 Inability to comply with study and/or follow-up procedures.  
5.2.8 Unable or unwilling to provide written informed consent. 
5.3 Study Duration and Withdrawal 
Study participation for subjects ends after the research blood sample is drawn. There is 
no study-related follow-up with the participants but time to progression on therapy 
given after liquid biopsy or disease status at one year after liquid biopsy will be 
captured.  
Subject participation is voluntary and can be discontinued at any time without loss of 
benefits or penalty. Should this occur, the reason for withdrawal must be documented in 
the original source document for the subject and written notification provided to 
Genomic Health. Participants are notified through the informed consent process that 
any de-identified research blood and tissue samples will be destroyed upon their request 
and not used for further analysis. If requested by the Investigator, a participant may be 
asked to discontinue the study if they are unable to meet the protocol defined study 
requirements. 
Subjects that are screened but who are unable to undergo a successful blood draw or do 
not meet the protocol requirements will be considered screen failures. 
 
6. STUDY OBJECTIVES 
6.1 Primary Objective 
Assess concordance of genomic alterations in EGFR (see appendix I) detected in 
plasma versus tumor tissue in stage IV non squamous NSCLC patients who are newly 
diagnosed or progressing on treatment. 
6.2 Secondary Objectives 
6.2.1 Assess concordance of genomic alterations in ALK (EML4-ALK fusions) 
detected in plasma versus tumor tissue. 
6.2.2 Assess concordance of all detected alterations in plasma versus tumor tissue.  

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6.2.3 Assess concordance of mutation-specific NCCN guideline-based clinical 
actions based on alterations found in plasma versus tumor tissue and versus 
treatment received based on findings in tumor tissue.  
6.2.4 Assess concordance of detected genomic alterations separately in patients 
with newly diagnosed metastatic disease and patients progressing on 
treatment. 
6.2.5 Summarize the distribution of genomic alterations present in plasma, tumor 
tissue or both overall. 
6.2.6 Characterize the detection of EGFR T790M alterations in plasma in patients 
progressing on EGFR targeted therapy (erlotinib, gefitinib, afatinib). 
6.3 Exploratory Objectives 
6.3.1 Explore the association of genomic alterations detected in plasma or tumor 
tissue and time to progression, defined as first objective sign of progression by 
clinical examination or imaging, and response to therapy initiated after the 
liquid biopsy test. 
6.4 Measures to Minimize Bias 
Genomic Health staff involved in the processing of liquid biopsy samples will remain 
blinded to the central assessment of FPE tissue, Pathology and Clinical data collected 
during the study. The Genomic Health staff involved in the central assessment of FPE 
tissue will be blinded to the results of the liquid biopsy.  
 
7. STUDY PROCEDURES 
7.1 Subject Screening 
Patients meeting the inclusion and exclusion criteria shall be offered enrollment in the 
study. Upon enrollment, a unique patient study identifier and unique specimen 
identifier(s) (for blood samples and tissue specimens), will be issued to each subject. 
The assigned identification numbers will not provide Genomic Health staff a direct link 
to private patient information. 
7.2 Obtaining Informed Consent 
 
Eligible patients may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/EC approved informed consent. The 
Informed Consent Form will be reviewed and approved by the Sponsor or its designee 
prior to submission to the IRB/EC and initiation of enrollment. All appropriate 

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bills/legislative actions are to be considered and the Informed Consent Form amended, 
as appropriate. For example, the California Experimental Subject's Bill of Rights will 
be placed on the forefront of the Informed Consent Form for sites in California. The 
Informed Consent Form will be administered by the investigator or research staff 
authorized by the investigator using the most recent version of the informed consent 
document containing the IRB/EC stamp with dates of approval and or expiration (as 
required by applicable regulations and IRB/EC standard procedures). All research staff 
administering informed consent will be trained on Human Participant Protection prior 
to administering informed consent. Prior to participation in the study, the written 
Informed Consent Form will be signed and personally dated by the participant, and by 
the person who conducted the Informed Consent Form discussion. In order to ensure 
compliance with the HHS HIPAA Administrative Simplification Regulations, 
participants will be asked to sign a HIPAA authorization form or equivalent privacy 
law dictated authorization, where this is applicable. The signed HIPAA authorization 
forms, or equivalent, will allow researchers to use the participants' Protected Health 
Information in the research study. 
7.3 Clinical Assessment and Data Capture 
Demographic and clinical data on each participant will be collected at the enrollment 
visit. All clinical and demographic variables will be obtained from the clinical sites 
through a validated electronic data capture (EDC) system. The demographic variables 
will include age and gender. The clinical variables will include diagnosis, stage, 
histology of the tumor, marker status of primary tumor/metastatic site if available, 
site(s) of metastatic disease and treatment (prior targeted therapy, last therapy given 
prior to study enrollment and therapy after liquid biopsy). Additionally, dates of 
diagnosis, surgery, treatment, metastatic tissue biopsy, liquid biopsy, and of 
documented disease progression (defined as first objective evidence of progression 
(increasing tumor size or new lesions) by clinical examination or imaging) after liquid 
biopsy will be collected, when applicable. The clinical site will provide follow up 
clinical information including treatment given after liquid biopsy, best response to this 
treatment (complete response, partial response, stable disease or progressive disease) 
and date of progression or, at 12 months after liquid biopsy, if still on treatment without 
progression at that time. Follow up should also be completed upon patient death should 
that occur prior to first progression or 12 months after liquid biopsy. Genomic Health or 
its designee will provide the clinical sites with access to a validated EDC system for 
electronic case report form (eCRF) documentation. The eCRFs will be completed for 
each study participant through chart abstraction. It is the investigator's responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the 
participant's eCRF. Source documentation and/or objective evidence supporting the 
eCRF data should indicate the participant's inclusion in the study and should document 
the dates and details of study procedures, adverse events, and participant status. The 

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investigator, or designated representative, should complete the relevant eCRF pages as 
soon as possible after information is collected, preferably on the same day that a study 
participant is seen for enrollment and blood draw. Any outstanding entries must be 
completed during data monitoring. An explanation should be given for all missing data. 
Individual subject files should be maintained in addition to the eCRFs. These files 
constitute "source data" and must be signed and dated by the study site research 
personnel who recorded the data (electronic signatures are acceptable for electronic 
medical records). All entries in the eCRFs must be supported by source data. The 
eCRFs must be kept up-to-date so that they reflect the latest observations on the 
subjects enrolled in the study. Each subject's file must include the original signed and 
dated Informed Consent Form and all specimen collection and shipping information. 
This study will be registered with and posted on ClinicalTrials.gov 
(www.clinicaltrials.gov). 
7.4 Collection, Shipment and Processing of Blood Samples 
 
A total of 20 mL of venous blood will be collected in two Streck tubes (10 mL each) 
and shipped to Genomic Health the same day of collection. Blood collection should 
coincide, when possible, with routine clinical blood draws to minimize discomfort. A 
Liquid Collection Form (LCF) will be filled out, one per participant’s blood collection, 
with the following information: 
• Subject ID – unique identifier assigned to each subject, to remain the same 
number throughout all study collection events. This number will be linked to the 
clinical data.  
• Collection Date and Time and additional administrative variables. 
• All samples are to be shipped to Genomic Health on the day of collection via the 
courier specified for that site. Collections on Fridays may be sent out same day 
for delivery to Genomic Health on the following Monday, unless otherwise 
instructed by Genomic Health or its designee. 
Genomic Health will perform blood pre-processing (plasma extraction) on the day of 
sample arrival. The blood samples received at Genomic Health will be handled and 
processed according to the liquid biopsy Specimen Preparation Instruction (SPI) 
manual and other Genomic Health related procedures. Genomic Health will notify the 
study site of all the samples received and their status as acceptable or rejected for 
further testing (i.e., quality or labeling issues) using the assigned de-identified study 
subject identifier. If the sample rejected or fails quality control metrics a second blood 
draw may be requested. 

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Any samples or remnant specimens (from blood) remaining after the conclusion of the 
study may be banked for future research. Future use will be explained in the ICF where 
the subject may elect to not approve banking their left over samples. All remaining 
samples or specimens will be de-identified and stored in an appropriate storage 
environment at Genomic Health. De-identified data associated with the banked left over 
samples will be stored in a secure Genomic Health database and will not be traceable to 
any identifiable protected health information. 
7.5 Collection, and Processing of Pathology Samples  
 
Enrolled subjects will have previously collected pathology tissue samples that will be 
utilized for the tissue-based sequencing if sufficient tumor material for analysis is 
available (as defined in section 4.1) and if patient approves of sending the material for 
analysis.  
 
Local assessment of tumor tissue samples will be performed at each participating 
institution as per their clinical standard of care practices and results from the local 
assessment of genomic alteration status will be used. Each site will need to provide a 
single H&E slide to Genomic Health for an independent pathology review. 
Genomic Health will receive and inspect the H&E slides according to approved internal 
receiving protocols. The received samples will be accessioned and quality inspected. 
Genomic Health standard histopathology assessments will be made from the single 
H&E slide of each FPE tumor tissue specimen by a Genomic Health designated 
pathologist(s) and will include: presence of tumor (adequate quantity).  
Additional pathology measures will be obtained from the tissue biopsy pathology and 
mutation reports and entered into the electronic data capture system by the clinical site 
personnel. 
Any residual DNA remaining after the conclusion of the study may be banked for 
future research. Tissue blocks or slides not used for analysis will be returned to the 
ordering physician but residual DNA will be stored by GHI. Future use will be 
explained in the ICF where the subject may elect to not approve banking their left over 
samples. All remaining samples or specimens will be de-identified and stored in an 
appropriate storage environment at Genomic Health. De-identified data associated with 
the banked left over samples will be stored in a secure Genomic Health database and 
will not be traceable to any identifiable protected health information. 
 
 

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8. STATISTICAL METHODS  
8.1 General Methods 
 
This section provides a general description of the statistical analysis methods. A 
detailed description of the analysis methods will be provided in the Statistical Analysis 
Plan, that will be developed blinded to any analytical test results (i.e. from the liquid 
biopsy tests and tumor tissue assessments) and finalized prior to the data lock for the 
interim analysis. 
 
This is a descriptive study to characterize the concordance between the results of the 
Genomic Health LBMP based on plasma and genomic assessment of the tumor tissue. 
Both the liquid biopsy and the tumor tissue assessments will report the status of the 
investigated alterations in a binary manner as detected or not detected. No formal 
hypothesis testing is planned. Unless otherwise stated, two-sided 95% Clopper-Pearson 
confidence intervals will be reported28. 
 
The analysis of a single tumor biopsy cannot yield a reference standard for a liquid 
biopsy assessment due to tumor multifocality and intra- and inter-tumor heterogeneity 
in stage IV disease. As described in the FDA Statistical Guidance on Reporting Results 
from Studies Evaluating Diagnostic Tests (2007), when a new test is evaluated by 
comparison to a non-reference standard, it is not possible to directly calculate unbiased 
estimates of sensitivity and specificity. Therefore, due to lack of reference standard for 
analysis of liquid biopsies, it would not be appropriate to describe the comparative 
results of the study in terms of sensitivity and specificity. Instead, we will characterize 
the concordance in terms of positive percent agreement (PPA) and negative percent 
agreement (NPA) as presented in section 8.3, Table 4.  
8.2 Analysis Populations 
 
Statistical analyses will involve samples from patients with stage IV non squamous 
NSCLC. Samples that are not collected according to the sample preparation 
instructions, fail pathology review, fail to meet pre-specified analytical quality control 
metrics as defined by the Genomic Health LBMP’s standard operating procedures, or 
fail to meet pre-specified quality control specification for the FPE assessment will be 
considered non-evaluable and will not be included in the analyses described in this 
section. Approximately 20% of enrolled patients are expected to have non-evaluable 
samples and thus results from approximately 248 evaluable patients are expected to be 
included in the analyses.  
 

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The primary analysis will be based on patients with non squamous NSCLC with 
evaluable plasma and tissue samples and reportable results from both the Genomic 
Health liquid biopsy test and tumor tissue assessments. The results of the central tissue 
assessments will be used when available. In patients without central CLIA laboratory 
results, local assessments of genomic alterations in tissue will be utilized. Exploratory 
analyses will include patients with evaluable samples from the Genomic Health liquid 
biopsy test and time to progression and available assessment of best response to therapy 
initiated after the liquid biopsy test. 
8.3 Primary Analysis  
The primary analysis will characterize the concordance of clinically relevant EGFR 
alterations (see appendix I) detected in plasma versus tumor tissue for patients with 
stage IV non squamous NSCLC. PPA, NPA and overall concordance will be calculated 
across all EGFR alterations, for all sensitizing alterations and for each individual 
alteration, separately. 
 
Two tables (Tables 4A and 4B) will be constructed and PPA, NPA, overall agreement 
and corresponding confidence intervals will be calculated as shown below. Of note, the 
NPA will be calculated based only on patients enrolled regardless of presence or 
absence of the genomic alterations (Section 4, Table 2). Patients enrolled after this 
initial period due to presence of ALK alteration in tissue will not be included in this 
analysis as they are unlikely to have EGFR mutations and their inclusion could result in 
overestimation of NPA.  
 
Table 4. Calculation of PPA and NPA. 
 
4A: Table based on all patients with available tissue biopsy with EGFR alterations 
detected in tumor tissue 
 
 
 
Genomic Health 
liquid biopsy 
mutation panel  
EGFR alteration 
detected in tumor 
tissue 
EGFR alteration 
detected 
a 
EGFR alteration not 
detected 
c 
Total 
a+c 
 
Positive Percent Agreement (PPA) = a / (a+c) * 100% 
 
 

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4B. Table based on all patients with available tissue biopsy enrolled regardless of 
presence or absence of genomic alterations as described in Section 4 and Table 2. 
 
Genomic Health 
liquid biopsy 
mutation panel  
EGFR alteration 
not detected in 
tumor tissue 
EGFR alteration 
detected 
b 
EGFR alteration not 
detected 
d 
Total 
b+d 
 
Negative Percent Agreement (NPA) = d / (b+d) * 100% 
 
 
If all patients were enrolled regardless of alteration status, the overall agreement would 
be calculated as (a+d)/(a+b+c+d) * 100%. However, since some patients are enrolled 
based on known alteration status, the overall agreement will be calculated as a weighted 
proportion to account for enrichment of the number of patients with marker positive 
tumors. Details of the calculations will be provided in the Statistical Analysis Plan.  
 
8.4 Secondary Analyses 
 
Secondary analyses will include assessments of PPA, NPA and overall agreement 
calculated as described in section 8.3 for ALK alterations (objective 6.2.1) and all other 
detected alterations (objective 6.2.2).  
 
In addition, we will report: 
1) the total number of all alterations detected in plasma, tumor tissue, or both. 
2) the number of patients with at least one alteration with clinical relevance detected 
in plasma, tumor tissue, or both. 
3) the number of hotspot mutations and non-hotspot mutations detected in plasma, 
tumor tissue, or both. 
 
The results will be presented separately for single nucleotide variant (SNV), copy 
number variant (CNV) and structural variant (indels, insertions, translocations) 
alterations. 
 
As described in study objective 6.2.3, mutation-specific NCCN-guideline based clinical 
actions based on alteration status in plasma will be compared to those based on tissue 

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and the actual treatment received based on findings in tumor tissue. For each patient, a 
clinical action will be defined in agreement with NCCN guidelines based on detected 
key genomic alterations and prior targeted therapies to mimic the clinical context for 
decision making. A detailed description of each clinical action will be provided in the 
Statistical Analysis Plan. To assess concordance of clinical actions based on alterations 
identified in plasma vs those based on tissue as well as concordance of clinical actions 
based on alterations identified in plasma and the actual treatment received based on 
tumor tissue findings, PPA, NPA and overall agreement will be calculated.  
 
We will assess PPA, NPA and overall agreement separately for patients with newly 
diagnosed metastatic disease and patients who progressed on treatment (study objective 
6.2.4).  
 
The concordance analyses will also be conducted in the subset of patients with 
available central CLIA laboratory assessment of tumor tissue. 
 
In addition, we will summarize the distribution of all genomic alterations detected in 
plasma, tumor tissue, or both using tabulations, histograms and descriptive statistics 
(study objective 6.2.5). We will provide such summaries for individual alterations, 
sensitizing vs resistance alterations within a gene (if applicable), all alterations within a 
given gene and across all genes.  
The detection of EGFR T790M alterations in plasma samples will be characterized 
descriptively in patients progressing on EGFR targeted therapy (erlotinib, gefitinib, 
afatinib) (study objective 6.2.6). 
8.5 Exploratory Analyses 
 
We will examine the association between the presence of alterations in plasma or tissue 
and endpoints such as time to progression and response to first therapy initiated after 
liquid biopsy.  
 
Time to progression is defined as time from first initiated therapy (after liquid biopsy) 
to progression as documented by imaging or clinical evaluation. Progression identified 
at the time of death will be considered an event. Patients still on therapy one year after 
the liquid biopsy assessment will be censored. We will use Cox proportional hazards 
regression models and Kaplan-Meier analyses and will consider non-linear techniques, 
including smoothing splines. Subset analyses based on alteration status in tissue and 
plasma may be conducted.  
 

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Response is defined as best response to therapy initiated after liquid biopsy (complete 
response, partial response, stable disease or progressive disease). We will use logistic 
regression models and will consider non-linear techniques, including smoothing 
splines.  
8.6 Interim Analysis 
 
An interim analysis will be performed when approximately 30 patients with EGFR 
mutations in tissue samples are enrolled. Should the laboratory not have finalized 
analytical validation at that time, enrollment will continue until analytical validation 
has been performed. The interim analysis will support the documentation of 
performance of the Genomic Health liquid biopsy test and may be used for submission 
of an abstract to a scientific conference. The results of this interim analysis will not be 
used to modify the design or conduct of this study, including the associated Laboratory 
Protocol and Statistical Analysis Plan. In particular, the sample sizes specified in 
section 4 will not be modified based on the results of this interim analysis.  
8.7 Sample Size 
 
The sample size considerations for this study were based on the probability of 
observing PPA/NPA estimates in the anticipated range as well as the size of the 
confidence intervals around these estimates. To account for possible losses (~20%), 
approximately 260 patients with plasma and tissue samples will be enrolled to obtain 
approximately 208 patients with evaluable samples for concordance analyses and 50 
patients with plasma samples only will be enrolled to obtain 40 evaluable patients to 
characterize the detection of EGFR T790M alterations in plasma. It is expected that the 
majority of patients with plasma and tissue samples will be newly diagnosed with stage 
IV non squamous NSCLC since metastatic lesions are not frequently biopsied.  
 
In patients with plasma and tissue samples, two EGFR alterations, L858R and exon 19 
deletion, are expected to be observed most often: each with ~45% prevalence in 
patients with EGFR-mutant tumors 29. The alteration-specific analyses for these 
alterations are expected to include ~25 evaluable patients each leading to a total of 50 
patients with activating EGFR alterations. T790M resistance alteration has a low 
prevalence in untreated NSCLC30 and hence is expected to be observed relatively 
rarely.  
 
Figure 2 displays the 20th (blue) and the 30th (green) percentiles of the distribution of 
positive percent agreement as a function of the sample size using a binomial 
distribution and assuming a true PPA of 80%. Based on these results, a study with 25 
patients with a known alteration will have a 70% probability to observe a PPA estimate 

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≥75%. A study with 50 patients with a known alteration will have an 80% probability 
to observe a PPA estimate ≥75%. 
 
Similar calculations for the true PPA of 90% indicate that a study with 25 marker 
positive patients will have a 75% probability to observe a PPA estimate ≥85% (not 
shown in figure below). A study with 50 patients with a known alteration will have an 
85% probability to observe a PPA estimate ≥85%. 
 
 
Figure 2. Percentiles of the PPA estimate as a function of sample size 
assuming true PPA of 80%* 
 
  
 
* Moving average smoother was applied to the estimates based on binomial distribution. 
Legend: blue line represents 20% percentile and green line – 30% percentile of PPA estimates. 
 
 
If a PPA of 80% is observed in 50 patients with a known alteration, the 95% exact Clopper-
Pearson confidence interval will have a lower bound of 0.66 (Table 5). Similar logic applies 
to the NPA estimates. These calculations were obtained using PASS version 13. 
 
 
 
65%
66%
67%
68%
69%
70%
71%
72%
73%
74%
75%
76%
77%
78%
79%
80%
20
30
40
50
60
70
80
90
Positive Percent Agreement 
Patients with mutations by comparator method

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Table 5. Lower bound of the 95% Clopper-Pearson confidence interval as a function of 
observed PPA estimate and sample size. 
 
Observed 
PPA 
Number of patients with detected alterations in tissue 
20 
30 
40 
50 
60 
0.90 
0.68 
0.74 
0.76 
0.78 
0.80 
0.85 
0.62 
0.67 
0.70 
0.72 
0.73 
0.80 
0.56 
0.61 
0.64 
0.66 
0.68 
0.75 
0.51 
0.56 
0.59 
0.61 
0.62 
 
 
In patients with plasma samples only who are progressing on EGFR targeted therapy 
(erlotinib, gefitinib, afatinib where tissue sample is not mandatory) approximately 50% of 
patients are excepted to have T790M alteration. If the true probability of T790M alteration in 
this population is 0.50, we will have an 85% chance of detecting these alterations in 40% to 
60% of samples from 40 patients progressing on EGFR targeted therapy (erlotinib, gefitinib, 
afatinib). In analysis with 40 patients, the width of the 95% confidence interval around the 
proportion of detected T790M alterations will be 0.32 if alterations are detected in 50% of 
plasma samples.  
 
9. DATA MANAGEMENT 
Subject demographic and clinical data from the eCRFs will be entered into a password 
protected database along with the participant’s unique and protected study subject ID 
number. The password protected database will be maintained by Genomic Health Data 
Management. Results of the Genomic Health liquid biopsy mutation panel and pathology 
review will be collected and entered into the password protected Genomic Health database.  
An independent password protected and validated database will be maintained by the clinical 
site that includes the subject ID number and results of the pathology report and NGS tissue 
mutation panel from the independent CLIA laboratory. 
A database containing the data collected on the Liquid Collection Form (LCF) will be 
maintained by Genomic Health BioMaterial Repository (BMR) via accessioning of the 
received blood samples. This data is associated with the handling and processing of the 
subject’s samples and accompanies all samples that are shipped to Genomic Health for 
processing and testing.  
All databases will be kept separate, and subject samples will be identified only by subject ID 
number. Databases will be merged only for the planned interim analysis and at the 
completion of the study.  

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10. ADVERSE EVENT REPORTING 
The investigator, clinical research staff, or a trained phlebotomist will monitor for the 
occurrence of adverse events for each subject at the time of the study venous blood draw. 
Adverse events related to the blood draw in subjects will be listed on the AE Form in the 
EDC. Only events that are clearly attributable to the study blood draw will be considered a 
study related adverse event and will be reported. Determination should be based on 
assessment of temporal relationships, biologic plausibility association or lack thereof with 
other procedures done as standard of care and presence (or adherence) of a more likely cause. 
All adverse events that occur during the biopsy/resection, clinical therapy, or other invasive 
diagnostic or treatment procedures, as a result of standard clinical care, and/or distant in time 
from the study phlebotomy will not be monitored and are not considered a study related 
adverse event in this study. The investigators will report adverse events to the IRB according 
to the local or central IRB reporting requirements.  
 
11. RISK VERSUS BENEFIT ANALYSIS 
11.1 Risk Analysis 
Subjects participating in the study shall be under minimal risk. The only intervention is 
an additional blood sample that will be de-identified and labeled with a unique study 
identification number. According to 21 CFR Part 812.3(k), blood sampling that 
involves simple venipuncture is considered noninvasive. Patients will not receive any 
diagnostic information or treatment recommendations based on the Genomic Health 
liquid biopsy mutation panel. Therefore, the risks and discomforts in this study are 
those associated with venipuncture a single venous blood draw. These risks include 
temporary discomfort, bruising, lightheadedness, and in rare occasions infection or 
fainting. Blood samples will be analyzed using the Genomic Health liquid biopsy 
mutation panel. If the samples are not exhausted at the end of the this study, the 
samples may be used for quality control purposes and for exploratory analysis of 
concordance of additional cancer relevant genes not included in the current panel with 
the approval of the participant. Test results generated from blood samples collected in 
this study will not be shared with the study participants or their health care providers; 
therefore, will not impact on their clinical care or outcome. 
11.2 Risk Management 
The investigators and designated study site staff will be trained in the conduct of the 
study and patient confidentiality requirements. Only centers with trained phlebotomists 
will participate in the study. Universal precaution will be utilized for handling blood 
samples. There will be quality assurance oversight for determining the proper labeling, 

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identification, shipping/receipt, and processing procedures for handling samples and 
specimens.  
11.3 Study Benefits 
There will be no direct benefits to the subject’s participation in the study. The 
advantages of liquid biopsy over tumor biopsy is that it may offer future patients an 
alternative, less invasive method to assess the genomic alterations of their disease. A 
liquid biopsy may also overcome issues with tumor heterogeneity associated with 
single biopsies of tumor tissue. 
 
12. ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 Study Conduct 
The study will be conducted in accordance with all federal, provincial, state, and local 
laws of pertinent regulatory authorities, and the applicable regulatory requirements. 
The investigator will ensure that this study is conducted in full conformity with the 
Declaration of Helsinki, as applicable, or with the laws and current regulations of the 
country in which the study is conducted, whichever affords the greater protection to the 
participant. The study will be conducted in accordance with all country specific privacy 
rules as applicable. In the US, the study will be conducted in accordance with the HHS 
Administrative Simplification Regulations (45 CFR Parts 160,162, and 164). If the 
study includes sites from the European Union, the study will be conducted in 
accordance with the Data Privacy Directive 95/46/EC. If the study includes sites from 
Canada, the study will be conducted in accordance with the Therapeutic Products 
Directorate. After reading the protocol, each investigator will sign a protocol signature 
page and return the signed page to the Sponsor. 
12.2 Subject Confidentiality 
Information that would allow identification of the individual, as defined by the HIPAA 
protected health information (PHI) identifiers (45 CFR § 160.103), includes but is not 
limited to name, social security number, and any number assigned by the hospital or 
medical office. PHI collection will be limited to data that are necessary for conducting 
the study and associated analyses. Patient-related materials (specimen, pathology 
report) will be identified only by a study-specific unique identifier, and will not be used 
to directly identify the patient. NGS results from a CLIA registered test service 
provider from the assessment of the tumor tissue will be reported to the participant’s 
physician but the results will be provided to Genomic Health using only the study-
specific identifier. It is the responsibility of the study investigators to ensure de-
identification of the specimen and pathology reports. The study investigators are also 

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responsible for maintaining the link between the participant and the study-specific 
subject identifier, and Genomic Health will have no access to this information. 
12.3 Institutional Review Board / Independent Ethics Committee  
The Institutional Review Board / Independent Ethics Committee (IRB/IEC) will review 
all appropriate study documentation in order to safeguard the rights, safety and well-
being of the participants. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, investigational plan, informed consent, 
advertisements (if applicable), written information given to the participants, safety 
updates, annual progress reports, and any revisions to these documents will be provided 
to the IRB/IEC by the investigator and/or sponsor. Prior to the start of the study the 
investigator will provide GHI or its designee with documentation that the IRB/IEC has 
reviewed and approved the protocol and the Informed Consent Form. Additional 
documentation may be submitted pending applicable local requirements. Each 
investigator must provide at least the following documentation: 
• The IRB/IEC approval of the protocol; 
• The IRB/IEC approval of the Informed Consent Form; 
• The IRB/IEC composition (membership list), 
• The IRB/IEC annual (or any other frequency when applicable - i.e. quarterly, 
semiannually according to the local/central EC standard operating procedure); 
• Renewed approval of the protocol; 
• The IRB/IEC approval of any revisions to the Informed Consent Form or 
amendments to the protocol; and 
• The IRB/IEC notification of the study termination. 
12.4 Site Monitoring, Audits, Reviews, and Inspections 
Genomic Health clinical operations or representative staff will monitor the study 
according to the study specific monitoring plan. Personnel selected to perform 
monitoring will be appropriately trained and qualified to perform the required 
monitoring activities. The study monitor will visit all the sites to ensure that site study 
staff have the information they need to conduct the study and that the trial is conducted 
and documented properly through the duration of the study, this includes verifying that: 
- 
The rights and the well-being of the participants are protected. 
- 
The collected data are accurate, complete and verifiable from the source 
documents. 
- 
The conduct of the trial is in compliance with the current approved protocol.  
 
Prior to study initiation, the study monitor ensures that the investigators: 
• Understand the investigational status of the LDT and the requirements for 
accountability of data and specimens; 

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• Understand the study protocol; 
• Understand the requirements for an adequate and well-controlled study; 
• Understand and accepts his or her obligations to obtain informed consent in 
accordance with 21 CFR Part 50; 
• Understand and accepts his or her obligation:  
o to obtain informed consent in accordance with 21 CFR Part 50, GCP and the 
applicable regulatory requirements;  
o to obtain EC review and approval of a clinical investigation before the 
investigation may be initiated; 
o to ensure continuing review of the study by the EC in accordance with 21 
CFR Part 56, GCP and the applicable regulatory requirements; 
o and to keep the sponsor informed of such EC approval and subsequent EC 
actions concerning the study; 
• Has adequate number of qualified staff and facilities for conducting the study; and 
• Has sufficient time from other obligations to carry out the responsibilities to 
which the investigator is committed by applicable regulations. 
 
The study monitor will visit the study site as defined in the monitoring plan to ensure 
that the facilities used by the investigator continue to be acceptable for the purposes of 
the study, has appropriate documentation and supplies (e.g., study protocol, most 
recently IRB/IEC approved Informed Consent Form, Case Report Forms, specimen 
collection kits) on site to conduct the study, monitor the informed consent process, 
adherence to the protocol, and the maintenance of adequate and accurate research 
records. During these visits, Informed Consent Forms and associated source documents 
will be reviewed to ensure that the consent process is appropriately documented and 
that there is an ICF on file for each participant in the study. In addition, electronic Case 
Report Form (eCRF) fields will be verified to ensure that data collected in the eCRF 
(EDC system) is consistent with data in the participants' medical records and other 
primary source documentation (verification of data integrity). The review of the subject 
records will be performed in a manner to ensure that participant confidentiality is 
maintained. Study investigators will be required to address any negative findings and 
submit a written response for corrective measures to be taken to correct and prevent 
future occurrence of any negative findings. 
 
The FDA, IRBs, and/or the Sponsor’s clinical quality assurance team may request an 
on-site inspection or Good Clinical Practice audit. Direct access to original source 
documents will be required for this inspections or audits. The process will be carried 
out giving due consideration to data protection and medical/patient confidentiality. The 
investigator agrees to give the auditor/investigator access to all relevant documents for 
review. 
  

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12.5 Financial Disclosure 
Financial interest of a clinical investigator is one potential source of bias in the outcome 
of a clinical study. To ensure the reliability of the data, the financial interests and 
arrangements of clinical investigators will be disclosed to the IRB/IEC, as required. 
The investigator is required to provide GHI accurate financial disclosure information. 
Financial Disclosure applies to investigators and sub-investigators including their 
spouses and dependent children. 
 
13. MODIFICATIONS TO THE PROTOCOL 
Any modification to the protocol which may impact the conduct of the study, affect subject 
safety or potential benefit of the subjects, including changes of primary study objectives, 
study design, subject population, sample sizes, study procedures or significant administrative 
aspects will require a formal amendment to the protocol. Protocol amendments may be 
initiated by GHI or at the request of an investigator. In either case, research specified in 
protocol amendments must not be initiated before approval by GHI and, if necessary, review 
and approval by the central and local IRB/IEC. A protocol amendment, if significant, may 
also require approval by the FDA and/or Medical Devices Bureau and/or local Regulatory 
Authorities, where applicable. All protocol amendments that require revisions to the informed 
consent form must be submitted to the IRB/IEC for approval prior to implementation. It is not 
expected due to the low-risk nature of the evaluation that emergency protocol deviations or 
modifications will be initiated without GHI and/or IRB/IEC approval. Administrative changes 
and/or clarifications that have no effect on the way the study is to be conducted are minor 
corrections. These administrative changes will be documented in a memorandum. The 
IRB/IEC will be notified of administrative changes at the discretion of Genomic Health. 
 
14. STUDY DOCUMENTS ACCESS AND AVAILABILITY 
The Investigator must ensure the reliability and accuracy of the data provided to Genomic 
Health and maintaining the confidentiality of the documents and tissue samples. The 
Investigator(s)/Institution(s) will permit research-related monitoring audits, IRB/IEC review, 
and regulatory inspections by providing direct access to service data/documents. The 
investigator must ensure the reliability and availability of the objective evidence including all 
source documents. 
14.1 Record keeping and Retention 
The investigator will maintain all study records according to ICH-GCP and applicable 
regulatory and clinical site requirement(s). Records will be retained for at least two 

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years after the last marketing application approval or two years after formal 
discontinuation of the clinical development of the investigational procedure.  
According to applicable regulatory or clinical site requirement(s) if the investigator 
withdraws from the study, the responsibility of keeping the study records, custody, 
must be transferred to a person willing to accept the responsibility. Genomic Health 
must immediately be notified in writing if a custodial change occurs. The records 
include the following: 
• The signed Development Protocol, and amendments; 
• Collection, processing, shipping, and receiving records of all specimens and 
study-related materials; 
• Dated and documented IRB approvals;  
• Signed informed consent; and 
• Financial disclosure. 
14.2 Inspection of Records 
In the event of an audit and for all monitoring visits, the investigator agrees to allow 
representatives of Genomic Health, its representative CRO, and other regulatory 
authorities or government agencies access to all study records.  
 
15. PUBLICATIONS 
All information regarding the procedure conducted by Genomic Health is privileged and 
confidential information. The site investigator agrees to use this information to accomplish 
the study and will not use it for other purposes without consent from Genomic Health. The 
investigators understand that there is an obligation to provide the sponsor with complete data 
obtained during the study. The information obtained from the clinical study may be disclosed 
to regulatory authorities, other investigators, corporate partners, or consultants as required. It 
is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific/medical journal. The publication or citation of study 
results will be managed in accordance with the publication policy of the study agreement. 
 
 
 
 
 
 
 
 
 
 

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16. APPENDICES 
APPENDIX I 
Clinically actionable alterations to be included in the primary analysis: 
Exon 19 deletions, L858R, L861Q, G719X and S768I 
 
APPENDIX II 
Table 6. Requirements for patients included in category A (See Figure 1) 
Patient category: 
Enrollment visit requirements  
Follow up requirements  
Newly diagnosed stage IV patient: 
 
1. 
Patients regardless of 
genomic alteration status in 
tumor (During First 
Enrollment Phase only) 
 
2. 
EGFR alterations in tumor 
 
3. 
ALK alterations in tumor 
-Available tumor tissue sample from primary or 
metastatic lesion. 
 
-Pathology report  
 
-Mutation report 
 
-Clinical data entry in EDC 
 
-Date of progression on first therapy 
initiated after liquid biopsy, one year 
after liquid biopsy if still responding, or 
date of patient death should that occur 
prior to first progression or 1 year after 
liquid biopsy. 
 
-Clinical and selected treatment data 
entry in EDC 
Patient progressing on therapy (except if 
progressing on EGFR inhibitors- see 
below): 
 
 
1. 
Patients regardless of 
genomic alteration status in 
tumor (During First 
Enrollment Phase only) 
 
2. 
EGFR alterations in tumor 
 
3. 
ALK alterations in tumor  
-Available tumor tissue sample from metastatic 
lesion. 
 
-Pathology report 
 
-Mutation report 
 
-Clinical data entry in EDC 
-Date of progression on first therapy 
initiated after liquid biopsy, one year 
after liquid biopsy if still responding, or 
date of patient death should that occur 
prior to first progression or 1 year after 
liquid biopsy. 
 
-Clinical and selected treatment data 
entry in EDC 
 
 
 
 
 
 
 
 

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Requirements for patients included in category B (See Figure 1) 
Patient category: 
Enrollment visit: 
requirements  
Follow up requirements  
Patient progressing on EGFR targeted therapy 
(erlotinib, gefitinib, afatinib).  
 
Note: Patients changing EGFR therapy due to 
toxicity or preference without documented 
disease progression will not be included. 
-Tumor tissue sample (at progression) 
preferable but not mandatory. 
 
-Pathology report from metastatic lesion at 
progression if available and from primary 
tumor if not available 
 
-Mutation report from metastatic lesion at 
progression if available and from primary 
tumor if not available 
 
-Blood sample in Streck tubes (2X 10 mL) 
 
-Date of progression on first therapy 
initiated after liquid biopsy, one year 
after liquid biopsy if still responding, or 
date of patient death should that occur 
prior to first progression or 1 year after 
liquid biopsy. 
 
-Clinical and selected treatment data 
entry in EDC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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