Clinical trial NCT02759835
Conditions: Lung Adenocarcinoma Lung Neoplasms
Keywords: EGFR Tyrosine Kinase Inhibitors T790M Mutation Local Ablative Therapies Oligoprogressive Disease Acquired Resistance
Sponsor: National Cancer Institute (NCI)
Start date: 2016-04-13; Completion date: 2022-09-20
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

Some non-small-cell lung cancers (NSCLC) have a mutation in a gene that makes a protein called EGFR. This particular cancer can be treated with certain drugs such as erlotinib (Tarceva), gefitinib (Iressa) and osimertinib (Tagrisso). But many tumors become resistant to these drugs because of a second mutation. Researchers want to test if adding local ablative therapy (LAT) extends the benefits of the drug, osimertinib. LAT can include techniques such as surgery, radiofrequency ablation, cryotherapy or radiation therapy.

Objective:

To test if re-taking osimertinib after LAT is safe, tolerable, and effective for people whose NSCLC has progressed after initial treatment with osimertinib.

Eligibility:

Adults ages 18 and older with certain types of NSCLC. Participants will be divided into various groups as described below.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Tumor scans

Eye exam

Review of tumor sample.

Participants will take the study drug by mouth once a day. They will continue until they can no longer tolerate it or their disease worsens. They will keep a dosage diary.

All participants will start each 21-day course with physical exam; blood, urine, and saliva tests; and electrocardiogram. They will have scans every 6 weeks and echocardiogram every 3 months.

Groups 1 and 2 will:

Start osimertinib right away.

Have LAT if their disease progresses and is suitable for LAT. If LAT cannot be performed or LAT consists of a procedure other than surgery, a tumor biopsy will be performed.

Re-start osimertinib after LAT, or other treatments if not suitable for LAT.

Group 3 will:

Have LAT.

If LAT consists of a procedure other than surgery, a tumor biopsy will be performed.

Start osimertinib after LAT.

After participants stop taking the drugs, they will have a final visit. This will include:

Medical history

Physical exam

Blood tests

Participants will be called every year for follow-up.

Detailed description:
Background:

* Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have significantly improved the response rate (RR) and survival in patients with tumors harboring EGFR-sensitizing mutations.
* An invariable consequence of treatment with EGFR-TKIs is the development of acquired resistance. The most common mechanism of resistance observed in approximately 50% of all cases in patients treated with 1st and 2nd generation EGFR-TKIs is the emergence of a secondary mutation (T790M) in exon 20.
* Osimertinib is a 3rd-generation EGFR-TKI designed to target the T790M mutation, which has shown impressive responses in both first- and second-line settings.
* Despite these developments, it is almost certain that selection pressure will lead to the emergence of newer clones that are resistant to treatment with osimertinib. One common mechanism of acquired resistance to osimertinib is the generation of EGFR C797S mutation.
* The use of local ablative therapies for patients who develop limited metastatic disease or oligoprogressive disease on EGFR-TKI therapy is promising.
* We hypothesize that following local ablative therapy to treat oligoprogressive disease after emergence of resistance, osimertinib can be resumed safely and re-initiation of osimertinib results in additional progression-free survival benefits.

Objectives:

* Determine the safety, tolerability, and efficacy (as assessed by progression free survival (PFS) upon re-initiation of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive disease after treatment with osimertinib
* Assess mechanisms of acquired resistance to osimertinib

Eligibility:

* Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). If biopsy for EGFR mutation status confirmation is not clinically feasible, EGFR mutations may be confirmed by circulating tumor deoxyribonucleic acid (ctDNA) analysis using a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified assay.
* Presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Adequate end organ function
* If patients are not eligible for LAT, they will be referred for standard of care chemotherapy as per treating physician's discretion. These patients may also be considered for other clinical trials.

Design:

* This is a single-institution, open-label phase II trial of osimertinib treatment in EGFR mutant lung cancer.
* Eligible patients not previously treated with osimertinib will be treated with osimertinib daily until disease progression. At the time of progression, patients with oligoprogressive disease (no more than 5 sites of progressive disease) will be assessed for LAT.
* If patients are eligible for LAT, osimertinib will be resumed after LAT and they will be followed for second progression on osimertinib (PFS2).
* If patients progress at the same site where LAT has been performed before, the progression will be considered to be a result of inadequate ablation and they will be considered for repeat LAT and again re-challenged with osimertinib if clinically feasible.
* Tumor samples will be obtained at baseline by a mandatory biopsy. At the time of first progression on osimertinib if a patient is eligible for surgery as a form of LAT, then a tissue sample will be obtained for genomic and proteomic studies to identify mechanisms of acquired resistance. For patients who are not eligible for LAT or a form of LAT that is not surgery (radiation, radiofrequency ablation, cryoablation), then a mandatory biopsy will be performed, if clinically safe, to obtain tissue for above studies.
* Re-treatment will be allowed for a small number of subjects.

Arms: arm 1: Cohort 1 - Osimertinib followed by LAT followed by osimertinib. Single daily dose of osimertinib until progression. The starting dose of osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline.

\*including germline T790M mutation arm 2: Cohort 2 - Osimertinib followed by LAT followed by osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, or radiofrequency ablation. arm 3: Cohort 3 - LAT followed by Osimertinib. Participants may undergo 1 of 3 local ablative procedures after initial progression on Osimertinib: surgery, radiotherapy, radiofrequency ablation. The starting dose of Osimertinib will be 80 mg per day for participants without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Single daily dose of Osimertinib until progression.
Interventions: intervention 1: osimertinib intervention 2: Local Ablative Therapy (LAT)
Intervention descriptions: intervention 1: Single daily dose of osimertinib until progression. The starting dose of osimertinib will be 80 mg per day for patients without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. intervention 2: local ablative therapy. Subjects may undergo 1 of 3 local ablative procedures after initial progression on osimertinib: surgery, radiotherapy, radiofrequency ablation

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
1 
CC Protocol #:  16-C-0092 M 
Abbreviated Title: LAT for NSCLC 
Version Date: December 26, 2019 
NCT Number: NCT02759835 
 
Title:  A Pilot Study of Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-
Mutated, Non-Small Cell Lung Cancer (NSCLC) After Treatment with Osimertinib 
(AZD9291, Tagrisso) 
 
 
 
NCI Principal  
 
Azam Ghafoor, MD, PhD  
Investigator:  
 
Thoracic & GI Malignancies Branch CCR/NCI/NIH 
9000 Rockville Pike 
Bldg. 10, Room RM 4-5330 
Bethesda, MD 20892-1906 
Telephone: 240-760-6232 
Email: azam.ghafoor@nih.gov  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Commercial Agent 
Drug Name: 
Osimertinib (AZD9291, Tagrisso) 
IND Number: 
Not Applicable - IND Exempt 
Manufacturer: 
AstraZeneca 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
2 
PRÉCIS  
Background:  
• EGFR tyrosine kinase inhibitors (TKI) have significantly improved the response rate (RR) 
and survival in patients with tumors harboring EGFR-sensitizing mutations.  
• An invariable consequence of treatment with EGFR-TKIs is the development of acquired 
resistance. The most common mechanism of resistance observed in approximately 50% of 
all cases is the emergence of a secondary mutation (T790M) in exon 20. 
• Osimertinib is a third-generation EGFR-TKI designed to target the T790M mutation, 
which has shown impressive responses in both first- and second-line settings. 
• Despite these developments, it is almost certain that selection pressure will lead to the 
emergence of newer clones that are resistant to treatment with osimertinib. In fact, a newly 
identified EGFR mutation (C797S) that results in acquired resistance to osimertinib has 
been reported recently.  
• The use of local ablative therapies for patients who develop limited metastatic disease 
(oligoprogressive disease) on EGFR-TKI therapy is promising. 
• We hypothesize that following local ablative therapy to treat oligoprogressive disease after 
emergence of resistance to AZD9291, osimertinib can be resumed safely and re-initiation 
of osimertinib results in additional progression-free survival benefits. 
Objectives:  
• Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation of 
osimertinib following local ablative therapy (LAT) for patients with oligoprogressive 
disease after treatment with osimertinib  
• Assess mechanisms of acquired resistance to osimertinib 
Eligibility:  
• Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic 
mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor 
(TKI) therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI 
therapy harboring somatic T790M mutation (Cohort 2); or patients with progressive 
disease after treatment with osimertinib who are eligible for local ablative therapy 
(Cohort 3).  If biopsy for EGFR mutation status confirmation is not clinically feasible, 
EGFR mutations may be confirmed by ctDNA analysis using a CLIA certified assay. 
• Presence of measurable disease per RECIST version 1.1 
• ECOG performance status 0-2 
• Adequate end organ function 
• If patients are not eligible for LAT, they will be referred for standard of care chemotherapy 
as per treating physicians’ discretion. These patients may also be considered for other 
clinical trials.  
Design: 
• This is a single-institution, open-label phase II trial of osimertinib.  


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
3 
• Eligible patients not previously treated with osimertinib will be treated with osimertinib 
daily until disease progression. At the time of progression, patients with oligoprogressive 
disease (no more than 5 sites of progressive disease) will be assessed for LAT.  
• If patients are eligible for LAT, osimertinib will be resumed after LAT and they will be 
followed for second progression on osimertinib (PFS2).  
• If patients progress at the same site where LAT has been performed before, the progression 
will be considered to be a result of inadequate ablation and they will be considered for 
repeat LAT and again re-challenged with osimertinib if clinically feasible.  
• Tumor samples will be obtained at baseline by a mandatory biopsy. At the time of first 
progression on osimertinib if a patient is eligible for surgery as a form of LAT, then a tissue 
sample will be obtained for genomic and proteomic studies to identify mechanisms of 
acquired resistance. For patients who are not eligible for LAT or a form of LAT that is not 
surgery (radiation, radiofrequency ablation, cryoablation), then a mandatory biopsy will be 
performed, if clinically safe, to obtain tissue for above studies. 
• Re-treatment will be allowed for a small number of subjects. 
 
SCHEMA 
 
 
 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
4 
 
Eligibility for local ablative therapy (LAT) is based on the following criteria:  
a. Oligoprogressive disease – no more than 5 sites of progressive disease that are 
amenable to treatment with LAT (surgery, radiation therapy, radiofrequency 
ablation, or cryoablation) independent of size and location of lesions.  
b. Patients with neurological or imaging signs of leptomeningeal disease and/or 
confirmed by a lumbar puncture occurring after initiation of osimertinib will be 
considered for LAT if radiation or intrathecal methotrexate can be administered for 
local treatment.  
 
 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
5 
TABLE OF CONTENTS 
PRÉCIS ............................................................................................................................................2 
SCHEMA .........................................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................5 
1 
INTRODUCTION ..................................................................................................................7 
1.1 
Study Objectives .........................................................................................................7 
1.2 
Background and Rationale ..........................................................................................7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT.......................................................16 
2.1 
Eligibility Criteria .....................................................................................................16 
2.2 
Recruitment ...............................................................................................................19 
2.3 
Screening Evaluation ................................................................................................20 
2.4 
Registration Procedures ............................................................................................21 
3 
STUDY IMPLEMENTATION ............................................................................................22 
3.1 
Study Design .............................................................................................................22 
3.2 
Re-Treatment of Subjects .........................................................................................23 
3.3 
Drug Administration .................................................................................................24 
3.4 
Dosing Delays/Dose Modifications ..........................................................................24 
3.5 
On Study Assessments ..............................................................................................27 
3.6 
Study Calendar ..........................................................................................................29 
3.7 
Radiation Therapy Guidelines ..................................................................................33 
3.8 
Criteria for Removal from Protocol Therapy and Off Study Criteria .......................33 
3.9 
Follow Up .................................................................................................................34 
3.10 
Off Study Criteria .....................................................................................................34 
3.11 
Off-Protocol Therapy and Off-Study Procedure.......................................................35 
4 
CONCOMITANT MEDICATIONS/MEASURES ..............................................................35 
4.1 
Concomitant medications..........................................................................................35 
5 
BIOSPECIMEN COLLECTION ..........................................................................................37 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ......................................37 
5.2 
Sample Storage, Tracking and Disposition ...............................................................49 
5.3 
Clinical Pharmacology Program ...............................................................................50 
5.4 
Samples for Genetic/Genomic Analysis ...................................................................51 
5.5 
Withdrawal of Informed Consent for donated biological samples ...........................52 
6 
DATA COLLECTION AND EVALUATION.....................................................................53 
6.1 
Data Collection .........................................................................................................53 
6.2 
Data Sharing Plans ....................................................................................................54 
6.3 
Response Criteria ......................................................................................................54 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
6 
6.4 
Safety assessments ....................................................................................................59 
6.5 
Toxicity Criteria ........................................................................................................60 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN ....60 
7.1 
Definitions.................................................................................................................60 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting .................................60 
7.3 
NCI Clinical Director Reporting ...............................................................................60 
7.4 
NIH Required Data and Safety Monitoring Plan ......................................................61 
8 
SAFETY 
REPORTING 
CRITERIA 
TO 
THE 
PHARMACEUTICAL 
COLLABORATOR ..............................................................................................................61 
9 
CLINICAL MONITORING  ................................................................................................62 
10 
STATISTICAL CONSIDERATIONS .................................................................................62 
10.1 
Statistical considerations and sample size estimate ..................................................62 
10.2 
Methods for statistical analyses ................................................................................64 
11 
COLLABORATIVE AGREEMENTS .................................................................................64 
11.1 
Clinical Trial Agreement ..........................................................................................64 
11.2 
Material Transfer Agreements ..................................................................................64 
11.3 
Cooperative Research and Development Agreement ...............................................65 
12 
HUMAN SUBJECTS PROTECTIONS ...............................................................................65 
12.1 
Rationale For Subject Selection ................................................................................65 
12.2 
Participation of Children ...........................................................................................65 
12.3 
Participation of Subjects Unable to Give Consent ....................................................65 
12.4 
Evaluation of Benefits and Risks/Discomforts .........................................................66 
12.5 
Consent Process and Documentation ........................................................................67 
13 
PHARMACEUTICAL INFORMATION ............................................................................67 
13.1 
Osimertinib (AZD9291)............................................................................................67 
14 
REFERENCES .....................................................................................................................70 
15 
APPENDICES ......................................................................................................................76 
15.1 
Appendix A: performance status criteria ..................................................................76 
15.2 
Appendix B. Guidance Regarding Potential Interactions with Concomitant 
Medications ...............................................................................................................77 
15.3 
Appendix C: Osimertinib Patient Medication Diary ............................................81 
15.4 
Appendix D. Guidance for the Management of Adverse Events in Studies using 
80mg osimertinib ......................................................................................................83 
15.5 
Appendix E. Potential Drug Induced Liver Injury....................................................97 
15.6 
Appendix F. AstraZeneca SAE Report Cover Sheet ..............................................101 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
 
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1 INTRODUCTION 
1.1 
STUDY OBJECTIVES 
 Primary Objectives: 
1.1.1.1 Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation of 
osimertinib following local ablative therapy (LAT) for patients with oligoprogressive 
disease after treatment with osimertinib 
1.1.1.2 Assess mechanisms of acquired resistance to osimertinib  
 Secondary Objectives: 
1.1.2.1 Evaluate the response rate (RR) and overall survival (OS) of patients treated with 
osimertinib after LAT  
1.1.2.2 Evaluate RR, PFS, and OS of patients treated with osimertinib prior to first progression 
on osimertinib   
 Exploratory Objectives:  
1.1.3.1 Establish patient-derived xenografts (PDX) from tumor tissue and assess PDX as a model 
for the identification of acquired resistance mechanisms 
1.1.3.2 Detect EGFR mutations in saliva sample collection and correlate the findings with the 
mutation testing from circulating tumor DNA (ctDNA) from plasma and tumor tissue 
specimens 
1.1.3.3 Conduct investigations on serum, plasma, and urine samples, and correlate the findings 
with treatment response and resistance 
1.1.3.4 Identify novel targeted agents in patient derived tumor tissue 
1.1.3.5 Compare amount of cfDNA, the quality and downstream analysis of mutation detection 
by ddPCR using existing methodology of plasma isolation from EDTA containing purple 
top tubes to same metrics using cell-free DNA BCT Streck tubes following manufacturer 
instructions 
1.1.3.6 Build a pipeline for the Gritstone proprietary for the neoantigen prediction model EDGE 
by sequencing data and validating predicted neoantigens by mass spectrometry from 
tumor tissue 
1.2 
BACKGROUND AND RATIONALE 
 NSCLC 
Overview of NSCLC 
Lung cancer is the leading cause of cancer deaths for both men and women in the United States 
and worldwide. 159,260 patients died of lung cancer in the United States in 2014, making up 27% 
of all cancer deaths(1). The 5-year survival rate for lung cancer (17%) is lower than most of other 
common solid tumors, such as colon cancer (65%) and breast cancer (89%)(1). Non-small cell lung 
cancer (NSCLC) is the most common type of lung cancer, comprising 86% of all lung cancer 
cases(2). Of these patients, more than 55% will present with advanced disease(1), which is not 
amenable to curative treatment. 
Platinum-based doublet chemotherapy regimens are the standard of care for patients with advanced 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
 
8 
NSCLC and good performance status(3), who do not have targetable driver mutations. The 
treatment with platinum-based doublet chemotherapy is unsatisfactory, with objective response 
rates generally in the range of 20-30%(4, 5), and the median survival in the range of approximately 
10-12 months(6). Adding a third chemotherapy drug to the platinum-doublet has not improved 
overall survival(7). Non-platinum-based regimens have been evaluated in several trials, but 
objective response rates were lower compared to platinum-containing regimens(8), and 
progression-free survival (PFS) was inferior(9). 
Targeted therapy for advanced NSCLC 
In the past decade, insights into the genetic and molecular pathogenesis of lung cancer have led to 
the development of targeted therapies. Erlotinib is an orally active reversible epidermal growth 
factor receptor tyrosine kinase inhibitor (EGFR-TKI), which has demonstrated marked clinical 
efficacy over standard chemotherapy in EGFR mutation-positive advanced NSCLC(10). EGFR 
mutations are the most frequent genetic abnormalities observed in NSCLC, especially in 
adenocarcinoma subtype(11). The most predominant EGFR mutations are in-frame deletions in 
exon 19 and L858R missense mutation(11), and the majority of patients whose tumor harbors these 
mutations are highly sensitive to EGFR-TKIs. Several randomized trials, which compared erlotinib 
with standard chemotherapy as first-line treatment for patients with advanced EGFR mutation-
positive NSCLC, demonstrated objective response rates of 58-83% for erlotinib, and 15-36% for 
chemotherapy(4, 5). The median PFS was also significantly longer in erlotinib-treated patients (9.7-
13.1 months) than in those treated with chemotherapy (4.6-5.2 months). Erlotinib received 
approval for the treatment of patients with locally advanced or metastatic NSCLC after failure of 
one or two chemotherapy regimens by the U.S. Food and Drug Administration (FDA) in 2004(12). 
In 2013, the indication for erlotinib was expanded to include first-line treatment of metastatic 
NSCLC harboring EGFR mutations(13). Erlotinib is well tolerated with most adverse events being 
grade 1 or 2(14, 15). The most common side effects of erlotinib are skin rash, diarrhea, and fatigue, 
which were primarily grade 1 or 2 in severity(4).  
Gefitinib is another first-generation orally administered EGFR-TKI. Randomized trials that 
compared gefitinib with standard chemotherapy for the treatment of advanced NSCLC with EGFR 
mutations in the first-line setting showed objective response rates of 62-74% for gefitinib, and 31-
32% for chemotherapy(16, 17). Patients who were treated with gefitinib had a prolonged 
progression-free survival (9.2-10.8 months), as compared with those who were treated with 
standard chemotherapy (5.4-6.3 months). Like erlotinib, most adverse events associated with 
gefitinib were grade 1 or 2. The most common adverse reactions of gefitinib included skin 
reactions, transaminitis, and diarrhea. Gefitinib was approved by the FDA for the first-line 
treatment of patients with advanced EGFR mutation-positive NSCLC in 2015(18). 
Afatinib is a selective, irreversible, orally bioavailable second-generation EGFR-TKI that was 
approved by the FDA in 2013(19). In a phase III study of 345 patients with metastatic NSCLC 
harboring EGFR mutations, 230 and 115 were randomized to afatinib and cisplatin/pemetrexed, 
respectively(20). The median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy 
(hazard ratio [HR]=0.58; 95% CI=0.43 to 0.78; p=0.001). In patients whose tumors carry exon 19 
deletions or L858R, the median PFS was 13.6 months for afatinib and 6.9 months for 
chemotherapy. In a pooled analysis of two randomized trials (LUX-Lung 3 and LUX-Lung 6), 
afatinib was shown to improve overall survival in patients whose tumors harbor exon 19 
deletions(21). The most frequent adverse events from afatinib were diarrhea, rash/acne, stomatitis, 
and decreased appetite(20). 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
 
9 
Resistance to EGFR-TKI 
Resistance to single-agent targeted therapies is virtually unavoidable in metastatic carcinomas(22), 
and it poses a major challenge to the treating physician. Although first and second-generation 
EGFR-TKIs produce remarkable clinical responses, 5-10% of patients with EGFR mutation-
positive NSCLC are refractory to EGFR-TKIs, and up to 40% of patients harboring EGFR 
sensitizing mutations do not attain a major response to the first-generation EGFR-TKIs (erlotinib 
and gefitinib)(4, 5, 16, 17), indicating the existence of intrinsic resistance mechanisms. Moreover, 
even those who achieved an objective response invariably develop acquired resistance. Largely, 
resistance mechanisms to targeted therapy involve alterations in the gene that encodes the target 
of targeted agent and activation of alternative signaling pathways(23). KRAS mutation, Cripto1 
overexpression, MET gene amplification, and HGF overexpression have been implicated in the 
molecular pathogenesis of intrinsic resistance to EGFR-TKIs(24-26). Known acquired mechanisms 
of resistance to EGFR-TKIs include EGFR T790M mutation (50-60%), and less frequently MET 
gene amplification, hepatocyte growth factor (HGF) overexpression, mutations in the PIK3CA 
gene, epithelial to mesenchymal transition, and small cell lung cancer transformation(25, 27-31). 
  Osimertinib 
Non-clinical studies of Osimertinib 
Osimertinib is an irreversible, potent, and selective third-generation EGFR-TKI that targets both 
sensitizing and T790M EGFR mutations(32). In EGFR recombinant enzyme assays (Millipore), 
osimertinib had approximately 200 times greater potency against L858R/T790M than wild-type 
EGFR, suggesting its wide selectivity margin. Compared to both first (erlotinib and gefitinib) and 
second generation (afatinib and dacomitinib) EGFR-TKIs, osimertinib demonstrated comparable 
potency in inhibiting EGFR phosphorylation in EGFR cell lines harboring activating EGFR 
mutations (PC-9, H3255, H1650). Importantly, osimertinib was much more potent in inhibiting 
EGFR phosphorylation in EGFR cell lines (H1975, PC-9VanR) carrying T790M mutation with 
mean IC50 less than 15 nmol/L. 
Osimertinib showed dose-dependent tumor regression in both PC-9 (ex19del) and H1975 
(L858R/T790M) tumor xenograft models(32). In both models, tumor shrinkage was observed at 
doses as low as 2.5 mg/kg/day after 14-day treatment. The response to  osimertinib was shown to 
be durable in tumor xenograft models. In PC-9 xenografts, there was a complete response 
following 40 daily doses of 5 mg/kg/day osimertinib, which lasted more than 200 days. By 
comparison, gefitinib at 6.25 mg/kg/day resulted in less tumor regression, and tumors began to 
regrow after nearly 90 days in the same xenograft model. The activity of osimertinib was further 
examined in in vivo transgenic mouse models. Tumors harboring EGFRL858R were sensitive to 
afatinib and osimertinib, but tumors carrying EGFRL858R+T790M were only sensitive to osimertinib. 
Osimertinib is metabolized into at least two metabolite species, AZD5104 and AZ7550(32). 
Biochemical assays showed that AZD7550 had a similar potency and selectivity profile to 
osimertinib, whereas AZD5104 exhibited significantly greater potency than osimertinib across 
mutant and wild-type EGFR assays, and thus displayed a smaller margin of selectivity against 
wild-type EGFR compared to EGFRm/T790M and EGFRm in vitro. Osimertinib has good 
bioavailability, and wide tissue distribution. When tumor tissues from H1975 xenografts were 
harvested 1, 6, 16, 24, and 30 hours after a single dose of osimertinib (5mg/kg), both phospho-
EGFR and downstream signaling pathway were inhibited after 6 hours. Although osimertinib had 
a half-life of approximately 3 hours after oral dosing in the mouse model, phospho-EGFR staining 
remained reduced even after the 30-hour time point, which was consistent with the fact that 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
 
10 
osimertinib is an irreversible inhibitor of EGFR. Osimertinib was well tolerated in the animals. 
There was minimal weight loss, which was defined as less than 5% loss of baseline body weight, 
even after administration for 200 days. 
Clinical studies of osimertinib  
The mesylate salt of osimertinib has been evaluated in a phase I dose-escalation clinical trial in 
patients with advanced EFGR-mutant NSCLC who progressed after treatment with EGFR-
TKI(33). The study included dose-escalation and dose expansion cohorts. Patients in the dose-
escalation cohort received a single oral dose of osimertinib, which was followed by a period of 
pharmacokinetic evaluation. After 7 days, the patients received the same dose of osimertinib in an 
oral form for the remainder of the study. Additional pharmacokinetic assessment was performed 
while patients were receiving daily continuous dosing. The first dose level was 20 mg daily. If 
there was evidence of clinical activity in a dose-escalation group, a dose-expansion cohort could 
be opened. In the dose-escalation cohort, daily dosing of osimertinib was initiated immediately. 
A total of 253 patients from 33 sites were enrolled in the study(33). 31 patients were treated in 
dose-escalation cohorts, and 222 patients were enrolled to dose-expansion cohorts. The dose range 
of osimertinib used in the dose-escalation cohorts was from 20 mg to 240 mg.  The first dose level 
of 20 mg was selected based on the preclinical data. The most common side effects included 
diarrhea, rash, nausea, and anorexia. Most of the adverse effects were grade 1 or 2. There was an 
increased incidence of adverse effects, most notably at the 160 mg and 240 mg dose levels. There 
were 6 cases of potential pneumonitis-like events. All 6 patients discontinued osimertinib at the 
time of the event, and received steroid treatment with subsequent resolution or improvement of 
symptoms. There were 6 patients who developed hyperglycemia, and 11 patients who had 
prolongation of QTc (corrected QT) interval; none of these events led to discontinuation or 
reduction of osimertinib. Fatal adverse events were observed in 7 patients, and it was reported that 
one case (pneumonia) was possibly drug-related. Pharmacokinetic analyses showed that 
osimertinib had a median time to reach the maximum observed concentration (Cmax) of 6 hours, 
and a mean half-life of 55 hours. Based on this information, it was estimated that steady-state 
concentrations would be reached within 22 days of daily dosing. 
Among 239 evaluable patients, 123 (51%) had a confirmed complete response (1 patient) or partial 
response (122 patients)(33). 78 (33%) had stable disease, 34 (14%) had progressive disease, and 4 
(2%) were unevaluable for response. The response rate was comparable at each dose level. EGFR 
T790M was detected in tumors from 138 of the 222 patients (62%). Of the 138 patients, 127 
patients were evaluable for response. The objective response rate was seen in 78 of the 127 patients 
(61%) in patients with EGFR T790M. The objective response rate in patients without EGFR 
T790M was 21% (13 of the 61 patients). Of the 105 patients in the dose-expansion cohorts who 
had a confirmed response, 85% had responses lasting equal to or longer than 6 months, and the 
median progression free survival was 8.2 months (9.6 months in EGFR T790M-positive patients, 
2.8 months in EGFR T790M-negative patients). Based on the safety and efficacy data from the 
phase I study, the recommended first dose level of osimertinib for phase II and III studies 
(NCT02094261, NCT02296125) was 80 mg daily. In 2015, osimertinib was approved by the FDA 
for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected 
by an FDA-approved test, who have progressed on or after EGFR-TKI therapy(34). 
The preliminary data of osimertinib as first-line therapy for patients with advanced NSCLC with 
EGFR mutations who were naïve to EGFR-TKI treatment were presented at the 51th annual 
meeting of the American Society of Clinical Oncology (ASCO)(35). In this trial, a total of 60 
patients were treated with osimertinib at doses of 80 mg daily (n=30) and 160 mg daily (n=30). At 


Abbreviated Title:  LAT for NSCLC 
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11 
the time of data analysis, the median duration of follow-up was 9.6 months. Osimertinib was well 
tolerated with most adverse events being grade 1 or 2. Most common adverse events were rash, 
diarrhea, dry skin, stomatitis, paronychia, decreased appetite, and fatigue. The incidences of 
hyperglycemia, QT prolongation, and interstitial lung disease (ILD)-like events were 5%, 7%, and 
5%, respectively. Dose reduction due to adverse events occurred in 10% of patients treated with 
80 mg daily and 43% of those treated with 160 mg daily. 3 (10%) patients treated with 80 mg daily 
and 1 (3%) patient treated with 160 mg daily discontinued osimertinib due to adverse events. The 
objective response rate in patients treated with 80 mg daily was 63% with all responses being 
partial response. In the group receiving 160 mg daily, 83% had objective responses with 1 (3%) 
complete response and 24 (80%) partial responses. The percentages of patients remaining 
progression-free at 9 months were 83% in patients receiving 80 mg daily and 78% in those 
receiving 160 mg daily. 
It has been shown that osimertinib has excellent penetration of the mouse blood-brain barrier 
compared to other EGFR-TKIs including gefitinib, rociletinib, or afatinib(36). Osimertinib also 
showed activity against brain metastases from EGFR-mutated NSCLC in early clinical reports(36). 
At the 2016 ASCO annual meeting, results from a phase I study of osimertinib for patients with 
leptomeningeal disease (NCT02228369) were presented(37). Patients were eligible if they had 
progressed on prior EGFR-TKI therapy and leptomeningeal disease is confirmed by positive 
cerebrospinal fluid cytology. Patients were treated with osimertinib 160 mg once daily. Of 12 
patients who were treated >3 weeks and reached a 12-week intracranial IC imaging assessment, 7 
had radiological improvement, 2 had stable disease, and 3 were not evaluable, indicating activity 
of osimertinib in patients with leptomeningeal disease. The most common treatment-associated 
side effects were skin rash (n=15; 11 grade 1, 4 grade 2) and diarrhea (n=8; 5 grade 1, and 3 grade 
2). In one patient, grade 3 neutropenia was observed, but the patient recovered to grade 2 after a 
dose interruption and resumed osimertinib at 80 mg once daily. 
 Treatment options after progression on EGFR-TKI 
Several clinical factors such as symptoms and disease burden need to be taken into account when 
choosing the best treatment option for patients who developed resistance to first-line EGFR-TKI 
targeted therapy(38). For patients who have disease progression based on the Response Evaluation 
Criteria in Solid Tumors (RECIST) and yet remain asymptomatic, the use of erlotinib beyond 
progression was associated with a delay in initiation of chemotherapy(39) and thus constitutes a 
reasonable option. Another line of evidence supporting this approach derives from previous 
observations that some patients experience a disease flare leading to hospitalization or death after 
discontinuation of erlotinib or gefitinib(40). 
In general, outside clinical trials, systemic chemotherapy is recommended for patients who have 
symptomatic disease progression, especially if there are multiple progressive lesions(41, 42). 
However, treatment outcomes associated with second-line chemotherapy are modest; the median 
PFS after second-line chemotherapy for patients who progressed on EGFR-TKI therapy is only 4-
5 months(41, 43, 44). Continuation of EGFR-TKI therapy beyond progression in addition to 
commencement of chemotherapy has not been shown to improve clinical outcomes. A randomized 
phase II study that compared chemotherapy (pemetrexed or docetaxel) with chemotherapy plus 
erlotinib in patients with progressive NSCLC following prior benefit from erlotinib demonstrated 
that continuation of erlotinib was associated with a significant increase in toxicities, but not with 
improvement in treatment outcomes(43). In a phase III trial of 265 patients with advanced NSCLC 
who progressed on first-line gefitinib, addition of gefitinib to platinum-based doublet 
chemotherapy did not prolong PFS(41). The use of afatinib beyond progression was evaluated in a 


Abbreviated Title:  LAT for NSCLC 
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12 
phase III study that involved 202 patients who progressed on erlotinib/gefitinib and afatinib(44).  
Study participants were randomized 2:1 to afatinib plus paclitaxel or single-agent chemotherapy 
of investigator’s choice. Although preliminary data showed that there was a significant 
improvement in PFS favoring continuation of afatinib (median 5.6 vs. 2.8 months, hazard 
ratio=0.60, p=0.003), study data are not mature yet. For patients who developed the EGFR T790M 
mutation after first-line EGFR-TKI, osimertinib is a treatment option. However, about half of 
patients with acquired resistance to first- or second-generation EGFR-TKI would not benefit from 
osimertinib. Moreover, it is almost certain that selection pressure will lead to the emergence of 
newer clones that are resistant to treatment with osimertinib. In fact, a newly identified EGFR 
mutation (C797S) that results in acquired resistance to osimertinib has been reported recently(45). 
Because targeted therapies are highly active in molecularly selected patients with NSCLC and 
generally better tolerated than chemotherapy, patients would benefit from continuation of a TKI 
and delay in initiation of subsequent therapy such as chemotherapy. Therefore various strategies 
need to be evaluated to delay a switch in systemic therapy due to emergence of acquired resistance 
to EGFR TKI therapy. In this regard, exploring the role of local therapies for patients with 
metastatic NSCLC who progressed on EGFR-TKI therapy merits further investigation. There are 
several theoretical benefits of using local therapies for advanced NSCLC. First, local progression 
is the predominant pattern of failure for patients with advanced NSCLC treated with first-line 
systemic therapy(46); among patients seen at the University of Colorado between 2005 and 2008, 
the pattern of failure analysis demonstrated that the first site of extracranial progression was local 
only in 64% of patients(47). Second, the Norton-Simon hypothesis suggests that the effect of 
systemic therapy is proportional to the rate of tumor growth at the time of treatment and tumor 
growth follows a sigmoidal pattern(48, 49). Local ablative therapy may move the tumor growth 
curve back to a state of exponential growth and thereby augment the antitumor activity of systemic 
therapy(46). Third, local therapy may serve as a means of eliminating an evolutionary reservoir of 
resistant subclones(50) and thus help extend the use of targeted therapy. 
While local therapies such as surgery, stereotactic radiation therapy, and radiofrequency ablation 
have been shown to be effective for several types of cancer including colorectal cancer, sarcoma, 
and renal cell carcinoma in the metastatic disease setting(51), the role of local therapies for the 
treatment of NSCLC with limited metastatic disease is not defined yet and available data are 
largely from retrospective case series studies or subgroup analyses of larger prospective studies(52-
55). Findings from these studies, however, indicate that there might be a subset of patients who 
benefit from aggressive local therapy (Table 1). The therapeutic utility of combining local ablative 
therapy and targeted therapy for the treatment of oligometastatic NSCLC was recently examined. 
In a single-arm phase II study, 24 patients with metastatic NSCLC and no more than 6 sites of 
extracranial disease who progressed through previous platinum-based chemotherapy were treated 
with stereotactic body radiation therapy (SBRT) combined with erlotinib(56). Of the 13 patients 
tested for EGFR mutations, no one was found to have activating EGFR mutations. This study 
showed that the combination of SBRT and erlotinib was well tolerated. The median PFS and 
overall survival were 14.7 months and 20.4 months, respectively. There results were superior to 
those from historical controls treated only with systemic chemotherapy, although it must be 
acknowledged that making a comparison to a historical control does not account for differences in 
patient populations or other confounding factors. 
To the best of our knowledge, there are two studies that have examined the efficacy of local 
ablative therapy with continued targeted therapy in patients with acquired resistance to EGFR-
TKIs. In a retrospective study of 184 patients who have documented progression on erlotinib or 


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13 
gefitinib, 18 patients were treated with one or more local therapies, excluding intracranial 
treatments, for progressive EGFR mutation-positive NSCLCs(57). The most common site of 
metastatic disease was lung, followed by lymph node, bone, and brain in the local therapy group, 
and all patients except one patient had oligometastatic disease, defined as less than 5 sites of 
disease. Local therapies consisted of metastasectomy (lobectomy, wedge resection, 
pneumonectomy, adrenalectomy), radiofrequency ablation (RFA), and stereotactic radiotherapy. 
Most local therapies were well tolerated, with 85% of patients restarting EGFR-TKI therapy within 
1 month of local therapy. The median time to progression after local therapy was 10 months (range 
1 to 51 months), and the median time from local therapy until a change in systemic therapy was 
22 months (range 1 to 54 months). The median overall survival from local therapy was 41 months 
(range 1 to >65 months). Another single-center study that assessed the benefits of the combination 
of local therapy and continued TKI therapy (crizotinib or erlotinib) in patients with 
oligoprogressive disease, defined as nonleptomeningeal CNS and/or 4 or fewer of extracranial 
progression(58). 15 of 28 patients (54%) treated with crizotinib and 10 of 23 patients (43%) treated 
with erlotinib were deemed suitable for local therapies involving surgery or radiation. Among the 
25 patients treated with local therapy and continued TKI therapy, 10 first progressed in the central 
nervous system (CNS) and 15 had disease progression in extracranial sites with the most common 
sites being lung and bone. Patients with less than four CNS metastases received stereotactic 
radiosurgery (SRS), and those with more than four CNS metastatic lesions were treated with whole 
brain radiation therapy (WBRT). Most of the 15 patients who had extracranial disease progression 
received SBRT, with 8 of 15 (53%) having a single site of progression ablated. One patient 
underwent adrenalectomy. The subsequent median progression-free survival from the time of first 
progression (PFS2) was 7.1 months for patients with initial CNS only progression. The median 
PFS2 for patients with initial extracranial progression was 4.0 months. The majority of adverse 
events in this case-series occurred in patients who received WBRT. Grade 1/2 fatigue, nausea, and 
anorexia were the most common side effects related to radiation therapy other than WBRT. These 
data indicate that the use of local therapies was safe and feasible in patients who acquired resistance 
to EGFR-TKIs, and may have a role in extending the duration of clinical benefit from targeted 
therapies. 
Based on these observations, we propose a phase II trial to explore the role of local ablative therapy 
after emergence of resistance to osimertinib in patients with oligoprogressive EGFR mutation-
positive NSCLC. Another important goal of this study is to study the mechanisms of resistance to 
osimertinib. Patients with EGFR mutation-positive NSCLC who are treatment-naïve or who 
progressed after EGFR-TKI therapy and acquired the T790M mutation will be eligible for the trial. 
The advantage of using osimertinib in the first-line treatment setting is that it not only inhibits the 
exon 19 deletion and L858R mutants, but also the T790M mutant. In addition, osimertinib appears 
overall to be better tolerated than other approved EGFR-TKIs. 
Table 
1. 
Selected 
Clinical 
Trials 
of 
Local 
Ablative 
Therapy 
for 
Pulmonary 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
 
14 
Oligoprogressive/Oligometastatic NSCLC 
Reference 
(Publication 
year) 
Study population Study design 
 
No. of 
Patients 
Median 
Follow-up 
(months) 
Previous
lines of 
systemic 
therapy 
Site of 
metastatic 
disease 
Types of 
procedures 
(1: Surgery, 2: 
Radiation, 3: 
Radiofrequency
ablation) 
Primary 
Endpoint 
 
 
Weickhardt
et 
al. 
(2012)(58) 
Oligoprogressive 
metastatic 
NSCLC 
with
acquired 
resistance 
to 
EGFR-TKI 
or 
crizotinib 
Retrospective 
25 
NA 
2.5 
Adrenal, bone, 
liver, lung, 
lymph node 
1, 2 
PFS1=9.8 
months, 
PFS2=6.2 
months, 
median 
OS
data 
not
mature at the 
time 
of 
analysis 
Yu et al.
(2013)(57) 
Oligoprogressive 
metastatic 
NSCLC 
with
acquired 
resistance 
to 
EGFR-TKI 
Retrospective 
18 
NA 
NA 
Bone, brain, 
lung, lymph 
node, visceral 
1, 2, 3 
PFS1=19 
months, 
PFS2=10 
months, 
median 
OS
from 
local 
therapy=41 
months 
Porte et al.
(2001)(59) 
Oligometastatic 
NSCLC with a
solitary adrenal
metastasis 
Retrospective 
43 
23.8 
NA 
Adrenal 
1 
Median 
PFS=13 
months, 
median 
OS=11 
months 
3 
patients 
survived 
more than 5
years 
Holy et al. 
(2011)(60) 
Oligometastatic 
NSCLC 
with
adrenal 
metastases  
Retrospective 
18 
21 
NA 
Adrenal 
2 
Median 
PFS=4.2 
months, 
median 
OS=23 
months 
PFS 
was
longer 
(12 
months) 
in
13 
patients
with 
a 
solitary 
adrenal 
metastasis 
Luketich et
al. 
(1996)(61) 
Oligometastatic 
NSCLC with a
solitary adrenal
metastasis 
Retrospective 
8 
NA 
NA 
Adrenal 
1 
Median 
OS=33 
months 
Median OS 
in 
patients 
treated with 
medical 
therapy only
was 
8.5 
months. 
Patchell  et
al. 
(1990)(62) 
Advanced solid
tumors with a
single metastasis 
to the brain 
Randomized 48 (37 
patients 
with 
NSCLC) 
7 
 
NA 
Brain 
1, 2 (surgery 
plus radiation
vs. 
radiation
only) 
Median 
OS=10 
months in the
surgery plus
radiation vs.
3.8 months in
the radiation 
group; 
P<0.01 
Patients 
in
the 
surgery 
group 
maintained 
Karnofsky 
score much 
longer.  


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15 
Reference 
(Publication 
year) 
Study population Study design 
 
No. of 
Patients 
Median 
Follow-up 
(months) 
Previous
lines of 
systemic 
therapy 
Site of 
metastatic 
disease 
Types of 
procedures 
(1: Surgery, 2: 
Radiation, 3: 
Radiofrequency
ablation) 
Primary 
Endpoint 
 
 
Andrews et
al. 
(2004)(63) 
Advanced solid
tumors with one
to three brain
metastases 
Randomized 
331 
(211 
patients 
with 
NSCLC) 
NA 
NA 
Brain 
2 (stereotactic 
radiosurgery 
plus WBRT vs.
WBRT) 
Median 
OS=6.5 
months in the
stereotactic 
radiosurgery 
group vs. 4.9 
months in the
WBRT only
group 
(p=0.04) 
A 
statistically 
significant 
improvement
in 
performance 
status in the 
stereotactic 
radiosurgery 
group  
Furak et al.
(2005)(64) 
Oligometastatic 
NSCLC 
with
brain metastases 
Retrospective 
65 
NA 
NA 
Brain 
1 
Median 
OS=19 
months 
for
synchronous 
patients, 
12 
months 
for
metachronous
patients  
Burt et al.
(1992)(65) 
Oligometastatic 
NSCLC 
with
brain metastases 
Retrospective 
185 
NA 
NA 
Brain 
1 
Median 
OS=14 
months 
10-year 
survival=7% 
De 
Ruysscher 
et 
la. 
(2012)(66) 
Oligometastatic 
NSCLC 
Prospective 
39 
27.7 
NA 
Adrenal, bone, 
brain, liver, 
lung, lymph 
node, muscle, 
ovary, pleura 
1, 2 
Median 
PFS=12.1 
months, 
median 
OS=13.5 
months 
Khan et al. 
(2006)(52) 
Oligometastatic 
NSCLC 
Retrospective 
23 
17 
NA 
Adrenal, bone, 
brain, 
intrapulmonary, 
lymph node, 
soft tissue 
1, 2 
Median 
OS=20 
months 
WBRT: whole brain radiation therapy 
PFS: Progress-free survival 
OS: Overall survival 
PFS1: Time from initiation of targeted therapy to first progression of disease or clinical progression, or 
death from any cause 
PFS2: Time from the first progression until second progression on the same targeted therapy 
 Rationale  
1.2.4.1 Rationale for study design, doses and control groups 
This is a single-institution, open-label phase II trial. This study aims to assess the role of local 
ablative therapy in the treatment of patients with EGFR mutation-positive NSCLC after 
oligoprogression on osimertinib.  Oligoprogression is defined as no more than 5 sites of 
progressive disease that are amenable to treatment with LAT (surgery, radiation therapy, 
radiofrequency ablation, or cryoablation) independent of size and location of lesions. There is no 
FDA-approved treatment for patients who progressed on osimertinib and thus assessing the 


Abbreviated Title:  LAT for NSCLC 
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16 
efficacy of local ablative therapy as a strategy to extend the benefits of osimertinib merits further 
investigation. 
In the phase 1 dose escalation study of osimertinib (D5160C00001, AURA), once daily doses of 
20, 40, 80, 160, and 240 mg of osimertinib were evaluated. Based on the totality of the safety, 
pharmacokinetic and preliminary efficacy data, 80 mg once daily was selected as the 
recommended phase II dose. In light of these data, the starting dose of osimertinib will be 80 mg 
per day for patients without leptomeningeal disease. For patients with leptomeningeal disease, the 
start dose of osimertinib will be 160 mg per day based on the results of the BLOOM trial 
(NCT02228369). Patients may continue to receive osimertinib as long as they are continuing to 
show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria. 
No dosage adjustment is required due to patient age, body weight, gender, ethnicity and smoking 
status. 
Patients who progress on their initial treatment with osimertinib and receive LAT therapy (surgery, 
radiation therapy, or RFA) followed by osimertinib will be evaluated for their time to second 
progression (PFS2). The objective will be to estimate the PFS2 for these patients and also to 
determine if the PFS2 result may be potentially superior to that of historic controls. Response and 
progression will be evaluated in this study using the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1(67). 
Another important goal of this study is to assess mechanisms of acquired resistance to osimertinib. 
Tumor samples will be obtained prior to initiation of treatment and upon development of acquired 
resistance. Whole exome, transcriptome and/or whole genome sequencing and proteomics 
analyses will be performed on the tumor samples. In addition, this protocol will involve 
longitudinal acquisition of  liquid biopsies (blood, saliva, urine), which will be used for 
comprehensive proteogenomic analysis. Germline DNA will be extracted from peripheral blood 
and the information will only be used for the identification of somatic variants. Leftover biological 
samples will be frozen and stored in Dr. Figg’s lab. 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
 Inclusion Criteria 
For inclusion in the study subjects should fulfill the following criteria: 
2.1.1.1 Provision of informed consent prior to any study specific procedures 
2.1.1.2 Patients (male/female) must be > 18 years of age. 
2.1.1.3 Patients with histologically confirmed, by the NCI Laboratory of Pathology or by CLIA-
certified Next Generation Sequencing or cobas® EGFR Mutation Test v1/2 at an outside 
institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or 
a germline T790M mutation (detected histologically or via ctDNA analysis using a CLIA 
assay) with: 
2.1.1.3.1 No prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1) 
OR 
2.1.1.3.2 Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic 


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17 
T790M mutation (Cohort 2) 
OR 
2.1.1.3.3 Progressive disease after treatment with osimertinib who are eligible for local ablative 
therapy (Cohort 3) 
2.1.1.4 Presence of measurable disease per RECIST version 1.1.  See Section 6.3.2 for the 
evaluation of measurable disease. 
2.1.1.5 In patients with suspected leptomeningeal disease, the diagnosis of leptomeningeal 
disease should be confirmed by the presence of neurological or imaging signs and/or 
positive CSF cytology. 
2.1.1.6 ECOG performance status 0-2. (See Appendix A) 
2.1.1.7 No uncontrolled arrhythmia; no myocardial infarction in the last 6 months. 
2.1.1.8 Females should not be breast feeding and must have a negative pregnancy test prior to 
start of dosing if of child-bearing potential or must have evidence of non-child-bearing 
potential by fulfilling one of the following criteria at screening: 
2.1.1.8.1 Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 
months following cessation of all exogenous hormonal treatments 
2.1.1.8.2 Women under 50 years old would be consider postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range for the institution 
2.1.1.8.3 Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation 
2.1.1.9 Females of child-bearing potential should use reliable methods of contraception from the 
time of screening until 3 months after discontinuing osimertinib. Acceptable methods of 
contraception include total and true sexual abstinence, tubal ligation, hormonal 
contraceptives that are not prone to drug-drug interactions (IUS Levonorgestrel Intra 
Uterine System (Mirena), Medroxyprogesterone injections (Depo-Provera), copper-
banded intra-uterine devices, and vasectomized partner.  All hormonal methods of 
contraception should be used in combination with the use of a condom by their male 
sexual partner for intercourse. 
2.1.1.10 Male patients should be willing to use barrier contraception. Male patients should be 
asked to use barrier contraceptives (i.e., by use of condoms) during sex with all of their 
female partners during the trial and for a washout period of 3 months.  Patients should 
refrain from donating sperm from the start of dosing until 6 months after discontinuing 
osimertinib treatment.  If male patients wish to father children they should be advised to 
arrange for freezing of sperm samples prior to the start of osimertinib treatment. 
2.1.1.11 Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up. 
 Exclusion Criteria  
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
2.1.2.1 Any unresolved toxicities from prior therapy greater than Common Terminology Criteria 


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18 
for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the 
exception of alopecia and grade 2, prior platinum-therapy related neuropathy. 
2.1.2.2 Treatment with an investigational drug within five half-lives of the compound. 
2.1.2.3 Major thoracic or abdominal surgery from which the patient has not sufficiently 
recovered yet. 
2.1.2.4 Untreated and uncontrolled second tumor in the past 2 years. 
2.1.2.5 Patients currently receiving (or unable to stop use prior to receiving the first dose of study 
treatment) medications or herbal supplements known to be potent inhibitors of CYP3A4 
(at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior) (Appendix 
B) will only be eligible at the PI’s discretion.  
2.1.2.6 Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, which in the investigator’s opinion makes it 
undesirable for the patient to participate in the trial or which would jeopardize compliance 
with the protocol. Screening for chronic conditions is not required. 
2.1.2.7 Patients with CNS metastases who are neurologically unstable. 
2.1.2.8 Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation 
pneumonitis requiring steroid treatment, or any evidence of clinically active ILD 
2.1.2.9 Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values: 
2.1.2.9.1 Absolute neutrophil count <1 x 109/L  
2.1.2.9.2 Platelet count <100 x 109/L 
2.1.2.9.3 Hemoglobin <90 g/L 
2.1.2.9.4 Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no 
demonstrable liver metastases or >5 times ULN in the presence of liver metastases 
2.1.2.9.5 Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 
times ULN in the presence of liver metastases 
2.1.2.9.6 Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence 
of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver 
metastases 
2.1.2.9.7 Creatinine >1.5 times ULN concurrent with creatinine clearance <30 ml/min (measured 
or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is 
only required when creatinine is >1.5 times ULN 
2.1.2.10 Any of the following cardiac criteria: 
2.1.2.10.1 Resting corrected QT interval (QTc using Fredericia’s formula) > 480 msec  
2.1.2.10.2 Any clinically important abnormalities in rhythm, conduction or morphology of resting 
ECG (e.g., complete left bundle branch block, third degree heart block, second degree 
heart block) 
2.1.2.10.3 Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT 


Abbreviated Title:  LAT for NSCLC 
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19 
syndrome or unexplained sudden death under 40 years of age in first degree relatives or 
any concomitant medication known to prolong the QT interval 
2.1.2.11.4 Significant symptomatic congestive heart failure, per PI judgement  
2.1.2.11 Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow 
the formulated product or previous significant bowel resection that would preclude 
adequate absorption of osimertinib   
2.1.2.12 History of hypersensitivity to osimertinib (or drugs with a similar chemical structure or 
class to osimertinib) or any excipients of these agents 
2.1.2.13 Judgment by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements 
 
2.2 
RECRUITMENT 
Trial information will be posted on NIH websites accessible to the public such as 
ClinicalTrials.gov and NIH social media forums. Patients will also be recruited from the patients 
seen in the TGMB clinic. 
 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
8 
+ 
8 
= 
16 
Not Hispanic or Latino 
42 
+ 
42 
= 
84 
Ethnic Category:  
Total of all subjects 
50 
+ 
50 
= 
100 
Racial Category 
 
American Indian or Alaskan 
Native 
2 
+ 
2 
= 
4 
Asian 
15 
+ 
15 
= 
30 
Black or African American 
5 
+ 
5 
= 
10 
Native Hawaiian or other 
Pacific Islander 
1 
+ 
1 
= 
2 
White 
27 
+ 
27 
= 
54 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
 
20 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Racial Category:  
Total of all subjects 
50 
+ 
50 
= 
100 
Accrual Rate:  2 patients/month  
 
 
Total Expected Accrual:  100 
2.3 
SCREENING EVALUATION 
Procedures will be performed according to the Study Calendar. At screening, consenting subjects 
are assessed to ensure that they meet eligibility criteria. Subjects who do not meet these criteria 
must not be enrolled in the study. All subjects will be required to provide consent for a mandatory 
tumor biopsy for entry into this study. This consent is included in the main subject informed 
consent form. All screening procedures must be performed within 4 weeks (28days) prior to 
starting osimertinib unless otherwise stated. The screening procedures include: 
• Complete history and physical examination including vital signs, height, weight and ECOG 
performance score (see Appendix A). 
• Imaging studies: Patients should have a radiographical evaluation with contrast-enhanced 
CT scan of the chest/abdomen/pelvis.  Whole-body FDG-PET scan may be done at the 
investigator’s discretion. Brain imaging will also be obtained via either MRI or CT of the 
brain with contrast. 
• Electrocardiogram (ECG) 
• Echocardiogram 
• Confirmation of diagnosis and mutation status by the NCI Laboratory of Pathology, or as 
follows: 
Patients whose EGFR mutation status was confirmed by CLIA-certified Next Generation 
Sequencing or cobas® EGFR Mutation Test v1/2 at an outside institution may forego 
confirmation of EGFR mutation status at the NCI before enrolling into the protocol.  EGFR 
mutations detected in ctDNA by CLIA assay are acceptable for enrollment.  If tumor tissue 
from the mandatory biopsy is available and the quality of the sample is adequate for further 
testing, it will be tested for the presence of EGFR mutations (included in the cancer gene 
mutation panel), or by whole exome sequencing (WES) under Clinomics to confirm EGFR 
mutation status. In case EGFR mutation is not detected at the NCI, the test will be repeated 
by the Laboratory of Pathology, and if EGFR mutation is still not detected, study 
investigators will determine whether or not to keep the patient on the protocol based on the 
patient’s clinical symptoms and an objective response evaluation at the first tumor imaging 
in 8 weeks.  
 
A block of primary tissue (or 15-20 unstained sections on charged slides) from the time of 
diagnosis and/or the latest biopsy at progression will be required from each patient. Referring 
institutions will send the tumor block or 15-20 unstained sections on charged slides to CCR/NCI 
for confirmation of diagnosis and mutation status. If adequate tissue is not available, a fresh biopsy 
will be performed that will also be a part of the baseline mandatory biopsy if patient is eligible and 
signs consent to this protocol. In case a biopsy at study entry is not clinically safe and biopsy 


Abbreviated Title:  LAT for NSCLC 
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21 
material from a previously performed procedure is available, archival tissue will be obtained for 
mutation testing required to determine eligibility for this protocol. ctDNA analysis for EGFR 
mutation detection may also be considered in patients where biopsy is not clinically feasible. 
 
• Laboratory evaluation (baseline tests to be obtained within one week prior to starting 
treatment unless otherwise indicated) 
o Hematological Profile: Complete blood count (CBC) with differential and platelet 
count, prothrombin time/international normalized ratio (PT/INR), activated partial 
thromboplastin time (aPTT). 
o Biochemical Profile: Sodium, potassium, calcium, phosphorous, magnesium, blood 
urea nitrogen (BUN), creatinine, glucose, aspartate aminotransferase (AST), 
alanine 
aminotransferase 
(ALT), 
alkaline 
phosphatase 
(ALP), 
lactate 
dehydrogenase (LDH), bilirubin, albumin, creatinine kinase. 
o Baseline glomerular filtration rate (GFR) calculation. 
o Serum or urine beta-hCG for female patients of childbearing potential within 72 
hours prior to starting treatment. 
• Cerebrospinal fluid analysis (cytology, cell counts, and protein and glucose levels) will be 
performed only in patients with suspected leptomeningeal disease. 
 
NOTE:  An ophthalmologic evaluation will also be performed during the screening period, but it is 
not an exclusion criterion.  See Section 6.4.4.  
 
Note:  Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural 
Research Program Clinical Protocols). 
2.4 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents.  Verification of Registration will be forwarded electronically via e-mail to the research 
team. A recorder is available during non-working hours. 
  Treatment Assignment and Randomization/Stratification Procedures 
Cohorts 
Number 
Name 
Description 
1 
Cohort 1 
Oligoprogressive EGFR-Mutated NSCLC EGFR TKI-naïve (EGFR 
mutation +) 
2 
Cohort 2 
Oligoprogressive EGFR-Mutated NSCLC post 1st/2nd gen EGFR 
TKI (T790M+) 


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22 
3 
Cohort 3 
Oligoprogressive EGFR-Mutated NSCLC; pts treated with 
osimertinib in other institutions and developed acquired resistance 
 
Arms 
Number 
Name 
Description 
1 
Arm 1 
Osimertinib followed by LAT followed by osimertinib 
2 
Arm 2 
LAT followed by osimertinib 
 
Stratifications 
Stratification is not applicable to this study. 
 
Randomization and Arm Assignment 
Randomization is not applicable to this study.  Subjects in Cohorts 1 and 2 will be directly assigned 
to Arm 1.  Subjects in Cohort 3 will be directly assigned to Arm 2. 
3 STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a single-institution, open-label phase II trial. Patients with EGFR mutation-positive NSCLC 
who are treatment-naïve (cohort 1) or who progressed on first- or second-generation EGFR-TKIs 
– erlotinib, gefitinib, afatinib – and acquired the T790M mutation (cohort 2) will be included in 
the study and treated with osimertinib.  These groups of patients will be followed for progression-
free survival (PFS1).  At the time of progression, their candidacy for local ablative therapy will be 
assessed at a multidisciplinary conference.  Eligibility for local ablative therapy (LAT) is based on 
the following criteria:  
1. Oligoprogressive disease – no more than 5 sites of progressive disease that are amenable 
to treatment with LAT (surgery, radiation therapy, radiofrequency ablation, or 
cryoablation) independent of size and location of lesions. 
2. Patients with neurological or imaging signs of leptomeningeal disease and/or confirmed by 
a lumbar puncture occurring after initiation of osimertinib will be considered for LAT if 
radiation or intrathecal methotrexate can be administered for local treatment.  In these 
cases, following LAT, osimertinib will be increased to 160 mg dose. The dose of 
osimertinib for leptomeningeal disease treatment under this protocol is 160 mg of 
osimertinib. Osimertinib has superior penetration of the blood brain barrier and the 160 mg 
dose has been used extensively in clinical studies with minimal side effects.   
If patients are eligible for local ablative therapy, osimertinib will be resumed at the discretion of 
the PI once the patient has completed LAT. They will be followed for second progression on 
osimertinib (PFS2). If patients are not eligible for local ablative therapy, they will be referred for 
standard of care chemotherapy as per treating physicians’ discretion. These patients may also be 
considered for other clinical trials. 


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23 
Those who were treated with osimertinib in other institutions in on-going clinical trials and 
developed acquired resistance (cohort 3) will also be assessed for their candidacy for local ablative 
therapy and may be enrolled onto the study if they are eligible for local ablative therapy. These 
patients will only be part of the LAT and re-challenge with osimertinib part of the study. 
Tumor samples will be obtained at baseline by a mandatory biopsy unless fresh tissue was 
collected at screening. At the time of first progression on osimertinib if a patient is eligible for 
surgery as a form of LAT, then tissue sample will be obtained for all correlative studies. For 
patients who are not eligible for LAT or a form of LAT that is not surgery (radiation, 
radiofrequency ablation, cryoablation), then a mandatory biopsy will be performed, if clinically 
safe, to obtain tissue for correlative studies. If a biopsy at this time is not clinically safe, then tissue 
obtained from the previous biopsy for mutation testing needed for eligibility for this protocol may 
be used. At the time of second progression on osimertinib, a fresh tumor biopsy is optional. 
 
3.2 
RE-TREATMENT OF SUBJECTS 
A small number of subjects may be eligible for re-treatment and would be required to meet all 
eligibility criteria at the time of re-treatment. We do not anticipate changes in the risk profile at 
the time of initial enrollment versus re-treatment. 
Patients who were initially thought to have progression by RECIST criteria, and hence taken off 
therapy, and were later found to have a biopsy-proven alternative diagnosis such as pneumonia or 
inflammation may be eligible for re-treatment on the study.  In such cases, interruption of 
osimertinib should not be more than one month.   
 
 


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24 
 
3.3 
DRUG ADMINISTRATION 
Treatment will be administered on an outpatient basis. Courses are defined as 28 days of dosing. 
The starting dose of osimertinib will be 80 mg per day for patients without leptomeningeal disease 
and 160 mg per day for those with leptomeningeal disease at baseline. Please see section 13.1.3 
for detailed drug administration instructions. There is no limit to the number of cycles a patient 
can receive. In the event of an adverse event at least possibly related to the agent, the dose of 
osimertinib should be adjusted according to the guidelines in Section 3.7. Reported adverse events 
and potential risks are described in Section 13.  
Patients will be requested to maintain a medication diary (See Appendix C) of each dose of 
medication.  The medication diary will be returned to clinic staff at the end of each course. The 
protocol will follow NIH policy for Conducting and Documenting Drug Accountability for Oral 
Investigational Agents that are Self-Administered by Patients. 
3.4 
DOSING DELAYS/DOSE MODIFICATIONS 
 Management of IP related toxicities  
Dose adjustment for adverse events should be in accordance with the following table: 
Table 2. Osimertinib dose adjustment information for adverse reactions 
Target Organ 
Adverse Reactiona  
Dose Modification  
Pulmonary  
ILD/Pneumonitis 
Permanently discontinue 
osimertinib   
Cardiac 
QTc interval greater than 500 msec Withhold osimertinib. If QTc 
interval recovers less than 481 


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25 
Target Organ 
Adverse Reactiona  
Dose Modification  
on at least 2 separate ECGs 
msec within 4 weeks, then restart at 
one dose level lower. If not 
resolved after 4 weeks, then the 
patient should be withdrawn from 
study therapy. 
If there is further increase of QTc 
greater than 500 msec at the lowest 
dose level, permanently discontinue 
osimertinib. 
QTc interval prolongation with 
signs/symptoms 
of 
serious 
arrhythmia 
Permanently discontinue 
osimertinib  
 
Asymptomatic, absolute decrease in 
LVEF of 10% from baseline  
Withhold osimertinib for up to 4 
weeks. If resolved to baseline 
LVEF, resume. If not improved to 
baseline, permanently discontinue. 
 
Symptomatic 
congestive 
heart 
failure 
Permanently discontinue 
osimertinib  
Other  
Grade 3 or higher adverse reaction, 
unless in the opinion of the PI the 
patient can safely continue 
Withhold osimertinib for up to 4 
weeks 
If Grade 3 or higher adverse reaction 
improves 
to 
Grade 
0-2 
after 
withholding of osimertinib for up to 
4 weeks  
Osimertinib may be restarted at the 
same dose or a lower dose per 
investigator discretion. 
Grade 3 or higher adverse reaction 
that does not improve to Grade 0-2 
after withholding for up to 4weeks  
Permanently discontinue 
osimertinib   
a Note: The intensity of clinical adverse events graded by the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade), 
where the clinician considers the event of concern to be specifically associated with osimertinib 
(and not attributable to the disease or disease-related processes for which patient is being treated), 
dosing will be interrupted and supportive therapy administered as required in accordance with 
local practice/guidelines. Once a patient has a dose reduction due to toxicity, the dose will not be 
re-escalated.  Only one dose reduction will be allowed per patient except for patients with 
leptomeningeal disease at baseline who started osimertinib at 160 mg per day (two dose reductions 
are allowed in those with leptomeningeal disease at baseline). Occurrence of an event requiring 
dose reduction at the 40 mg dose will result in removal from study therapy. 
If the toxicity resolves or reverts to ≤CTCAE grade 2 within 4 weeks of onset, treatment with 
osimertinib may be restarted at the same dose or a lower dose using the rules below for dose 
modifications (Table 3). There will be no individual modifications to dosing schedule in response 


Abbreviated Title:  LAT for NSCLC 
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26 
to toxicity, only potential dose reduction or dose interruption. 
If the toxicity does not resolve to ≤CTCAE grade 2 after 4 weeks, (then the patient should be 
withdrawn from study therapy and observed until resolution of the toxicity.  
Table 3. Dose Interventions 
Intervention 
Osimertinib Dose 
Starting Dose* 
80 mg daily 
Reduced Dose 
40 mg daily 
* The starting dose for patients with leptomeningeal disease at baseline is 160 mg daily. Two dose 
reductions to 80 mg daily and 40 mg daily are allowed in these patients. 
On resolution of toxicity within 4 weeks: 
If an event subsequently requires dose interruption, osimertinib may restart at the same dose or the 
reduced dose, on resolution/improvement of the event at the discretion of the clinician. 
3.4.1.1 Pulmonary Symptoms 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive 
of interstitial lung disease is observed, an interruption in osimertinib dosing is recommended. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of ILD should be considered and study drug should be permanently 
discontinued. Where ILD is suspected, administer corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper.  
In the absence of a diagnosis of interstitial lung disease, osimertinib may be restarted. 
3.4.1.2 QTc Prolongation 
Patients with QTcF prolongation fulfilling the following criteria (i.e., confirmed QTcF 
prolongation to > 500 msec should have osimertinib interrupted and regular ECGs performed until 
QTc interval is less than 481 msec. If QTc interval recovers to less than 481 msec within 4 weeks, 
then restart at a reduced dose (40 mg). If not resolved after 4 weeks, then the patient should be 
withdrawn from study therapy. If there is further increase of QTc greater than 500 msec at 40 mg 
dose, permanently discontinue osimertinib. 
 
3.4.1.3 Corneal Ulceration 
Patients experiencing corneal ulceration will not be permitted to restart osimertinib treatment. 
 
3.4.1.4 Skin reactions  
Recommendations for appropriate management of skin reactions, including guidance on dose-
adjustments for clinically significant and/or intolerable skin reactions that are considered by the 
clinician to be causally related to osimertinib is provided in Appendix D, Guidance for the 
Management of Adverse Events in Studies using 80 mg osimertinib.” 


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27 
 
3.4.1.5 Diarrhea 
Recommendations for appropriate management of diarrhea, including dose-adjustments for 
adverse events of diarrhea that are of CTCAE grade ≥3 or that are clinically significant and/or 
intolerable and considered by the clinician to be causally related to osimertinib, is provided in 
Appendix D,  “Guidance for the Management of Adverse Events in Studies using 80 mg 
osimertinib.” 
3.5 
ON STUDY ASSESSMENTS 
Tumor samples will be obtained at baseline by a biopsy unless fresh tissue is available at screening. 
Patients will be seen on Days -1 and 7 (±2 days) of cycle 1, and on Day -1 of each subsequent 
treatment cycle. On study assessments can be performed within ±5 days of the specified time point, 
unless otherwise indicated. The following will be done: 
• History and physical exam 
• Laboratory evaluation: Hematologic and biochemical profile as listed in section 2.3 
• Cerebrospinal fluid analysis (cytology, cell counts, and protein and glucose levels) will be 
performed only in patients with suspected leptomeningeal disease. 
• ECG 
• Blood sample for correlative studies  
• Saliva sample for detection of EGFR mutation  
• Urine sample for correlative studies 
• Tumor imaging will be performed every 56 days (every 2 cycles). 
• At the time of progression if a patient is eligible for surgery as a form of LAT, then tissue 
sample will be obtained. For patients who are not eligible for LAT or a form of LAT that 
is not surgery (RT, RFA, cryoablation), then a mandatory biopsy will be performed, if 
clinically safe. 
 
Note 1: If patients progress on osimertinib and are eligible for LAT, appropriate testing such as 
pulmonary function tests and a whole-body FDG-PET scan will be performed.  
Note 2: If patients progress at the same site where LAT has been performed before, the progression 
will be considered to be a result of inadequate ablation and they will be considered for repeat LAT 
and again re-challenged with osimertinib if clinically feasible. Re-initiation of osimertinib 
treatment in this case also has to be within a month.   
Note 3: Every attempt will be made to collect urine and saliva samples at each protocol specified 
timepoint. Collection of the urine and saliva samples is to be strongly pursued but is not required 
and may be waived at the discretion of the PI.  
Before re-initiation of osimertinib following LAT, the following will be done. 
• History and physical exam 
• Laboratory evaluation 
o Hematological Profile: Complete blood count (CBC) with differential and platelet 
count, prothrombin time/international normalized ratio (PT/INR), activated partial 
thromboplastin time (aPTT). 


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28 
o Biochemical Profile: Sodium, potassium, calcium, phosphorous, magnesium, blood 
urea nitrogen (BUN), creatinine, glucose, aspartate aminotransferase (AST), 
alanine 
aminotransferase 
(ALT), 
alkaline 
phosphatase 
(ALP), 
lactate 
dehydrogenase (LDH), bilirubin, albumin, creatinine kinase. 
o Baseline glomerular filtration rate (GFR) calculation. 
o Serum or urine beta-hCG for female patients of childbearing potential within 72 
hours prior to therapy. 
• ECG 
• Tumor imaging  
• Blood samples for correlative studies  
 
After re-initiation of osimertinib, patients will be seen on day 7 (±2 days) and Day -1 of each 
subsequent treatment cycle (+/-5 days), then the following will be done. 
• History and physical exam 
• Laboratory evaluation: Hematologic and biochemical profile 
• ECG  
• Tumor imaging will be performed every 56 days (every 2 cycles) 
• Blood sample for correlative studies 
• Saliva sample for detection of EGFR mutation  
• Urine sample for correlative studies 
• At the time of second progression on osimertinib, a fresh tumor biopsy is optional. 
 
An echocardiogram will be performed every 4 months (± 7 days) while the patient receives 
treatment. 
 
After 30 days (±7 days) from treatment termination, the following will be obtained: 
• History and physical exam 
• Laboratory evaluation: Hematologic and biochemical profile 
• ECG 
• Research blood, urine and saliva collection


Abbreviated Title:  LAT for NSCLC 
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29 
3.6 
STUDY CALENDAR 
Screening assessments must occur within 28 days prior to study drug initiation unless otherwise indicated.   
Dosing cycles after cycle 1 may be delayed for up to two weeks to accommodate schedule conflicts, Federal holidays, inclement 
weather, etc. 
Visit 
 
1  
Screening 
(within 
28 days) 
2 
3 
4 
5 
6 
7 
8+ 
30 day post 
therapy 
visitg 
Long 
term 
follow up 
For details 
see Protocol 
Section 
Week 
 
1 
2 
5 
9 
13 
17  
21+ 
(every 4 w 
unless 
otherwise 
specified) 
 
 
 
Cycle 
 
1 
 
2 
3 
4 
5 
6+ 
 
 
 
Written informed 
consent (including 
tissue samples) 
X 
 
 
 
 
 
 
 
 
 
 
NIH Advance 
Directives Form f 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
diagnosis and 
mutation status 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical 
history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Version Date:  12/26/2019 
 
30 
Visit 
 
1  
Screening 
(within 
28 days) 
2 
3 
4 
5 
6 
7 
8+ 
30 day post 
therapy 
visitg 
Long 
term 
follow up 
For details 
see Protocol 
Section 
Week 
 
1 
2 
5 
9 
13 
17  
21+ 
(every 4 w 
unless 
otherwise 
specified) 
 
 
 
Cycle 
 
1 
 
2 
3 
4 
5 
6+ 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECGa 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
Section 
6.4.3.1 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ophthalmologic 
evaluation 
X 
 
 
 
 
 
 
 
 
 
Section 6.4.4 
Echocardiogram 
X 
 
 
 
 
 
X 
(every 
4 mths) 
 
 
 
Section 3.5 
Treatment 
dispensed/returned 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse event review 
(AEs and SAEs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood samples for 
hematology and 
clinical chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 2.3 
Βeta-hCG 
Xb 
 
 
 
 
 
 
 
 
 
 
Research urineh  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 3.5 


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31 
Visit 
 
1  
Screening 
(within 
28 days) 
2 
3 
4 
5 
6 
7 
8+ 
30 day post 
therapy 
visitg 
Long 
term 
follow up 
For details 
see Protocol 
Section 
Week 
 
1 
2 
5 
9 
13 
17  
21+ 
(every 4 w 
unless 
otherwise 
specified) 
 
 
 
Cycle 
 
1 
 
2 
3 
4 
5 
6+ 
 
 
 
Research blood  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 3.5 
Research salivai 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 3.5 
MRI or CT of the 
brain 
X 
 
 
 
 
 
 
 
 
 
Section 2.3 
CSF analysise 
X 
 
 
 
 
 
 
 
 
 
 
Computed 
tomography (CT) scan 
of the 
chest/abdomen/pelvis 
X 
Radiologic measurements should be performed every 8 weeks. 
 
 
Section 3.5 
Tumor measurement 
X 
Tumor measurements are repeated every 8 weeks 
 
 
Section 3.5 
Tumor biopsyc 
A mandatory tumor biopsy will be obtained at baseline (unless fresh tissue 
available from screening) and at first progression. At second progression, a 
fresh tumor biopsy is optional. 
 
 
Section 3.5 
Annual visit or phone 
call to assess survival, 
progression and new 
cancer therapy 
 
 
X 
Section 3.5 
a: 12-lead ECGs can be performed on day -1 (+/- 5 days) of each cycle. 
b: Serum pregnancy test (women of childbearing potential) within 72 hours prior to therapy. 
c: Tumor samples will be obtained at baseline (unless fresh tissue available from screening) by a mandatory biopsy. At the time of first 
progression on osimertinib if a patient is eligible for surgery as a form of LAT, then tissue sample will be obtained for all correlative 


Abbreviated Title:  LAT for NSCLC 
Version Date:  12/26/2019 
 
32 
studies. For patients who are not eligible for LAT or a form of LAT that is not surgery (radiation, radiofrequency ablation, 
cryoablation), then a mandatory biopsy will be performed, if clinically safe, to obtain tissue for correlative studies. If a biopsy at this 
time is not clinically safe, then tissue obtained from the previous biopsy for the mutation testing needed for eligibility for this protocol 
may be used. At the time of second progression on osimertinib, a fresh tumor biopsy is optional. 
e: Cerebrospinal fluid analysis (cytology, cell counts, and protein and glucose levels) will be performed only in patients with suspected 
leptomeningeal disease 
f:  As indicated in section 12.3, all subjects ≥ age 18 will be offered the opportunity to complete an NIH advance directives form.  This 
should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained.  The 
completion of the form is strongly recommended but is not required. 
g. The post treatment visit should occur 30 days (± 7 days) after terminating treatment.  This applies to both the first treatment course 
and second, if applicable.  The assessments listed refer to those that will be performed if the patient is seen in clinic (first course and 
second course).  If the patient is unable to return to the clinic for the follow up visit, adverse event assessments will be performed by 
telephone or email.  We will request that required labs and ECG be performed locally and provided to us, and if the patient has visited a 
local oncologist in this timeframe, the progress notes will also be requested. If any aspect of the required assessments as listed in the 
calendar is not performed, it will be recorded and reported to the IRB as a deviation. 
h. Every attempt will be made to collect urine samples at each protocol specified timepoint. Collection of these samples is to be 
strongly pursued but is not required and may be waived at the discretion of the PI. 
i. Every attempt will be made to collect research saliva samples at each protocol specified timepoint.  Collection of these samples is to 
be strongly pursued but is not required and may be waived at the discretion of the PI. 
 
 


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33 
3.7 
RADIATION THERAPY GUIDELINES 
Patients with oligoprogressive disease will be referred for radiation therapy if they are not 
eligible for surgery as a form of LAT. The treating radiation oncologist will evaluate the 
feasibility of safely treating the site(s) of progressive disease, for which he/she may require a 
CT simulation/planning session. He/she may determine at any time during the 
consult/simulation/planning process that radiation therapy is not feasible.  
Each site of progressive disease should be treated to a definitive dose. Brain metastases may be 
treated with whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), or the 
combination of WBRT + SRS. Sites of extracranial disease may be treated with conventionally 
fractionated external beam radiation therapy (EBRT) or stereotactic body radiation therapy 
(SBRT)/stereotactic ablative radiotherapy (SABR).  The specific dose and fractionation scheme 
is at the discretion of the treating radiation oncologist.  If multiple sites are to be treated with 
radiation therapy, they may be treated either concurrently or sequentially at the discretion of the 
treating radiation oncologist.   
As of Amendment J, patients may receive radiation therapy concurrently with osimertinib. The 
type and amount of radiation therapy to be administered will be determined by the treating 
radiation oncologist.  
In the opinion of the treating radiation oncologist, if any site cannot be safely treated to a 
definitive dose for any reason, patient will be considered not to be eligible for radiation as a 
form of LAT. Palliative radiation may still be given if clinically indicated.  Patients will not be 
eligible for LAT in such cases.  
Each patient must be specifically consented for unknown side effects and/or toxicities, either 
acute or chronic, resulting from the prior and subsequent osimertinib treatment in addition to 
radiation treatment under this protocol.  
3.8 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
 Criteria for removal from protocol therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• Disease progression, per RECIST*, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s) as described in section 3.4, 
• Delay of treatment of ≥ 4 weeks,  
• Patient decides to withdraw from the study therapy 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
• Severe non-compliance with the study protocol  
Note: *Some subjects may be eligible for re-treatment if removed for this reason.  See Section 


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34 
3.2. 
Procedures for discontinuation of a subject from investigational product  
At any time, subjects are free to discontinue investigational product or withdraw from the study, 
without prejudice to further treatment. A subject that decides to discontinue investigational will 
always be asked about the reason(s) and the presence of any adverse events.  If possible, they 
will be seen and assessed by an Investigator(s).  Adverse events will be followed up for 
minimum of 4 weeks after the final dose of osimertinib. All study drugs should be returned by 
the subject. 
3.9 
FOLLOW UP 
Patients will be followed either with clinic visits or phone interviews yearly until death.  Patients 
removed from treatment for unacceptable adverse event(s) will be followed clinically until 
resolution or stabilization of the adverse event, and then via clinic visits or phone interviews 
yearly until death. 
The following information will be collected: 
• Date of follow up 
• Is patient dead or alive? 
• If dead, document exact date of death. 
• Further treatment(s), if any  
• Document date of disease progression 
3.10 OFF STUDY CRITERIA 
At any time, patients are free to discontinue treatment and withdraw from the study (i.e., study 
treatment and assessments). A patient who decides to discontinue treatment and assessments 
will always be asked about the reason(s) and the presence of any AEs.  If possible, they will be 
seen and assessed by an Investigator. Adverse events will be followed up; all investigational 
product should be returned by the patient or caretaker. The term withdrawal from the study 
refers to both the discontinuation from the treatment and study assessments. Withdrawn subjects 
will not be replaced. 
Once a patient has been removed from study, no further data can be collected; therefore, with 
completion of the duration of follow-up described in Section 3.9, the criteria for removal from 
study are: 
• Lost to follow-up 
• Death 
• The patient decides to withdraw from the study. 
• Investigator discretion 
The reason for study removal and the date the patient was removed must be documented in the 
database.  


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3.11 OFF-PROTOCOL THERAPY AND OFF-STUDY PROCEDURE 
Authorized staff must notify the NCI Central Registration Office (CRO) when a patient is 
taken off protocol therapy and when a subject is taken off study. A Participant Status Update 
Form from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm)  main page 
must be completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov.   
4 CONCOMITANT MEDICATIONS/MEASURES 
4.1 
CONCOMITANT MEDICATIONS  
Once enrolled all patients must try to avoid concomitant use of medications, herbal supplements 
and/or ingestion of foods with known potent inhibitors or inducers of CYP3A4 whenever 
feasible; however, patients may receive any medication that is clinically indicated for treatment 
of adverse events. Such drugs must have been discontinued for an appropriate period before 
they enter screening and for a period of 3 months after the last dose of osimertinib. All 
concomitant medications should be captured on the CRF.  Guidance on medicines to avoid, 
medications that require close monitoring and on washout periods is provided (see Appendix 
B). 
If medically feasible, patients taking regular medication, with the exception of potent inhibitors 
or inducers of CYP3A4 (see above), should be maintained on it throughout the study period. 
Patients taking concomitant medications whose disposition are dependent upon CYP3A4, and 
BCRP and which have a narrow therapeutic index should be closely monitored for signs of 
changed tolerability as a result of increased exposure of the concomitant medication whilst 
receiving osimertinib. Additionally, due to the potential CYP450 and p-glycoprotein induction 
risk exposure of drug that are metabolized by CYP3A4, CYP1A2 or CYP2C or whose 
deposition is mediated by p-glycoprotein could also be reduced and should also be monitored 
for reduction in therapeutic activity (especially those which have narrow therapeutic index).  
Guidance on medications to avoid, medications that require close monitoring and on washout 
periods should be provided. 
Patients should be advised of the potential reduction in effectiveness of oral hormonal 
contraceptives (due to CYP3A4 induction) when used with osimertinib. A change to a non-oral 
method of contraception (e.g. IUS Levonorgestrel Intra Uterine System, Medroxyprogesterone 
injections), or addition of a barrier method (e.g. condoms, diaphragm) to the primary hormonal 
method, is recommended prior to the commencement of treatment. 
Up to 1.5-fold increase in exposure may occur in statin exposure when co administered with 
osimertinib. It is recommended that the starting and maintenance dose of statins should be as 
low as possible and should be guided by the statin label. Monitoring of low- density lipoprotein 
(LDL) cholesterol levels is advised. If the patient experiences any potentially relevant adverse 
events suggestive of muscle toxicity including unexplained muscle pain, tenderness, or 
weakness, particularly if accompanied by malaise or fever, the statin should be stopped, creatine 
kinase (CK) levels should be checked, and any appropriate further management should be taken. 
Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. 


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 Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form. 
 Supportive care guidelines  
• Nausea/vomiting may be treated with anti-emetics.  
• Diarrhea should be managed with loperamide:  4 mg at first onset, then 2 mg every 
2-4 hours until diarrhea is controlled (maximum = 16 mg loperamide per day).  
• Hand-foot syndrome may be treated with topical emollients (such as Aquaphor), 
topical/systemic steroids, and/or antihistamine agents.  Vitamin B6 (pyridoxine; 50-
150 mg orally each day) may also be used.  Avoid exposure to heat, hot water, 
pressure, or friction. Use of soft, well-fitting shoes may help, as may use of 
acetaminophen if needed for analgesia. 
• Patients with neutropenic fever or infection should be evaluated promptly and 
treated with IV antibiotic therapy or therapeutic colony-stimulating factors as 
appropriate following the ASCO guidelines.(68) Packed red blood cell and platelet 
transfusion should be administered as clinically indicated.  Erythropoietic agents 
may be used at the discretion of the treating physician. 
 Additional Restrictions 
If medically feasible, patients taking regular medication, with the exception of potent inhibitors 
or inducers of CYP3A4 (see above), should be maintained on it throughout the access program 
period (30 days post-last dose). Patients taking concomitant medications whose disposition is 
dependent upon CYP3A4 and breast cancer resistance protein (BCRP) and which have a narrow 
therapeutic index should be closely monitored for signs of changed tolerability as a result of 
increased exposure of the concomitant medication whilst receiving osimertinib.  Patients taking 
concomitant medications whose disposition is dependent upon CYP3A4, CYP1A2, CYP2C or 
p-glycoprotein and which have a narrow therapeutic index should be closely monitored for 
reduction in therapeutic activity as a result of the reduced exposure of the concomitant 
medication while receiving osimertinib. Guidance on medications to avoid, medications that 
require close monitoring and on washout periods is provided (see Appendix B). 
Up to 1.5-fold increase in exposure may occur in statin exposure when co-administered with 
osimertinib. It is recommended that the starting and maintenance dose of statins should be as 
low as possible and should be guided by the statin prescribing information.  
Patients taking warfarin should be monitored regularly for changes in prothrombin time or 
international normalized ratio (INR). 
Patients who wear contact lenses must discontinue wearing their lenses if they have any mild to 
moderate eye symptoms (CTCAE grade ≤2) while receiving treatment with osimertinib until at 
least one week after symptoms have resolved.  If a patient has a recurrence of eye symptoms or 
experiences any severe (CTCAE grade ≥3) ocular events, they must discontinue wearing their 
contact lenses until at least one week after treatment with osimertinib is permanently 
discontinued.  Patients must not use any eye drops or ointment for treatment of eye symptoms, 
unless agreed to by an access program doctor, at any time during the access program until 1 


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week after osimertinib has been permanently discontinued. Patients should consult their 
clinician promptly if they have any concerns.  
5 BIOSPECIMEN COLLECTION 
Research tissue samples will initially be sent to the laboratory of Dr. Doug Figg (see Section 
5.1.1), and samples for clinical testing will be directly transported to the Laboratory of 
Pathology.  All blood, urine, and saliva samples will initially be sent to the laboratory of Dr. 
Doug Figg (see Section 5.1.2), where they will be stored until ready for transfer to the recipient 
labs for the correlative studies as described below.  Coded, linked data will be shared with 
collaborators as specified below, however, the collaborators will not have access to the key that 
links the data back to the patients in which it was obtained. 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
 Pathology correlative studies 
5.1.1.1 Timing 
Tumor samples will be obtained at the following times. 
• At baseline prior to initiation of the study treatment 
• At the time of first progression on osimertinib  
• At the time of second progression on osimertinib, a fresh tumor biopsy is optional. 
5.1.1.2 Tissue sampling and handling  
An excision biopsy of accessible lymph node or cutaneous nodule, or CT or bronchoscopy 
guided core needle biopsy using a 16-18 gauge needle will be obtained at baseline. At the time 
of first progression on osimertinib, if a patient is eligible for surgery as a form of LAT, then 
tumor sample will be obtained for all correlative studies. For patients who are not eligible for 
LAT or a form of LAT that is not surgery (radiation, radiofrequency ablation), then a mandatory 
biopsy will be performed, if clinically safe, to obtain tissue for correlative studies.  If a biopsy 
at this time is not clinically safe, then tissue obtained from the previous biopsy for the mutation 
testing needed for eligibility for this protocol may be used. 
Material released for research studies will be documented on form NIH 2803-1 Request & 
Certification for Research Procurement of Human Biological Materials. Initial processing of 
samples for research will depend on the size of the tumor biopsy. For core biopsies the research 
sample will typically consist of up to 4 cores. The first core will be processed and stored in the 
NCI Laboratory of Pathology.  
The second core (when successfully obtained without additional risk to the patient) will be snap 
frozen in a microcentrifuge vial in liquid nitrogen. The third core will be frozen in an OCT block 
in Liquid Nitrogen. The investigators may decide to use either the 3rd or 4th core to generate a 
cell line or patient-derived xenograft (PDX). These research samples will be stored in Dr. Figg’s 
laboratory (10/3B52) at -80°C on site.   
Tumor may be viably frozen, typically at concentrations of 20-100x106/mL in FBS with 10% 
DMSO using a temperature controlled freezing process to optimize sample viability. Samples 
will be transferred to liquid Nitrogen tanks for long-term storage. 


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Attempts will be made to generate cell lines from viable tumor or normal lung tissue and body 
fluids, such as pleural effusion in a subset of patients.  
Tumor tissue from a subset of patients may also be incorporated as xenograft in NOD/SCID 
mice to grow tumor tissue in vivo as patient derived xenografts (PDX).  
Each patient sample set will be assigned a unique patient identifier. The protocol scientific 
investigator(s) handling the samples will be blinded as to the patient identification, patient data 
and outcome. 
5.1.1.3 Studies 
5.1.1.3.1 Mutational analysis will be conducted using the cancer gene mutation panel and 
whole exome and transcriptome sequencing. Whole genome sequencing will be 
performed in select cases. The cancer gene mutation panel will be performed in the 
Ion Torrent platform in Dr. Mark Raffeld’s Molecular Pathology Core. These genes 
include ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, 
EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, 
GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, 
MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, 
RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53, and VHL. 
 
5.1.1.3.2 Proteomic approaches using mass spectrometry, luminex assay, Simple Western 
assay (NanoPro) and reverse phase protein array (RPPA) will be used for quantitation 
of proteome and post-translational modifications, including phosphorylation to 
identify changes in signaling pathways before and after treatment with osimertinib. 
 
5.1.1.3.3 Pre- and post- treatment tumor tissue will also be grown in patient-derived xenograft 
(PDX) models to study mechanisms of resistance. Efforts will be made to generate 
cell lines from these tissues. Preclinical evaluation in murine cancer models that 
emulate the complexities of human cancers and yet remain tractable for therapeutic 
and diagnostic discovery has recently shown success in guiding clinical research and 
is expected to improve success rates, reduce cost, accelerate timelines, and minimize 
the human toll exacted by current practices wherein efficacy is determined first in 
patients. In early passages, PDX tumors typically retain the histologic and molecular 
heterogeneity and stromal composition characteristic of those in patients and thus are 
essentially patient “avatars”. As such, human target specificity is retained allowing 
for direct evaluation of lead human-specific therapeutics that are in clinical 
development. Although host mouse stroma incorporates into tumors with passage, 
even serially established models have been valuable for first-line evaluation of many 
therapeutics. Additionally, PDX models have been demonstrated as powerful tools 
for the identification of drug resistance mechanisms(69) and targets for second-line 
treatment(70). Programs are also underway to employ PDX models to help guide 
individual patient therapy decisions(71, 72). Therefore, use of PDX models is relevant 
to the study of resistance to osimertinib and potential approaches to abrogate 
resistance. PDX models will be established from fresh tumor material in 
collaboration with the Center for Advanced Preclinical Research (CAPR), at NCI-


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Frederick. CAPR, founded by the Center for Cancer Research (CCR) under the 
direction of Dr. Terry Van Dyke, is a dedicated organization adept in the use of 
modern mouse cancer models for applied preclinical research. Its mission is to 
develop, disseminate, and apply reproducible preclinical practices effective in 
guiding clinical research toward improved cancer patient management. CAPR has 
extensive expertise in preclinical research utilizing modern murine cancer models of 
a variety of cancer types. Broadly applicable and specialized methodologies have 
been optimized and are executed under standard operating procedures. Coded, linked 
samples will be sent to: 
Zoe Weaver Ohler, PhD 
Principal Scientist/Team Leader, Preclinical Evaluation 
Center for Advanced Preclinical Research 
Leidos Biomedical Research, Inc.  
Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. Bldg. 539 
Frederick, MD   21702 
 
5.1.1.3.4 A correlative study of treatment response to novel targeted agents or combination 
targeted agents along with osimertinib will be conducted using CANScriptTM – a 
platform to grow patient derived tumor tissue in three dimensional cultures along 
with proprietary tumor microenvironment components. This study will be done in 
collaboration with Mitra Biotech in a subset of patients. Osimertinib -resistant tumor 
tissue obtained at surgery for LAT will be cultured as explants using CANScriptTM. 
Novel combination agents or specific targeted agents will be used to test sensitivity 
of these osimertinib -resistant tumors to other targeted agents. Positive “hits” will be 
then used in the PDX models generated from the same patient to assess tumor 
response in vivo. If this approach to identify and validate novel targeted agents is 
successful, the protocol will be amended to potentially use this information to treat 
patients after PFS2.  For each sample collection a “kit” will be provided by Mitra 
Biotech that will contain sterile labeled containers with sterile isotonic proprietary 
buffer containing antibiotics. The collected core/s of tumor tissue will be coded and 
linked and transferred into the provided containers and shipped in temperature 
controlled containers provided by the company. In addition, 10 ml of blood will be 
collected in BD Vacutainer SSTTM tubes (serum separating tubes) and a CPT (cell 
preparation tube): BD Vacutainer CPTTM with sodium citrate. These coded, linked 
samples will be sent to Mitra Biotech at the following address: 
Parker Cassidy 
Laboratory Director 
Mitra Biotech 
12 Gill Street 
Suite 3150 
Woburn, MA 01801 
 339 999-2300 
info@mitrabiotech.com 
 


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5.1.1.3.5 Proteo-genomics data analysis will be done in collaboration with Dr. Olga Vitek at 
Northeastern University.  Coded, linked genomics or proteomics data generated at 
the NCI will be sent to Dr. Vitek for bioinformatics analysis. Dr. Vitek’s group will 
perform bioinformatics and statistical analysis on the data. Data will be transferred 
securely, and no patient identification will be transferred. 
The data will be sent to: 
Olga Vitek, Ph.D. 
Northeastern University 
440 Huntington Avenue, 310F West Village H 
Boston, MA 02115 
o.vitek@northeastern.edu 
617 373-6305 
https://www.ccis.northeastern.edu/people/olga-vitek/ 
 
5.1.1.3.6 Analysis of genomic data will be completed in collaboration with Dr. Anna 
Panchenko at the National Library of Medicine.  Coded, linked genomic data 
generated at the NCI will be sent to Dr. Panchenko for bioinformatic analysis using 
a secure drive.  Using this data, Dr. Panchenko’s group will evaluate the evolution of 
tumor mutations.  Coded, linked data will be sent securely, and no patient 
identification will be transferred. 
The data will be sent to: 
 
 
Anna Panchenko, M.D. 
 
 
NIH/National Library of Medicine 
 
 
Computational Biology Branch 
 
 
8600 Rockville Pike 
 
 
Building 38A Room 6N607 
 
 
Bethesda, MD 20894 
 
 
301-435-5891 
 
 
panch@ncbi.nlm.nih.gov  
 
5.1.1.3.7 Proteogenomics analysis (Collaboration with S. Cenk Sahinalp, PhD) 
Dr. Sahinalp’s group will perform a temporal proteogenomic analysis of genomics 
and proteomics data obtained from the existing studies performed in this study. WES, 
RNA-seq and mass spectrometry-based proteomics data obtained from the 
experiments performed on the tumor tissue obtained from the mandatory biopsies 
will be used by Dr. Sahinalp’s group to perform further bioinformatics analysis for 
molecular characterization of tumor evolution. In particular, fusion and structural 
variation discovery tools developed by Dr. Sahinalp’s group such as defuse, nFuse, 
MistrVar, and destruct for exomic and transcriptomic sequence analysis will be used 
to match breakpoint signals with novel peptide signals from mass spectrometry data 
through their ProTie pipeline. Tumor phylogenies will be obtained and conserved 
evolutionary trajectories involving DNA, RNA and protein data will be 
characterized. Coded, linked NGS and mass spectrometry-based proteomics data 


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without patient identifiers will be sent to: 
Dr. S. Cenk Sahinalp, PhD 
Cancer Data Science Laboratory 
National Cancer Institute 
Building 10, Room 6N119 
Bethesda, MD. 20892 
Ph: 240-858-7117 
 
5.1.1.3.8 Collaboration with Dr. Ramaswamy Govindan at Washington University 
Genomics analysis on select tumor samples from this study will be performed at the 
McDonnell Genome Institute of the Washington University School of Medicine in 
collaboration with Dr. Govindan. Coded tumor samples without patient identifiers 
will be sent to Dr. Govindan’s laboratory. WES, WGS (in a subset of samples sent) 
and RNA-seq will be performed on select tumor samples using the genomics core at 
Washington University. Coded linked sequencing data on samples analyzed at the 
NCI will also be sent to Dr. Govindan’s group for further bioinformatics analysis and 
comparing with the data obtained at Washington University. The tumor tissue and 
the sequencing data will be sent to: 
Dr. Ramaswamy Govindan  
Anheuser Busch Chair in Medical Oncology 
Director, Section of Medical Oncology 
Washington University School of Medicine 
660 S Euclid Avenue 
Campus Box 8056 
St. Louis, MO 63110 
Phone: 314-747-7405/314-362-5737  
 
5.1.1.3.9 PDX Models - CAPR 
Tumor tissue of selected patients will be grown in patient-derived xenograft (PDX) models 
to study mechanisms of resistance. Efforts will be made to generate cell lines from these 
tissues. Preclinical evaluation in murine cancer models that emulate the complexities of 
human cancers and yet remain tractable for therapeutic and diagnostic discovery has 
recently shown success in guiding clinical research and is expected to improve success rates, 
reduce cost, accelerate timelines, and minimize the human toll exacted by current practices 
wherein efficacy is determined first in patients. In early passages, PDX tumors typically 
retain the histologic and molecular heterogeneity and stromal composition characteristic of 
those in patients and thus are essentially patient “avatars”. As such, human target specificity 
is retained allowing for direct evaluation of lead human-specific therapeutics that are in 
clinical development. Although host mouse stroma incorporates into tumors with passage, 
even serially established models have been valuable for first-line evaluation of many 
therapeutics. Additionally, PDX models have been demonstrated as powerful tools for the 
identification of drug resistance mechanisms and targets for second-line treatment. 
Programs are also underway to employ PDX models to help guide individual patient therapy 


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42 
decisions. PDX models will be established from fresh tumor material in collaboration with 
the Center for Advanced Preclinical Research (CAPR), at NCI-Frederick. CAPR, founded 
by the Center for Cancer Research (CCR), is a dedicated organization adept in the use of 
modern mouse cancer models for applied preclinical research. Its mission is to develop, 
disseminate, and apply reproducible preclinical practices effective in guiding clinical 
research toward improved cancer patient management. CAPR has extensive expertise in 
preclinical research utilizing modern murine cancer models of a variety of cancer types. 
Broadly applicable and specialized methodologies have been optimized and are executed 
under standard operating procedures. 
5.1.1.3.10 Tumor Microenvironment - Medgenome 
Medgenome offers cancer immunotherapy solutions which help in identifying biomarkers 
for patient selection, monitoring durability of response, evaluating mechanisms of drug 
unresponsiveness/resistance, mapping gene expression to pathways and identifying cancer 
vaccine candidates. We will use NGS data (RNA-seq and WES) from patients under this 
protocol for tumor microenvironment analysis solution that can be used as a stand-alone 
solution to analyze the tumor microenvironment at the cellular and molecular level, or can 
complement IHC and FACS-based approaches. We will also use Medgenome’s NGS based 
neo-antigen prediction and neo-epitope prioritization solution that involves HLA binding 
peptides identification, TCR binding peptides identification, Structural Analysis of peptides 
to prioritize TCR binding, Peptide Processing and TAP binding. MedGenome has a CLIA 
certified, CAP accredited and ISO 15189 compliant NGS lab in Foster City, 
California. Coded, linked data will be sent to Medgenome.  The contact information is: 
 
Dr. Amit Chaudhuri, VP, R&D 
Medgenome 
348 Hatch Drive 
Foster City, CA 94404 
888 440-0954 
amitc@medgenome.com 
 
5.1.1.4 Plasma samples for next generation targeted sequencing – Inivata, Inc. 
Coded, linked patient plasma samples for next generation targeted sequencing will be sent to 
Inivata, Inc., a global clinical cancer genomics company utilizing a proprietary liquid biopsy 
platform, Invision™, to transform patient care.  Inivata will provide next-generation sequencing 
testing on circulating tumor DNA isolated from plasma utilizing the Invision™ platform.  This 
amplicon-based platform interrogates 36 genes for common somatic changes found in human 
cancer and was developed with a focus on therapeutically actionable somatic changes. 
Utilizing a target of 2 mls of plasma, DNA will be isolated, quantified and profiled by the 
InVision platform.  Samples with codes (the key for patient identification retained only at NCI) 
will be provided to Inivata and will be sent to Inivata’s CLIA accredited testing laboratory 
located in Research Triangle Park, NC.   Data will be aggregated and communicated after each 
batch of samples sent for testing.  Inivata will be available to provide their expertise in assisting 
with the interpretation of the sequencing results as needed.  Coded, linked patient plasma 


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samples will be sent to:  
Greg Jones 
Inivata, Inc 
7020 Kit Creek Road 
Suite 140 
Research Triangle Park, NC 27709 
+1-919-313-9687 
 
5.1.1.5 Blood and Tissue Samples – FDA 
Plasma and tissue samples from select patients will be sent to the FDA for NGS studies in 
collaboration with Dr. Julia Beaver’s group at the FDA, who will run a targeted NGS panel, 
exome sequencing (WES) and/or TCR (T-cell receptor) sequencing on the samples. The 
platform is Illumina NextSeq500. At this time they plan to use the UMI Toolkit and TruSeq 
170 library prep kits from Illumina to prepare the ptDNA for sequencing.    
5.1.1.6 Blood samples for Cell Free DNA Isolation 
Patients may undergo an optional blood collection of two (2) additional 10 ml Cell-free DNA 
BCT tubes from Streck which will be used for cell-free DNA (cfDNA) isolation. These tubes 
are blood collection tubes which stabilize nucleated blood cells. The proprietary preservative 
prevents the release of genomic DNA, allowing isolation of high quality cell free DNA. These 
tubes will preserve cfDNA in a blood sample for up to 14 days in room temperature. Our 
existing methodology of plasma isolation from EDTA containing purple top tubes with twice 
centrifugation will be compared with that from Cell-free DNA BCT Streck tubes following 
manufacturer’s instructions. The amount of cfDNA, the quality and downstream analysis of 
mutation detection by ddPCR will be compared. A cost-benefit analysis will be performed after 
at least 10 patients’ blood have been collected and analyzed by the two methodologies and a 
decision will be made as to use the Streck tubes or continue with our standard EDTA containing 
purple top tubes.(73)  
Method for plasma isolation: Blood tubes will be centrifuged at 1600Xg for 10 minutes at RT 
using a swing-out rotor and a smooth braking profile. Using a 1ml pipet, plasma will be 
transferred to a fresh 15 ml collection tube leaving around 500µl plasma in the blood collection 
tube to avoid transfer of cellular fraction. The supernatant will be centrifuged a second time at 
6,000 X g for 10 min to remove any residual blood cells. The resulting supernatant will again 
be transferred to a fresh collection tube leaving around 300µl at the bottom to prevent transfer 
of any cellular debris. Plasma will be gently mixed by pipetting and aliquoted in cryogenic vials 
and frozen at -80C until DNA extraction.(73) 
5.1.1.7 Collaboration with Dr. Haixu Tang, Indiana University 
This collaboration is aimed at building a pipeline for neoantigen discovery for the purpose of 
cancer vaccine development and T cell receptor (TCR)-directed cellular therapy.  Two datatypes 
will sent to Dr. Tang’s group.  One is mass spectrometry-based immunopeptidomics data from 
Figg laboratory in Cancer Signaling Networks section of TGMB. The other is whole exome 
sequencing (WES) and RNA-seq data from the analysis of tumor tissue from patients in our 
clinical study. ImmuNOVO software suite built in Dr. Tang’s group will be used process the 


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immunopeptideomics data to provide better identification of neoantigens.  RNA-seq and WES 
data will be used for mutation detection and quantification. The NGS data will also be utilized 
for HLA typing, confirming the typing output from ImmuNOVO. Artificial intelligence (AI)-
models will be built based on neoantigens predicted from immunopeptideomics along with the 
RNA-seq and WES data, including the mutation detection, quantification and HLA typing.    
All sequencing data will be coded and linked. The code is retained by investigators of this 
clinical protocol.   
The immunopeptidomics, WES and RNA-seq data will be sent to: 
 
Dr. Haixu Tang 
Professor, Department of Computer Science 
School of Informatics, Computing, and Engineering 
Indiana University, Bloomington 
700 N. Woodlawn Avenue    
Bloomington IN 47408 
Email: hatang@indiana.edu 
5.1.1.8 Collaboration with Gritstone Oncology  
WES and RNA-seq data from sequencing studies performed on tumor tissue from patients will 
be sent to Gritstone Oncology. All sequencing data will be coded without any patient 
information attached. The code is retained by investigators of this clinical protocol. Gritstone 
will first analyze this data by applying the Gritstone neoantigen prediction algorithm, EDGE.   
For each patient with a putative EGFR neoantigen (to be identified by applying the Gritstone 
neoantigen prediction model EDGE to the mutation calls and HLA types from the individual 
patient tumor exome data), one or both of the following will be sent: 
(1) Fresh frozen resected tumor, 10-50 mg, snap frozen in liquid nitrogen, stored at <-80C 
(2) PBMCs cryopreserved within 4-5h of collection, viable and functional upon thaw 
(>107 PBMCs total) 
  
Gritstone will perform on these samples the following: 
• 
Resected tumors: transcriptome sequencing, if not done already and targeted mass 
spectrometry in triple quadrupole (QQQ) mass spectrometer will be performed for 
EGFR mutations and any other shared neoantigen 
o HLA types would be confirmed from txTomes; txTomes also used to assess 
level of EGFR expression and other genes 
• 
PBMCs: Standard immune assays (such as elispot or tetramer) to identify T cell 
responses against EGFR or any another shared neoantigens 
• 
Optionally, depending on interest and in part on amount of sample available: HLA 
presentation or T cell recognition of other tumor specific antigens such as cancer testis 
antigens. 


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The sequencing data will be sent to Dr. James Sun: 
Dr. James Sun 
40 Erie Street, Suite 120,  
Cambridge MA 02139 
Ph : 857.327.9805 
jsun@gritstone.com 
Tumor tissue for MS/MS analysis will be sent to Dr. Jennifer Busby: 
Jennifer Busby, PhD 
Senior Director of Mass Spectrometry and Proteomics 
Gritstone Oncology, Inc. 
40 Erie Street; Suite 120 
Cambridge, MA 02139 
Office: 857-327-9806 
Cell: 561-889-3492 
jbusby@gritstone.com 
www.gritstone.com 
 
5.1.1.8.1 Plasma Samples 
After the blood samples are spun down within two hours of collection, the plasma portion will 
be stored in a -80°C freezer until shipment via FedEx to: 
ATTN: Elliot Rosen 
DBRR III/OBP/OPQ/CDER 
Food and Drug Administration 
10903 New Hampshire Ave, 
Bldg 52/72, Room 2248, 
Silver Spring, MD 20993 
Phone: 240-402-7353 
Email: Elliot.Rosen@fda.hhs.gov  
During shipment, samples will be stored on dry ice and sealed in a Styrofoam container in the 
absence of any PHI. Upon arrival, samples will be immediately stored in a locked -80°C 
freezer (number 859) in building 75 room G631 at The Food and Drug Administration until 
use.  
These plasma samples will undergo DNA extraction and library preparation followed by 
targeted or whole exome next generation sequencing (NGS) on the CDER/FDA Illumina 
NextSeq500. Genomic data will be analyzed and the ptDNA portion elucidated from the 
underlying normal DNA using various algorithms. Subsequent analysis of mutational load, 
and somatic alterations in the ptDNA will be performed and quantified. Additional analyses 
including evaluation of alternative transcripts, base substitutions, mutations, gene fusions, 
allele-specific expression patterns will also occur. Subsequent samples will also be sequenced 
and analyzed. Further expression analysis may also occur.  


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5.1.1.8.2 Tumor samples 
If available, matched specimens from primary tumors collected will be sent to FDA as well to 
the same address as above, either FFPE or fresh frozen samples, in order to screen for somatic 
mutations and genomic rearrangements using NGS from samples obtained at the time of 
surgery or in the advanced/metastatic setting. As available, concordance of somatic mutations 
in tissue and plasma will be compared and followed longitudinally, correlated to clinical 
course.  
5.1.1.8.3 Additional Information 
Any data or results generated from this project are intended for research purposes only and 
will not presently change the diagnosis or management of individual patients from whom the 
data were collected; therefore, no information will be provided back for inclusion in the 
medical records of the participants whose data are used. 
 
 Blood and urine correlative studies  
All blood and urine samples will initially be sent to the laboratory of Dr. Doug Figg (BPC), 
where they will be stored until ready for transfer to the recipient labs for the correlative 
studies as described below. 
Please e-mail the BPC lab at NCIBloodcore@mail.nih.gov at least 24 hours before 
transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact the BPC lab 
at NCIBloodcore@mail.nih.gov . 
5.1.2.1 Timing 
Blood and urine samples will be obtained at the following times.  Note:  Urine samples for 
correlative studies will be collected when feasible.  Collection of these urine samples is not 
required and may be waived at the discretion of the PI 
• For cycle 1, blood and urine samples will be obtained on Days -1 (±2 days) and 7 (±2 
days) of cycle 1. 
• For subsequent cycles, blood and urine samples will be obtained Day -1 (±5 days) of 
each subsequent treatment cycle. 
• Blood and urine samples will be collected at the 30 day post therapy visit. 
5.1.2.2 Tissue sampling and handling 
Phlebotomy will be performed by standard procedures. Sampling limits established by the NIH 
Clinical Center will be adhered to: no more than 550 ml per 8 week interval will be drawn. 
There is minimal discomfort associated with the procedure and a very small chance of bruising, 
bleeding, or infection. About 45 ml of random urine specimen will be collected. The specimen 
should be collected in a sterile cup and placed on ice. A 24 hour urine specimen may also be 
collected. Each patient sample set will be assigned a unique patient identifier. 


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One 10 ml red top tube will be used to isolate serum samples. Serum will be snap frozen and 
stored in liquid nitrogen for future proteomic biomarker studies.  
Red top tubes 
i) Allow the blood to clot by standing at room temperature for 30 minutes. 
ii) Separate serum from cells by centrifuging at 4 degrees C for 5 minutes at 1200g. 
iii) Pipette aliquots of 1.5mLs each into two 2mL cryovials. 
iv) Freeze immediately at -20C or lower 
v) Maintain in -80C freezer or liquid nitrogen for storage 
Two 10cc lavender top tubes will be used for plasma isolation for circulating tumor DNA 
(ctDNA) extraction and proteomics studies and one additional 10 cc lavender top tube will be 
collected for isolation of PBMC, circulating tumor cells (CTCs), other viable cell types, 
including immune subsets, and exosomes and delivered to Jane Trepel’s laboratory (Phone: 
240-760-6330; e-mail trepel@helix.nih.gov).  Isolated PBMC and circulating tumor cells will 
be analyzed by FACS, stored in liquid nitrogen, or grown in culture if feasible. 
5.1.2.3 Studies 
• Serum and plasma DNA will be isolated and analyzed for genomic alterations by next 
generation sequencing or digital droplet PCR (ddPCR). 
• Serum and plasma samples will also be analyzed for proteomic and metabolic profiling 
to correlate potential biomarkers with treatment response and resistance. 
• Urine samples will be used for metabolomic studies and proteomic studies, including 
urinary exosome analyses in the Laboratory of Metabolism under the direction of Dr. 
Frank Gonzalez and the Laboratory of Human Carcinogenesis under the direction of Dr. 
Curtis Harris. 
5.1.2.3.1 Targeted sequencing of ctDNA  
Blood samples will be collected to evaluate cancer gene mutations and genome markers during 
therapy. Analysis of liquid biopsies can potentially improve disease subclassification, improve 
monitoring of disease burden and response to treatment, and provide new knowledge of 
resistance mechanisms during disease relapse in patients with NSCLC.  Targeted Next-
Generation Sequencing (NGS) will be performed with a panel of approximately 300 cancer 
related genes or their subset, and other genomic aberrations. Analysis will be performed to 
determine the association with clinical response. Blood samples will be obtained at baseline 
prior to therapy after therapy has been completed. For existing samples, 2 cc of EDTA plasma 
will be obtained per sample timepoint. For prospective sample collection, EDTA plasma will 
be isolated from 10 ml of blood at Dr. Figg’s lab within 5 hours of blood draw. The plasma 
samples (4-5cc) will be stored in two 3cc tubes at -80℃. The coded, linked samples will be sent 
for analysis to: 
Liang Cao, Ph.D. 
Head, Molecular Targets Core Genetics Branch 
NCI – Center for Cancer Research 
37 Convent Dr. MSC 4265 


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Bldg 37, Rm 6134 
Bethesda, MD 20892-1906 
Phone: (240) 760-6893  
Cell: (240) 271-3786 
caoli@mail.nih.gov 
 
 Saliva correlative studies 
5.1.3.1 Timing  
Every attempt will be made to collect saliva samples at the following times: 
• For cycle 1, saliva samples will be obtained on days 1 and 7. 
• For subsequent cycles, saliva samples will be obtained every four weeks (± 5 days). 
• Saliva will be collected at the 30 day post therapy visit 
5.1.3.2 Tissue sampling and handling 
Saliva samples will initially be sent to the laboratory of Dr. Doug Figg (CPP), where they will 
be stored until ready for transfer to the recipient lab for the correlative studies as described 
below. 
The saliva will be collected using the PureSalTM oral specimen collection system from Oasis 
Diagnostics.  This device is a non-invasive rapid collection system for isolating DNA/cell free 
RNA or proteins in a single step. The saliva procured by this system is immediately stabilized 
and available for downstream applications, such as PCR, genotyping, sequencing, and 
proteomics.  The coded, linked saliva samples collected using this kit will be sent at room 
temperature to: 
David T.W. Wong DMD, DMSc 
University of California Los Angeles 
Felix & Mildred Yip Endowed Professor & Associate Dean of Research 
School of Dentistry 
Director, Center for Oral/Head & Neck Oncology Research 
10833 Le Conte Avenue, 73-017 CHS 
Los Angeles CA 90095 
310 206-3048 
dwong@dentistry.ucla.edu 
 
5.1.3.3 Studies 
Dr. David Wong’s group at UCLA has developed a method of detecting EGFR mutations in 
body fluids using a technology that is based on electric field-induced release and measurement 
(EFIRM). This uses a multiplexible electrochemical sensor that can detect EGFR mutations in 
bodily fluids(74, 75). EFIRM-liquid biopsy (eLB) showed near 100% concordance with biopsy-
based genotyping for actionable mutations in non-small cell lung carcinoma (NSCLC) lung 
cancer patients in two independent blinded clinical studies in Taiwan(75) and China (preliminary 
data). In collaboration with Dr. David Wong and his group at UCLA, we will detect EGFR 
mutations from serial saliva collection from patients and correlate the findings with the mutation 


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testing from plasma DNA and tumor tissue specimens. The eLB will be performed on an ACEA 
96-well electrochemical plate (E Plate 96), manufactured by ACEA Biosciences Inc. (San Diego 
CA) under GMP. To avoid imprecision due to human operation, all the liquid handling 
procedures will be done with the BioMek 3000 robotic system and BioRad platewasher. The 
detection device is a 96-channel electrochemical workstation. Electrochemical signals for all 
channels on the electrochemical plate are analyzed simultaneously, in real-time. 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through the Clinical Trial Data Management 
system.  Should a CRIS screen not be available, the CRIS downtime procedures will be 
followed. Samples will not be sent outside NIH without appropriate approvals and/or 
agreements, if required. 
 Figg Laboratory 
All research specimens will be coded.  
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. The PI will 
report any loss or unanticipated destruction of samples per section 7.2.1 . 
A full chain of custody is maintained for all samples throughout their lifecycle. The Principal 
Investigator keeps full traceability of collected biological samples from the subjects while in 
storage at the center until shipment or disposal (where appropriate) and keeps documentation of 
receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. The 
PI keeps oversight of the entire life cycle through internal procedures, monitoring of study sites 
and auditing of external laboratory providers. Samples retained for further use should be 
documented and stored during the entire life cycle. 
Freezer problems, lost samples or other problems associated with samples that meet expedited 
reporting requirements (see section 7.2.1) will also be reported. 
 Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation.  Unutilized excess tissue that is not placed 
in paraffin blocks is stored in formalin for up to three months, in accordance with College of 
American Pathologists/Joint Commission on Accreditation of Healthcare Organizations 
(CAP/JCAHO) guidelines, and then discarded.  Following completion of the diagnostic 
workup, the slides and tissue blocks are stored indefinitely in the LP’s clinical archives.  All 
specimens are catalogued and retrieved utilizing the clinical laboratory information systems, in 
accordance with CAP/JCAHO regulations.  The use of any stored specimens for research 
purposes is only allowed when the appropriate IRB approval has been obtained.  In some cases, 


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this approval has been obtained via the original protocol on which the patient was enrolled.  
 Laboratory of Jane Trepel  
Samples will be processed immediately by the Trepel laboratory.  Biospecimens will be 
collected and processed using validated SOPs that will ensure both specimen quality and patient 
confidentiality. Using a computerized inventory system and a backup hardcopy process, all 
specimen collection and processing steps will be documented and the specific location of each 
specimen will be tracked. Each new specimen collected will be assigned a unique barcode 
identifier that can be linked to the original specimen collected and other relevant information 
within the inventory system.  Specimen labels will indicate: protocol number, order in which 
the patient enrolled on the trial, type of sample, collection time, and total volume collected, as 
appropriate.  The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality. Access to the inventory system and associated documents 
will be restricted to appropriate individuals. Requests to use specimens stored in the repository 
must be approved. SOPs ensure that any changes in informed consent made by a patient and 
relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed 
as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored 
for high-quality performance. 
5.3 
CLINICAL PHARMACOLOGY PROGRAM  
 Procedures for sample data collection for the Clinical Pharmacology Program:  
• All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with 
data entered and stored in the Patient Sample Data Management System (PSDMS) 
utilized by the CPP. This is a secure program, with access to PSDMS limited to 
defined CPP personnel, who are issued individual user accounts. Installation of 
PSDMS is limited to computers specified by Dr. Figg. These computers all have a 
password restricted login screen. All CPP personnel with access to patient information 
annually complete the NIH online Protection of Human Subjects course.  
• PSDMS creates a unique barcode ID for every sample and sample box, which cannot 
be traced back to patients without PSDMS access. The data recorded for each sample 
includes the patient ID, name, trial name/protocol number, time drawn, cycle time 
point, dose, material type, as well as box and freezer location. Patient demographics 
associated with the Clinical Center patient number are provided in the system. For 
each sample, there are notes associated with the processing method (delay in sample 
processing, storage conditions on the ward, etc.).  
 Procedures for sample storage at the Clinical Pharmacology Program:  
• Barcoded samples are stored in barcoded boxes in a locked freezer at either -20oC or - 
80oC according to stability requirements. These freezers are located onsite in the CPP 
and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to 
the laboratory are required to be accompanied by laboratory staff at all times.  
• Access to stored clinical samples is restricted. Samples will be stored until requested 
by a researcher named on the protocol. All requests are monitored and tracked in 
PSDMS. All researchers are required to sign a form stating that the samples are only to 


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be used for research purposes associated with this trial (as per the IRB approved 
protocol) and that any unused samples must be returned to the CPP. It is the 
responsibility of the NCI Principal Investigator to ensure that the samples requested 
are being used in a manner consistent with IRB approval.  
• Following completion of this study, samples will remain in storage as detailed above. 
Access to these samples will only be granted following IRB approval of an additional 
protocol, granting the rights to use the material.  
• If, at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt 
of this request, the samples will be destroyed (or returned to the patient, if so 
requested), and reported as such to the IRB. Any samples lost (in transit or by a 
researcher) or destroyed due to unknown sample integrity (i.e. broken freezer allows 
for extensive sample thawing, etc.) that meet expedited reporting requirements (see 
section 7.2.1) will be reported.  
• Sample barcodes are linked to patient demographics and limited clinical information. 
This information will only be provided to investigators listed on this protocol, via 
registered use of the PSDMS. It is critical that the sample remains linked to patient 
information such as race, age, dates of diagnosis and death, and histological 
information about the tumor, in order to correlate genotype with these variables. 
5.4 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
 Description of the scope of genetic/genomic analysis 
Tumor tissue and liquid biopsies (plasma, saliva) will be used for genomic analysis to identify 
somatic alterations. Blood will be used for “normal” DNA isolation and sequenced to identify 
somatic alterations. Whole exome, transcriptome, whole genome and/or targeted NGS will be 
performed in the DNA/RNA isolated from these specimens.   
 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
As part of study efforts to provide confidentiality of subject information, this study will obtain 
a Certificate of Confidentiality which helps to protect personally identifiable research 
information.  The Certificate of Confidentiality allows investigators on this trial to refuse to 
disclose identifying information related to the research participants, should such disclosure have 
adverse consequences for subjects or damage their financial standing, employability, 
insurability or reputation.  The informed consent includes the appropriate coverage and 
restrictions of the Certificate of Confidentiality. 
Tissue and blood samples collected will be coded and linked. DNA, RNA and protein isolated 
from these tissues and cell lines and xenografts generated will all be similarly coded. Only 
personnel involved in this study will have access to both the code and the name of the patient. 
Coded, linked tumor tissue will be sent to collaborator, Dr. Christopher Albanese, at 
Georgetown University for generating cell lines.  All samples will be coded and linked without 
any patient identifiers and the Georgetown investigators will have no access to patient 
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To facilitate genetic research, and for the purpose of publication of research work, data from 
genomic and proteomic studies may be deposited in appropriate public databases. Coded, linked 
data will be deposited in a manner that the patient’s identity cannot be traced.  
 Management of Results   
The analyses performed in various NCI laboratories under this protocol are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing for clinical purposes. Changes observed unrelated to our 
research may or may not be valid.  Therefore, we do not plan to inform participants of the results 
of testing on the tissue, saliva and blood that is performed in our research lab.   
However, in the unlikely event that clinically relevant incidental findings are discovered, 
subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis.  (A list of current guidelines 
is maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).  Subjects 
or their designee will be contacted at this time with a request to provide a blood sample to be 
sent to a CLIA certified laboratory. If the research findings are verified in the CLIA certified 
lab, the subject will be referred to an NCI CCR Genetics Branch certified genetic health care 
provider for the disclosure of the results.   
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
The costs of CLIA testing will be paid for by the Center for Cancer Research, the Branch, or 
the Principal Investigator.  If the health history, family history, or tumor diagnosis from the 
Laboratory of Pathology at the NIH Clinical Center suggests that the participant might benefit 
from genetic testing, we will discuss this with him/her. 
At the time of consent, subjects will be informed that incidental genetic findings may arise from 
this study.  Participants will be asked complete and sign an NIH-527 Release form at the time 
of consent. The completion of the form is optional, but a note will be made in the medical record 
to document refusal. In the event that the participant dies or becomes incapacitated in the time 
frame between providing a sample for germline analysis and results being available, results will 
be provided to the individual specified on the release form. 
 Genetic counseling 
Should any incidental findings be discovered, the NCI CCR Genetics Branch will be asked to 
provide genetic counseling.  In the event a result of urgent importance to immediate family 
members has to be divulged, family members will be offered genetic counseling. 
5.5 
WITHDRAWAL OF INFORMED CONSENT FOR DONATED BIOLOGICAL SAMPLES 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. The participant’s data will be excluded from 
future distributions, but data that have already been distributed for approved research use will 
not be able to be retrieved.  If samples are already analyzed, the PI is not obliged to destroy the 


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results of this research.  As collection of the biological samples is an integral part of the study, 
then the subject is withdrawn from further study participation. 
The Principal Investigator: 
• Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site 
• Ensures that the subject is informed about the sample disposal. 
6 DATA COLLECTION AND EVALUATION 
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into the in-house password protected 
electronic systems, C3D and LabMatrix, and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a 
contracted data manager will assist with the data management efforts. All data obtained during 
the conduct of the protocol will be kept in secure network drives or in approved alternative sites 
that comply with NIH security standards.  Primary and final analyzed data will have identifiers 
so that research data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.   
Document AEs from the first study drug administration, C1D1, until 30 days after the last dose 
is given. Beyond 30 days after the last intervention, only adverse events which are serious and 
related to the study intervention need to be recorded. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms 
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization. 
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per the 
requirements in section 7.2.1.  
The following data will be collected: 


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6.2 
DATA SHARING PLANS 
 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ Coded, linked data in an NIH-funded or approved public repository.   
___  Coded, linked data in another public repository.   
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
 
How and where will the data be shared?  
Data will be shared through: 
_X_ 
An 
NIH-funded 
or 
approved 
public 
repository. 
 
Insert 
name 
or 
names:____clinicaltrials.gov; dbGAP. 
_X_ BTRIS (automatic for activities in the Clinical Center) 
_X_ Approved outside collaborators under appropriate individual agreements. 
_X_ Publication and/or public presentations. 
 
When will the data be shared? 
_X_ Before publication. 
_X_ At the time of publication or shortly thereafter. 
 
 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).(67)  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 


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 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with osimertinib. 
Evaluable for objective response: Only those patients who have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the definitions stated below.  
(Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will also 
be considered evaluable.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease reevaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as: 
• By chest x-ray: >20 mm 
• By CT scan: 
o Scan slice thickness 5 mm or under: >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: ≥10 mm. 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are located in a previously irradiated area might or might not be 
considered measurable at the discretion of the PI.  
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 slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 


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Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically). A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters.  If lymph nodes are to be included in 
the sum, then only the short axis is added into the sum. The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable dimension 
of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
Post-LAT Lesions 
Progression:  As defined in Section 4.3.1 of the RECIST version 1.1 manuscript(69), at least a 
20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The 
appearance of one or more new lesions is also considered progression. 
Note:  If patients progress only at the same site where LAT has been performed before, the 
progression will be considered to be a result of inadequate ablation and they will be considered 
for repeat LAT if clinically feasible by any of the previous modalities (surgery, RT, RFA, 
cryoablation) and again re-challenged with osimertinib. Progression only at the site of previous 
LAT will not be considered progression for the PFS2. Re-initiation of osimertinib treatment in 
this case has to be within one month. 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 28 days 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 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI: CT and MRI - CT and MRI are the best currently available and 
reproducible methods to measure target lesions selected for response assessment. For this study 
helical multidetector CT will be performed with cuts of 5 mm in slice thickness for chest, 
abdomen and pelvis lesions and 2-3 mm thickness for head and neck lesions. 


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Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
RECIST criteria will be used to determine disease progression unless there is cytological or 
histological confirmation of an alternative diagnosis such as pneumonia or inflammation. At the 
time of first progression when a biopsy is mandatory, biopsy will confirm disease progression.  
For instances of second progression when a biopsy is not mandatory, progression determined 
using RECIST criteria will be adequate to take patient off treatment.   
FDG-PET: New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up 
may be a sign of progressive disease. If the positive FDG-PET at follow-up corresponds to a 
new site of disease confirmed by CT, this is progressive disease (PD). If the positive FDG-PET 
at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are 
needed to determine if there is truly progression occurring at that site. If so, the date of PD will 
be the date of the initial abnormal FDG-PET scan. If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD.  
Note: A positive FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 Response Criteria 
6.3.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two separate 
observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. 
Any pathological lymph nodes must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of target lesions, taking as reference 
the baseline sum diameters. There can be no appearance of new lesions. 
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 (this includes the baseline sum if that is the 
smallest on study). The appearance of one or more new lesions is also considered progression). 
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. 
6.3.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis) 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 


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Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
6.3.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
Table 4. Evaluation of patients with measurable disease 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
when 
Confirmation 
is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline*** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.  
** Only for non-randomized trials with response as primary endpoint.  
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.  
 
Note:  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
Table 5. Evaluation of patients with non-measurable disease 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 


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Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
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 until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started.  
 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression. 
 Overall Survival 
Overall survival is defined as the duration of time from start of treatment to death from any 
cause. 
6.4 
SAFETY ASSESSMENTS 
 Laboratory safety assessments 
Blood for determination of clinical chemistry, hematology and coagulation will be taken at the 
times indicated in the Study Calendar. Additional safety samples may be collected if clinically 
indicated at the discretion of the Investigator.  The date, time of collection and results (values, 
units and reference ranges) will be recorded on the appropriate eCRF.  
Please refer to section 2.3 for the list of laboratory variables assessed. 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at center 
as source data for laboratory variables.  For information on how AEs based on laboratory tests 
should be recorded and reported, see Section 6.4.1 and section 7. 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to 
Appendix E ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
 Physical examination 
A physical examination will be conducted at screening and at subsequent visits according to 
the schedule in section 3.6. 
 ECG 
Patients should be monitored for ECG changes according to the schedule in section 3.6  ECGs 
should be reviewed and any abnormalities noted. 


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6.4.3.1 Resting 12-lead ECG 
Twelve-lead ECG will be obtained after the patient has been resting semi-supine for at least 10 
minutes prior to times indicated.  All ECGs should be recorded with the patient in the same 
physical position.  A standardized ECG machine should be used and the patient should be 
examined using the same machine throughout the study if possible. 
The investigator or designated physician will review the ECG and may refer to a cardiologist if 
appropriate. A paper copy should be filed in the patient’s medical records.  If an abnormal ECG 
finding at screening or baseline is considered to be clinically significant by the investigator, it 
should be reported as a concurrent condition.  For all ECGs, ECG intervals and an overall 
evaluation will be recorded. 
 Ophthalmologic exam 
Full ophthalmic assessment, including slit lamp examination, should be performed at screening 
and if a patient experiences any visual symptoms (including blurring of vision), with additional 
tests if clinically indicated. Ophthalmology examination results should be collected in the eCRF. 
Any clinically significant findings, including those confirmed by the ophthalmologist must be 
reported as an AE. Photographs should be performed to record any clinically significant 
findings.  
6.5 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
AE reporting.  All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research event found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. 
•  
 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 


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Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at dahutw@mail.nih.gov and to NCICCRQA@mail.nih.gov within one business day of 
learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. All data will be collected in a timely manner and reviewed 
by the principal investigator or the lead associate investigator. Events meeting requirements for 
expedited reporting as described in section 7.2.1 will be submitted within the appropriate 
timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL 
COLLABORATOR 
The PI or designee will send all reports to the manufacturer as described below. 
 Expedited Adverse Event Reporting Criteria to the IND Manufacturer 
Any serious or unexpected adverse events occurring from the start of treatment until 30 days 
after the last dose of study medication will be faxed or emailed to AstraZeneca at the time the 
event is discovered.  The PI or designee should send reports to 
jennifer.defrancisco@astrazeneca.com and AEMailboxClinicalTrialTCS@astrazeneca.com. 
 
* A cover page (see Appendix F) should accompany the MedWatch form indicating the 
following: 
• Investigator Sponsored Study (ISS) 
• The investigator’s name and address 
• The trial name/title and AstraZeneca ISS reference number 
* The investigative site must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications and if the SAE is related to disease 
progression, as determined by the principal investigator. 
* Send the SUSAR report and accompanying cover page by way of fax or email to 
AstraZeneca’s designated fax line or by email as listed on the cover page in Appendix F 


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 Additional Information Sent to AstraZeneca 
The following items must be provided to AstraZeneca: 
1. IRB approval of initial protocol 
2. Any other information affecting the safety of human subjects research conducted 
under the CTA.  
3. Quarterly Reports Entered into the AstraZeneca Database 
a. Cumulative frequency table of adverse events in a table listing event name 
and CTC grade 
b. Number of subjects screened, enrolled, completed, withdrawn 
Unless otherwise indicated, the information should be sent to by email to Jennifer 
DeFrancisco,  Jennifer.defrancisco@astrazeneca.com  
9 CLINICAL MONITORING  
Although this study is IND-exempt, the CCR will maintain a monitoring program. The CCR’s 
program allows for confirmation of: study data, specifically data that could affect the 
interpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; 
and human subjects protection. This is done through independent verification of study data 
with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment 
 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
10 STATISTICAL CONSIDERATIONS 
10.1  STATISTICAL CONSIDERATIONS AND SAMPLE SIZE ESTIMATE 
The primary objective is to determine PFS in patients with oligoprogressive disease after 
treatment with LAT followed by osimertinib. Patients who progress on their initial treatment 
with osimertinib and receive LAT therapy (surgery, radiation therapy, RFA, or cryoablation) 
followed by osimertinib will be evaluated for their time to second progression (PFS2). The 
objective will be to estimate the PFS2 for these patients and also to determine if the PFS2 
results may be potentially superior to the expected results. Data from a recently published 
study indicated that patients with NSCLC who have progressed after receiving LAT would be 
expected to have approximately a 6.2 month median PFS2. With 41 evaluable patients 
receiving LAT, assuming accrual would take place over approximately 3 years, and that there 


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would be at least 6 months of additional potential follow-up after the last patient has received 
the LAT followed by osimertinib , there would be 80% power to determine that there is a 
difference between a 6 month median PFS and an improved 10 month median PFS, with a one 
sided 0.10 alpha level test, using the method of Brookmeyer and Crowley as calculated via the 
following website: http://www.swogstat.org/stat/public/one_nonparametric_survival.html. 
The trial also aims to better define PFS in patients with EGFR mutation-positive NSCLC treated 
with osimertinib prior to LAT. Data from recently published studied indicated that patients with 
T790M-positive EGFR inhibitor-resistant NSCLC experienced a median 9.6 month PFS 
following osimertinib treatment and 83% of patients treated with osimertinib at a dose of 80 mg 
daily as a first-line treatment remained progression-free at 9 months. Using a combined 
population of patients who are chemo-naïve or who had progressive disease after prior EGFR-
TKI therapy, the present trial aims to treat both cohorts of patients with osimertinib in order to 
replicate the findings and to report the results in the two populations. 
In order to obtain 41 patients who receive LAT followed by osimertinib, it is anticipated that at 
least 100 patients would need to enroll onto the trial and receive treatment initially with 
osimertinib. These patients will all be followed for PFS and will have their initial PFS reported 
in an overall group as well as separately by prior treatment status (TKI naïve vs. prior 1st or 2nd 
generation EGFR TKI treatment).  In order to recruit patients fast for the evaluation of LAT and 
re-treatment with osimertinib, a cohort of patients already treated with osimertinib in other 
institutions in on-going clinical trials and developed acquired resistance will be included in the 
trial.  These patients will be enrolled in this study if they are eligible for LAT and be followed 
for PFS after LAT and re-treatment with osimertinib. 
In order to ensure that the trial does not continue to enroll patients in the event that outcomes 
are not adequate the following stopping rules will be implemented. For the patients initially 
receiving osimertinib on the trial, the initial median PFS would be expected to be approximately 
9.6 months, with a lower two-sided 95% confidence interval bound of approximately 8.3 
months. After 50 patients have been treated with osimertinib and potentially followed for at 
least one year, if the median PFS is below 8.3 months, then no further patients will be treated 
on the trial since the results associated with the first administration of osimertinib are 
substantially below what would be expected based on the previous study.  
For the patients who receive LAT, based on results from the prior published study, the median 
PFS would be 6.2 months, with a lower two-sided 95% confidence interval bound of 3.7 months. 
If after 20 patients on the present trial have received LAT followed by osimertinib  and were 
followed for a potential of 9 months, the median PFS is 3.7 months or less, then no further 
patients will be enrolled on the trial since this would indicate results which are substantially 
below what would be expected based on the previous study. 
As re-treatment is allowed on this study, first treatment and second treatment patients will be 
included in the analysis of PFS as patients will not have been off osimertinib more than 1 month.  
Response criteria will be also assessed for both treatments as part of the analysis.  
In order to obtain 41 evaluable patients who receive LAT followed by osimertinib, the trial will 
have an initial accrual ceiling of 100 patients. When appropriate, based upon the fraction of all 
patients who are able to receive LAT, the trial will be amended to request additional patients 
expected to be necessary to result in 41 evaluable patients receiving LAT and osimertinib.  It is 


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anticipated that 3 to 5 years may be required to enroll adequate patients to obtain 41 who will 
receive LAT. 
10.2 METHODS FOR STATISTICAL ANALYSES 
The progression-free survival of patients with oligoprogressive disease after treatment with 
LAT followed by osimertinib will be estimated and plotted by the Kaplan–Meier method. In 
addition, the median progression-free survival will be reported along with the 95% confidence 
intervals. The results for the patients who undergo LAT are not expected to vary substantially 
according to whether they were initially EGFR TKI-naïve or not.  However, the results will be 
evaluated including all patients who receive LAT as well as divided according to their initial 
EGFR TKI experience before treatment on this trial.  The progression-free survival of patients 
treated with osimertinib prior to LAT will be estimated by the Kaplan-Meier method.  
Other important objectives include evaluating responses and overall survival (OS) in the 
patients who receive osimertinib after LAT, as well as determining the feasibility of evaluating 
EGFR mutation status using liquid biopsies (using blood or saliva samples). The response rate 
will be reported using a 95% confidence interval and OS will be reported using a Kaplan-Meier 
curve. The percentage of positive EGFR mutation in blood or saliva samples will be reported 
and the sensitivity and specificity of liquid biopsies will be assessed. 
Except for the evaluation of PFS2 in patients with oligoprogressive disease after treatment with 
LAT followed by osimertinib for which a one-sided 0.10 evaluation will be performed, all 
statistical tests will be two-sided and considered statistically significant when the p-value is 
<0.05. All statistical analyses will be performed using SAS (Version 9.4; SAS Institute, Cary, 
NC). 
11 COLLABORATIVE AGREEMENTS  
11.1 CLINICAL TRIAL AGREEMENT 
A Clinical Trial Agreement (CTA # 990-16) with AstraZeneca was executed on 02/05/2016 
for the clinical development of AZD-9291.   
11.2 MATERIAL TRANSFER AGREEMENTS 
Human Materials Transfer Agreements with the following collaborators have been obtained or 
will be obtained prior to sending materials from NCI. 
1. Parker Cassidy at Mitra Biotech in order to perform the studies described in Section 
5.1.1.3 
2. Dr. David Wong’s group at UCLA in order to perform the studies described in Section 
5.1.3  
3. Dr. Christopher Albanese at Georgetown University in order to perform the studies 
described in Section 5.4.2. 
4. Dr. Amit Chaudhuri at Medgenome to perform the studies described in Section 
5.1.1.3.10. 


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5. Dr. Julia Beaver and Dr. Elliot Rosen at the Food and Drug Administration in order to 
perform the studies described in Section 5.1.1.5. 
6. Dr. Olga Vitek at Northeastern University in order to perform the studies described in 
Section 5.1.1.3.5. 
7. Dr. Greg Jones at Inivata in order to perform the studies described in Section 5.1.1.4. 
8. Dr. Haixu Tang at Indiana University to perform the studies described in Section 5.1.1.7. 
9. Drs. James Sun and Jennifer Busby at Gritstone Oncology to perform the studies 
described in Section 5.1.1.8. 
11.3 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
A Materials Cooperative Research and Development Agreement (CRADA) #03288 with 
Aurigene was executed on 05/06/2019 and includes experiments described in the 
Experimental Plan - Section 5 which involve the use of patient-derived xenograft mouse 
models under this clinical protocol. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1  RATIONALE FOR SUBJECT SELECTION 
This study will be open to all individuals regardless of gender, ethnicity, or race provided that 
the aforementioned inclusion and exclusion criteria are met. To date, there is no information 
that suggests that differences in drug metabolism or disease response would be expected in one 
sex, racial or ethnic group compared to another. Efforts will be made to extend accrual to each 
representative population, but in this preliminary study, a balance must be struck between 
patient safety considerations and limitations on the number of individuals exposed to potentially 
toxic and/or ineffective treatments on the one hand and the need to explore racial/ethnic aspects 
of clinical research on the other hand. If differences in outcome that correlate to ethnic identity 
are noted, accrual may be expanded or a follow-up study may be written to investigate those 
differences more fully. 
This study will be recruited through internal referral, our local physician referral base, and 
through various websites (i.e., clinicaltrials.gov). 
12.2  PARTICIPATION OF CHILDREN 
Patients under the age of 18 will be excluded from study due to the low occurrence of these 
oncologic histologies in the pediatric population. In addition, the risk of exposure to an 
investigational agent without proven benefit in the targeted histologies supports excluding 
children until additional safety and efficacy data is available. 
12.3  PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.4.2), all subjects ≥ age 18 will be offered the opportunity to 
fill in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 


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or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of 
the capacity to appoint a surrogate.  For those subjects that become incapacitated and do not 
have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 
14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally 
impaired, and (b) who do not have a legal guardian or durable power of attorney, will be 
followed. 
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
 Risks 
12.4.1.1 Risks of study therapy 
Potential risks include the possible occurrence of any of a range of side effects that are listed in 
section 13.1.2 and the consent document. The procedure for protecting against or minimizing 
risks will be to medically evaluate patients on a regular basis as described earlier. 
12.4.1.2 Non-physical risks of genetic research 
12.4.1.2.1 Risk of receiving unwanted information 
Anxiety and stress may arise as a result of the anticipation that unwanted information 
regarding disease related DNA sequencing or disease tendencies, or misattributed 
paternity. Patients will be clearly informed that the data related to DNA sequencing and 
genetic analysis is coded investigational and will not be shared with patients, family 
members or health care providers. 
12.4.1.2.2 Risk related to possibility that information may be released 
This includes the risk that data related to genotype, DNA sequencing or risk for disease 
tendency or trait can be released to members of the public, insurers, employers, or law 
enforcement agencies. Although there are no plans to release results to the patients, family 
members or health care providers, this risk will be included in the informed consent 
document. 
As part of study efforts to provide confidentiality of subject information, this study has obtained 
a Certificate of Confidentiality which helps to protect personally identifiable research 
information.  The Certificate of Confidentiality allows investigators on this trial to refuse to 
disclose identifying information related to the research participants, should such disclosure have 
adverse consequences for subjects or damage their financial standing, employability, 
insurability or reputation.  The informed consent includes the appropriate coverage and 
restrictions of the Certificate of Confidentiality. 
12.4.1.3 Risks of biopsy 
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site.  Lung 
biopsies also present the risk for pneumothorax. Tumor biopsies will be done only if it is 
clinically safe and feasible. In addition, as up to 3 research biopsies may be collected under CT 


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guidance, this will result in exposure to approximately 2.4 rem. This amount is below the 
guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety 
Committee. 
 Benefits 
Taken together, benefits of combining osimertinib and local ablative therapy outweigh risks 
associated with the treatment. Patients should realize that we are hopeful that they may gain 
benefit from this study, but there is no objective evidence to support our optimism at this time. 
The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, 
which may or may not have a favorable impact on symptoms and/or survival. 
12.5  CONSENT PROCESS AND DOCUMENTATION 
An associate or principal investigator on the trial will inform patients of the purpose, 
alternatives, treatment plan, research objectives and follow-up of this trial.  The patient will be 
provided an IRB-approved consent for review and signature and his/her questions will be 
answered.  After a decision is made to enroll into the study, a signature will be obtained from 
the patient at a subsequent visit.    All patients must have a signed informed consent form and 
an on-study (confirmation of eligibility) form filled out and signed by a participating 
investigator before entering on study. The informed consent process will be documented on a 
progress note by the consenting investigator. 
 Telephone consent  
For re-consent in the case of protocol amendments, the informed consent document may be sent 
to the subject.  An explanation of the study will be provided over the telephone after the subject 
has had the opportunity to read the consent form.  The subject will sign and date the informed 
consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented in the medical record. 
13 PHARMACEUTICAL INFORMATION 
13.1 OSIMERTINIB (AZD9291) 
Note: The commercial drugs used in this study will not alter labelling of the FDA approved 
drugs nor does the investigation involve a route of administration or dosage level in use in a 
patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product.  The FDA has determined 
that this protocol is IND exempt based on this. 
 
 Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 


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AZD9291 (osimertinib) 
40mg Tablets 
80mg Tablets  
AstraZeneca 
AstraZeneca will supply AZD9291 as tablets for oral administration as a single daily dose of 80 
mg. AZD9291 will usually be supplied as either bulk or unlabeled bottles for ISS/ESR studies. 
 Toxicity 
Based on the phase I study by Janne et al., most of the adverse effects were grade 1 or 2(33). 
The incidences of grade 3-5 diarrhea, rash, nausea, and anorexia were 2%, 1%, 1%, and 2%, 
respectively. There were 6 cases of potential pneumonitis-like events. There were 6 patients 
who developed hyperglycemia, and 11 patients who had prolongation of QTc interval; none of 
these events led to discontinuation or reduction of AZD9291. Based on population 
pharmacokinetic analysis, no dose adjustment is recommended in patients with mild or 
moderate renal impairment as well as those with mild hepatic impairment(76). Exploratory 
analyses of clinical trials of AZD9291 suggest a higher incidence of Grade 3 or 4 adverse 
reactions (32% vs. 25%) and more frequent dose modification for adverse reactions (23% vs. 
17%) in patients 65 years or older as compared with those younger than 65 years(76). Based on 
the two retrospective studies and one prospective study, it has been shown that local ablative 
therapies are well tolerated in combination with EGFR-TKI(56-58). 
 Administration Procedures 
Osimertinib is administered as 80 mg once daily for patients without leptomeningeal disease 
and 160 mg per day for those with leptomeningeal disease at baseline. Osimertinib can be taken 
without regard to food.  Doses should be taken approximately 24 hours apart at the same time 
point each day. Doses should not be missed.  If a patient misses taking a scheduled dose, within 
a window of 12 hours, it is acceptable to take the dose.  If it is more than 12 hours after the dose 
time, the missed dose should not be taken, and patients should be instructed to take the next 
dose at the next scheduled time.  If a patient vomits after taking their osimertinib, they should 
not make up for this dose, but should take the next scheduled dose. 
If a patient misses more than 5 scheduled doses of osimertinib within one cycle, this will be 
reported as a protocol deviation.  If a patient misses 1-4 doses of osimertinib within one cycle, 
this will not be considered a deviation.  If instructed by the study team to hold the investigational 
drug, held doses will not be considered a missed dose.  A patient that interrupts therapy for more 
than 4 weeks will be taken off treatment. 
The dose of osimertinib can be reduced based on the rules described in Section 3.4. Further dose 
reductions are not possible. Once a dose has been reduced, it should not be re-escalated at future 
cycles. Any change from dosing schedule, dose interruptions, or dose reductions should be 
recorded.   
Patients may continue to receive osimertinib as long as they are continuing to show clinical 
benefit, as judged by the Investigator, and in the absence of discontinuation criteria. 
 Formulation 
Osimertinib is presented for oral administration as a beige, film-coated tablet containing either 
40 mg or 80 mg of osimertinib (expressed as the free base). Osimertinib tablets are packed in 
high-density polyethylene (HDPE) bottles. Bottles are secured with a child resistant closure; 


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69 
induction-sealed membranes provide tamper evidence. 
 Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labeling. 
 Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle specifies the appropriate storage. 
 Stability 
The investigational product label on the bottle specifies the stability/expiration date. 
 Incompatibilities 
As CYP3A4 is the principal P450 protein responsible for the metabolism of osimertinib, 
AZ5104 and AZ7550, co-administration with a potent CYP3A4 inhibitor or inducer may affect 
their exposure. 
Osimertinib, AZ5104 and AZ7550 are substrates for P-gp and BCRP but are not substrates for 
OATP1B1 and OATP1B3. 
Osimertinib is a direct inhibitor of CYP 3A4/5 in vitro using nifedipine as the probe substrate 
(IC50 5.1 μM) although lower inhibition was observed with midazolam (IC50 >26.5 µM) and 
is a weak time-dependent inhibitor of CYP3A4 in vitro (KI and kinact of 1090 µM and 0.0617 
min-1). The exposure of medications dependent on CYP3A4/5 may be increased when 
coadministered with osimertinib. 
Osimertinib is an inhibitor of BCRP in vitro (IC50 of 2.0 μM). The exposure of medications 
dependent on BCRP may be increased when co-administered with osimertinib due to BCRP 
inhibition. 
Osimertinib induces CYP3A4 and CYP1A2 in vitro in human hepatocytes. The exposure of 
medications dependent on CYPs 3A4 and 1A2 (also CYP2C and P-gp which may be induced) 
may be reduced when co-administered with osimertinib. 
 Compliance 
The administration of all study drugs (including investigational products) should be recorded in 
the appropriate sections of the eCRF. 


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70 
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15 APPENDICES 
15.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


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15.2 APPENDIX B. GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS 
The use of any natural/herbal products or other “folk remedies” should be discouraged, but use 
of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF.  
Osimertinib is an investigational drug for which no data on in vivo interactions are currently 
available. Based on in vitro data and predicted clinical exposure data, osimertinib is considered 
unlikely to cause clinically significant drug interactions through inhibition or induction of 
cytochrome P450 enzyme activity. In vitro data have shown that the principal CYP enzymes 
responsible for the Phase I metabolism of osimertinib are CYP2C8, CYP3A4, and CYP3A5. 
 
1. DRUGS 
INHIBITING 
CYP3A4 
OR 
CYP2C8 
METABOLISM 
THAT 
ASTRAZENECA STRONGLY RECOMMEND ARE NOT COMBINED WITH 
OSIMERTINIB   
The contribution of Phase I metabolism to the total clearance of osimertinib is currently 
unknown but, to ensure patient safety, the following potent inhibitors of CYP3A4 should be 
avoided during this study if possible for any patient receiving osimertinib.  If no alternative 
exists, the patient should be closely monitored for signs of toxicity. 
 
Table 1. Drugs inhibiting CYP3A4  
Contraindicated drugs 
 
Clarithromycin, telithromycin, troleandomycin 
Consider withdrawing 1 week prior to osimertinib 
Conivaptan 
osimertinib start 
Indinavir, 
lopinavir, 
nelfinavir, 
ritonavir,  
Itraconazole, 
ketoconazole, 
posaconazole,  
Mibefradil 
 
Nefazodone 
 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that 
are known to strongly modulate CYP3A4 activity. Appropriate medical judgment is required.  
 
2. DRUGS INDUCING CYP3A4 METABOLISM THAT ASTRAZENECA 
STRONGLY RECOMMEND ARE NOT COMBINED WITH OSIMERTINIB   
 
The following potent inducers of CYP3A4 should be avoided during this study if 
possible for any patient receiving osimertinib because concomitant use may decrease 
osimertinib plasma concentrations. 
Table 2. Drugs inducing CYP3A4 
Contraindicated drugs  
  start  
Carbamazepine, phenobarbital, phenytoin  
Consider withdrawing 3 weeks prior to 
Rifampicin, rifabutin, rifapentine  


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St John’s Wort 
osimertinib start 
Phenobarbitone  
Consider withdrawing 5 weeks prior to 
 
osimertinib start 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that 
are known to strongly modulate CYP3A4 activity. Appropriate medical judgment is required.  
 
3. MEDICINES WHOSE EXPOSURES MAY BE AFFECTED BY OSIMERTINIB 
THAT ASTRAZENECA CONSIDERS MAY BE ALLOWED WITH CAUTION 
Table 3. Exposure, pharmacological action and toxicity may be increased or decreased by 
osimertinib   
Warning of possible interaction  
Advice  
Alfentanil  
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions. Please refer to full 
prescribing information for all drugs prior to co-
administration with osimertinib.  
Amodiaquine  
Repaglinide  
Sirolimus  
Tacrolimus  
Torsemide  
Fentanyl  
Dihydroergotamine  
Ergotamine  
Simvastatin  
Lovastatin  
Atorvastatin  
Rosuvastatin  
Fluvastatin  
Sulfasalazine  
Warfarin  
Phenytoin (also see Table 2)  
s-Mephenytoin  
Cyclosporine  
Theophylline  
Tizanidine  
Aliskiren  
Ambrisentan  
Colchicine  


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Dabigatran etexilate  
Digoxin  
Fexofenadine  
Maraviroc  
Ranolazine  
Talinolol  
Tolvaptan  
Maraviroc  
Ranolazine  
Talinolol  
Tolvaptan  
There are currently no data confirming that there is a pharmacokinetic (PK) interaction between 
these agents and osimertinib; in vitro data suggest osimertinib has the potential to cause drug 
interactions at the intestinal level through CYP3A4 and BCRP, it has also been shown to be an 
inhibitor of CYP2C8 and inducer of CYP3A4, CYP1A2 and CYP2C and p-glycoprotein. This 
list is not intended to be exhaustive, and a similar restriction will apply to other agents that are 
known to depend on CYP3A4, CYP2C8, CYP1A2 and CYP2C for metabolism or BCRP and 
p-glycoprotein for deposition disposition. Appropriate medical judgement is required.  
 
4. DRUGS THAT MAY PROLONG QT INTERVAL  
The drugs listed in this section are taken from information provided by The Arizona Center for 
Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and 
Rockville, Maryland. Ref: http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm. 
4.1.  Drugs known to prolong QT interval  
The following drugs are known to prolong QT interval or induce Torsades de Pointes and should 
not be combined with osimertinib. Recommended withdrawal periods following cessation of 
treatment with these agents are provided in the table.  
Table 4. Drugs prolonging QT interval  
Contraindicated drug  
Withdrawal period prior to osimertinib  
start  
Clarithromycin, 
droperidol, 
erythromycin, 
procainamide  
2 days  
Cisapride, disopyramide, dofetilide, domperidone, 
ibutilide, quinidine, sotalol, sparfloxacin, thioridazine  
7 days  
Bepridil, chlorpromazine, halofantrine, haloperidol, 
mesoridazine  
14 days  
Levomethadyl, methadone, pimozide  
4 weeks  


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Arsenic trioxide  
6 weeks*  
Pentamidine  
8 weeks  
Amiodarone, chloroquine  
1 year  
* Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
4.2.  Drugs that may possibly prolong QT interval  
The use of the following drugs is permitted (notwithstanding other exclusions and restrictions) 
provided the patient has been stable on therapy for the periods indicated. 
 
Table 5. Drugs that may prolong QT interval 
Drug  
Minimum treatment period on medication 
prior to osimertinib start  
Alfuzosin, chloral hydrate, ciprofloxacin, 
dolasetron, 
foscarnet, 
galantamine, 
gemifloxacin, 
isradipine, 
ketoconazole, 
levofloxacin, 
mexiletine, 
nicardipine, 
octreotide, ofloxacin, ondansetron, quetiapine, 
ranolazine, 
telithromycin, 
tizanidine, 
vardenafil, venlafaxine, ziprasidone  
2 days  
Amantadine, 
amitriptyline, 
amoxapine, 
clozapine, doxepin, felbamate, flecainide, 
fluconazole, 
fosphenytoin, 
gatifloxacin, 
granisetron, imipramine, indapamide, lithium, 
moexipril/HCTZ, moxifloxacin, risperidone, 
roxithromycin, sertraline, trimethoprim-sulfa, 
trimipramine, voriconazole 
7 days 
Azithromycin, 
citalopram, 
clomipramine, 
itraconazole, 
nortriptyline, 
paroxetine, 
solifenacin, tacrolimus  
14 days  
Fluoxetine  
5 weeks  
Protriptyline  
6 weeks  
Tamoxifen  
8 weeks  
 


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15.3 APPENDIX C: OSIMERTINIB PATIENT MEDICATION DIARY 
INSTRUCTIONS TO THE PATIENT: 
1. Complete 1 diary for each 4-week (28-day) cycle of treatment. 
2. You will take your dose of osimertinib once daily at around the same time.  You may take it 
with or without food. You should take the tablet whole with water. The tablet should not be 
crushed, split or chewed.   
3. Record the date, the number of osimertinib tablets you swallowed and the time you took the 
medicine. 
4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit 
after taking the tablets, do not make up the dose, but take the next scheduled dose. 
5. If you miss a dose of osimertinib and it is more than 12 hours after your usual dose time, the 
missed dose should not be taken, but take your next scheduled dose. If you miss taking a 
scheduled dose, within a window of 12 hours, it is acceptable to take the dose. 
6. If you have any comments or notice any side effects, please write them in the comments 
column.  
7. Please bring this diary and your bottle(s) of osimertinib when you return for each appointment. 
 
Today’s Date:____________   Cycle:__________  OSIMERTINIB Dose:_________   
Patient Study ID:_______________ 
DAY 
DATE 
TIME  
TAKEN 
DOSE 
TAKEN 
# OF TABLETS 
TAKEN 
COMMENTS 
1. 
 
 
 
 
 
2. 
 
 
 
 
 
3. 
 
 
 
 
 
4. 
 
 
 
 
 
5. 
 
 
 
 
 
6. 
 
 
 
 
 
7. 
 
 
 
 
 
8. 
 
 
 
 
 
9. 
 
 
 
 
 
10. 
 
 
 
 
 
11. 
 
 
 
 
 
12. 
 
 
 
 
 
13. 
 
 
 
 
 
14. 
 
 
 
 
 
15. 
 
 
 
 
 
16. 
 
 
 
 
 
17. 
 
 
 
 
 
18. 
 
 
 
 
 
19. 
 
 
 
 
 
20. 
 
 
 
 
 
21. 
 
 
 
 
 
22. 
 
 
 
 
 
23. 
 
 
 
 
 


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24. 
 
 
 
 
 
25. 
 
 
 
 
 
26. 
 
 
 
 
 
27. 
 
 
 
 
 
28. 
 
 
 
 
 
 
Patient Label 


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15.4 APPENDIX D. GUIDANCE FOR THE MANAGEMENT OF ADVERSE EVENTS IN STUDIES 
USING 80MG OSIMERTINIB  
Osimertinib is a potent irreversible small molecule inhibitor of both the single EGFRm (tyrosine 
kinase inhibitor (TKI) sensitivity conferring mutations) and dual EGFRm/T790M (TKI 
resistance conferring mutation) receptor forms of EGFR, with weaker inhibition towards wild 
type EGFR.  
Clinical experience with 80mg osimertinib has shown an association with the occurrence of 
dermatological adverse events (particularly rash and dry skin) and diarrhea.  The considerable 
majority of these events have been mild, transient events that have not always required 
treatment. 
Based on experience with other EGFR and HER2 inhibitors, decreases in LVEF, anterior ocular 
effects and ILD/pneumonitis should be monitored for.   
Some guidance is provided in this document regarding these events. 
The purpose of these treatment guidelines is: 
• 
To prevent tolerable adverse events becoming intolerable for the patient and leading to 
discontinuation of treatment. 
• 
To promote consistency of treatment for specific adverse events across the osimertinib 
clinical program. 
 
 


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1. Skin Events – Rashes & Acnes, Dry Skin / Xerosis, Paronychia 
Patients may consider applying over-the-counter moisturising cream to face, hands and 
feet twice daily from the start of treatment with osimertinib.  
Skin effects may occur at any time, but most likely to start within 2 weeks of starting treatment.   
Rashes and Acne 
 
 


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Dry Skin / Xerosis 
 
 
 
 
 
 
 
 


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Pruritis 
 
 
 
 
 
 
 
 
 


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Paronychia 
 
 
Dermatologic Guidance Summary: 
• Patients may consider applying over-the-counter moisturising cream to face, hands and 
feet bid from the start of treatment. 
• Physicians may consider issuing a prescription for topical treatment to patients.  
However, topical steroids and topical or oral antibiotics should not be implemented 
prophylactically and treatment should only be started when confirmed by the treating 
physician.  
• As soon as an acneiform / papulopustular rash occurs, treatment with moderate 
strength topical steroids and antibiotics should be implemented.  
 


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• The occurrence of non-papulopustular skin reactions should be treated appropriately, 
as defined by the treating physician, and in consultation with a dermatologist where 
necessary 
• Use of topical benzoyl peroxides and other irritating anti-acne agents should be 
avoided. 
• Patients should be fully informed regarding skin reactions  
o may occur during treatment with osimertinib   
 skin reactions are not contagious, and  
 do not result from allergy to treatment  
o may consider applying over-the-counter moisturising cream to face, hands and feet 
bid from the start of treatment 
o to contact the study team to report any instances of skin reaction as soon as they arise 
so that appropriate treatment can be promptly initiated 
 and, especially if the skin reaction changes (e.g. if it spreads or becomes painful) 
o It may be beneficial to avoid irritating skin products (e.g. irritating soaps, products 
containing retinol or retinoic acid) 
o Camouflage make-up (non-comedogenic or non-pore blocking) can be used during 
treatment 
 


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2. Diarrhea Treatment Guidance 
 
Diarrhea Guidance Summary: 
• Patients should be fully informed regarding diarrhea  
o May occur during treatment with osimertinib   
 diarrhea is not contagious, and  
 does not result from allergy to treatment  
o Contact the study team to report any instances of diarrhea as soon as they arise 
so that appropriate treatment can be promptly initiated 


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3. Ophthalmic Guidance 
There is a known association between the use EGFR TKIs and the occurrence of ophthalmic 
adverse events.   
Patients on EGFR TKIs, including osimertinib, should be  
• Fully informed that ophthalmic events may occur during treatment with osimertinib  
• Monitored periodically for these events 
• Osimertinib should not be administered on the first scheduled day if the patient has any 
clinically significant eye symptoms. 
• Encouraged to report any instances of ophthalmic symptoms and/or vision changes to 
allow the appropriate treatment to be initiated.  Symptoms may include: 
o Burning  /  itching  /  irritation / smarting 
o Redness with / without discharge 
o Blurred vision 
o Light sensitivity 
Patients who wear contact lenses must discontinue wearing them if  
• They have any mild to moderate eye symptoms (CTCAE grade ≤2) until at least one 
week after symptoms have resolved. 
• Patient has a recurrence of eye symptoms or experiences any severe (CTCAE grade ≥3) 
ocular events until at least one week after treatment with osimertinib is permanently 
discontinued. 
Patients must not use any eye drops or ointment for treatment of eye symptoms, unless agreed 
by treating physician, at any time during the study until 1 week after osimertinib has been 
permanently discontinued.  
 
Assessments During Treatment 
• If the patient reports any eye symptoms during treatment with osimertinib or if signs are 
observed during a study visit, the Investigator should perform a clinical examination 
including a best corrected near and distant visual acuity assessment as appropriate 
• Findings 
should 
be 
documented 
in 
the 
patient’s 
notes 
 
Referral to Ophthalmologist 
Patients with ophthalmic AEs of CTCAE Grade > 3 or eye symptoms that are clinically 
significant and/or persistent (>7 days) should be referred to the ophthalmologist.  For example: 


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• Deterioration in near or distant visual acuity by more than one level 
• Persistence or worsening of: 
o Burning/ irritation/ smarting  
o Light sensitivity (photophobia) 
o Itching  
o Blurred vision 
o Redness with or without discharge   
 


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Ophthalmic Dose Adjustments 
Confirmed CTCAE Grade >3 
OR 
Clinically significant or persistent  
(present for >7 days) event 
AND  
Considered causally related to osimertinib  
 
Initiate ophthalmic treatment as appropriate and withhold dose for up to 4 weeks  
• If event improves to CTCAE Grade <1 within 4 weeks, reinstate osimertinib at the 
current dose maintaining ophthalmic treatment as appropriate 
• If event improves to CTCAE Grade 2 within 4 weeks, consider reinstating osimertinib 
at reduced dose of 40 mg daily,  maintaining ophthalmic treatment as appropriate 
• Permanently discontinue osimertinib and maintain ophthalmic treatment as appropriate, 
where  
o CTCAE Grade >3 or clinically significant or persistent adverse event 
does not improve to a lower CTCAE Grade within 4 weeks of osimertinib 
interruption, OR  
o Any ulcerative event 
Ophthalmic Guidance Summary 
• It is important that patients are fully informed that ophthalmic events may occur during 
treatment with osimertinib. 
• Osimertinib should not be administered on the first scheduled day if the patient has any 
clinically significant eye symptoms. 
• Patients should be encouraged to report any instances of ophthalmic symptoms and/or 
vision changes to allow the appropriate treatment to be initiated (or ophthalmic referral).   
• Patients who wear contact lenses must discontinue wearing them if  
o They have any mild to moderate eye symptoms (CTCAE grade ≤2) until at least 
one week after symptoms have resolved. 
o Patient has a recurrence of eye symptoms or experiences any severe (CTCAE 
grade ≥3) ocular events until at least one week after treatment with osimertinib  
is permanently discontinued. 
• Patients must not use any eye drops or ointment for treatment of eye symptoms, unless 


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94 
agreed by a study doctor, at any time during the study until 1 week after osimertinib has 
been permanently discontinued  
• Osimertinib dose should be interrupted, modified or permanently discontinued as 
appropriate for any ophthalmic events 
4. Left Ventricular Ejection Fraction (LVEF) 
Osimertinib and its active metabolite may also inhibit HER2.  For this reason: 
• Measurement of LVEF should be performed if the investigator has clinical suspicion of 
new onset impaired cardiac function 
• Patients are to be managed clinically according to standard of care 
 
5. Interstitial Lung Disease (ILD) / Pneumonitis Guidance 
If you have clinical suspicion of interstitial lung disease (ILD), dosing with osimertinib should 
be interrupted while further investigations are performed.   
A diagnostic workup (including HRCT, blood and sputum culture, laboratory parameters) 
should be performed, to exclude conditions such as lymphangitic carcinomatosis, infection, 
allergy or pulmonary haemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms 
have been excluded a diagnosis of interstitial lung disease should be considered and study 
treatment permanently discontinued.   
 


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ILD / Pneumonitis Guidance Summary 
• Interrupt osimertinib dosing, if you have clinical suspicion of interstitial lung disease 
(ILD), while further investigations are performed.   
• Perform full diagnostic workup (including HRCT, blood and sputum culture, laboratory 
parameters to exclude conditions such as lymphangitic carcinomatosis, infection, allergy 
or pulmonary haemorrhage 
• Contact the Medical Lead as soon as a potential pneumonitis event is identified.   
• Complete and submit pneumonitis questionnaire  


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• Resume osimertinib dosing as appropriate 
 
6. Summary 
• Patients should be fully informed of common adverse events associated with EGFR 
TKIs, including AZD921. Counselling should include 
o Important aspects of preventative self-care measures 
o When to notify physician of symptoms that may require further evaluation or 
treatment 
o Appropriate treatments associated with EGFR TKIs adverse events 
o Importance of osimertinib dosing adherence or the importance of dose holds or 
reductions when appropriate 
• Physicians should do the following: 
o Review the protocol and all associated documents provided by the study team 
o Familiarize themselves with the clinical management of EGFR TKI toxicity and 
required reporting as outlined in study documents  
 
 
 


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15.5 APPENDIX E. POTENTIAL DRUG INDUCED LIVER INJURY 
1. INTRODUCTION 
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator assesses cases meeting PHL criteria to determine whether Hy’s Law (HL) 
criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the elevations 
in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
 
2. DEFINITIONS 
Potential Hy’s Law (PHL) 
A Potential Hy’s Law (PHL) case is defined as a study patient with an increase in serum 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN irrespective of serum Alkaline 
Phosphatase (ALP), at any point during the study following the start of study medication. 
Hy’s Law (HL) 
An HL case is defined as a study patient with an increase in serum AST or ALT ≥ 3x ULN 
together with TBL ≥ 2xULN, where no other reason can be found to explain the combination of 
increases, e.g., elevated serum ALP indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL to be met the elevation in transaminases must precede or be coincident with 
(i.e., on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur.  
 
3. IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥ 3xULN 
• AST ≥ 3xULN 
• TBL ≥ 2xULN  
The Investigator will, without delay, review each new laboratory report and if the identification 
criteria are met, will:  
• Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits.  
• Promptly enter the laboratory data into the laboratory eCRF.  
 


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4. FOLLOW-UP 
4.1. Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria, the Investigator will: 
• Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol. 
 
4.2. Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• Determine whether PHL criteria were met at any study visit prior to starting study treatment in 
the presence of liver metastases (See Section 6). 
The Investigator will: 
• Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated.  
• Investigate the etiology of the event and perform diagnostic investigations.  
• Complete the three Liver eCRF Modules as information becomes available.  
• If at any time the PHL case meets serious criteria, report it as an SAE using standard 
reporting procedures. 
 
5. REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES  
The instructions in this Section should be followed for all cases where PHL criteria are met.  
The Investigator will follow the instructions below.  
If there is an alternative explanation for the ALT or AST and TBL elevations, a determination 
of whether the alternative explanation is an AE will be made and subsequently whether the AE 
meets the criteria for a SAE: 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.  
• If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF 
accordingly.  
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations 
other than the IMP:  
• Record an SAE (report term ‘Hy’s Law’).  
o The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply.  
o As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.  
 
6. ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 


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99 
This section is applicable to patients who meet PHL criteria on study treatment (including the 
30 day follow-up period post discontinuation of study treatment) after having previously met 
PHL criteria at a study visit prior to starting study treatment. 
At the first ‘on-study treatment’ occurrence of PHL criteria being met, the Investigator will: 
Determine if there has been a significant change in the patient’s condition compared with the 
last visit where PHL criteria were met: 
• If there is no significant change, no action is required. 
• If there is a significant change, follow the subsequent process described in Section 4.2 of 
this Appendix. 
A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms such as fatigue, 
vomiting, rash, right upper quadrant pain, jaundice, and/or eosinophilia. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Study Physician if there is any uncertainty. 
 
7. ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a patient meets PHL criteria on study treatment (including the 
30-day follow-up period) and has already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• Was the alternative cause for the previous occurrence of PHL criteria being met chronic 
or progressing malignant disease or did the patient meet PHL criteria prior to starting 
study treatment and at their first ‘on-study treatment’ visit as described in Section 6?  
If No: Follow the process described in Section 6 of this Appendix.  
If Yes: Determine if there has been a significant change in the patient’s condition compared with 
when PHL criteria were previously met.  
• If there is no significant change, no action is required.  
• If there is a significant change, follow the process described in Section 4.2 of this 
Appendix.  
A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms, such as fatigue, 
vomiting, rash, right upper quadrant pain, jaundice, and/or eosinophilia. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Study Physician if there is any uncertainty.  
 


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8. REFERENCES  
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM174090.pdf 
 
 


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101 
15.6 APPENDIX F. ASTRAZENECA SAE REPORT COVER SHEET 
US ESR SAE REPORT COVERSHEET 
 
Date: 
 
To: 
AZ Patient Safety - TCS 
Fax #: 
1-302-886-4114 
Email: 
Jennifer.defrancisco@astrazeneca.com 
and 
AEMailboxClinicalTrialTCS@astrazeneca.com 
Senders Name: 
 
Total number of pages: 
(including cover page) 
 
 
 
D-code: 
 
ESSROS Number: 
 
Sponsor Investigator/Site: 
 
Protocol Title: 
 
Initial or Follow Up: 
 
 
Message: 
 
 
 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
16-C-0092 
PRINCIPAL INVESTIGATOR: 
Udayan Guha, M.D., Ph.D. 
STUDY TITLE:  
 
A Pilot Study of Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-
Mutated, Non-Small Cell Lung Cancer (NSCLC) After Treatment with Osimertinib 
(AZD9291, Tagrisso) 
 
 
Continuing Review Approved by the IRB on 01/28/19 
Amendment Approved by the IRB on 06/28/19 (L) 
 
 
Date posted to web: 07/04/19 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
This study is being done in order to test the effect of local ablative therapy (LAT) in the 
treatment of your cancer after progression of disease on the investigational drug, osimertinib 
(AZD9291, Tagrisso), provided there are no more than 5 sites of your disease suitable for 
treatment with LAT (surgery, radiation therapy, radiofrequency ablation, or cryoablation).  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 16-C-0092 
 
CONTINUATION: page 2 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Normally, cells in your body divide in an orderly way. However, in cancer, some cells start to 
behave abnormally resulting in faster growth and multiplication.  Osimertinib is an experimental 
treatment for patients with non-small cell lung cancer (NSCLC) whose lung cancer is due to the 
development of specific changes in the gene that produces a protein on the surface of the cell 
called the epidermal growth factor receptor (EGFR).  When the gene changes it is said to have 
developed a mutation.  Patients who have NSCLC with a mutation in EGFR can be treated by 
specific drugs called EGFR tyrosine kinase inhibitors (EGFR TKIs).  Unfortunately, after a 
period of therapy with EGFR TKIs, a significant number of tumours will develop resistance to 
this treatment due to a second EGFR mutation called T790M. 
Osimertinib has been approved by the Food and Drug Administration (FDA) for treatment of 
recurrent lung cancer with T790M mutation in EGFR after progression on drugs targeting other 
“sensitizing” mutations in EGFR and has been shown to delay cancer progression. However, 
osimertinib is not approved for use as the initial treatment of lung cancer with EGFR mutations, 
treatment of patients without the T790M mutation, or re-initiation of treatment after LAT. Hence 
treatment with osimertinib is experimental in this study.  
There are only two FDA-approved treatments for patients whose disease has progressed on 
osimertinib (Nivolumab/Opdivo and Pembrolizumab/Keytruda). Thus, assessing the 
effectiveness of LAT as a strategy to extend the benefits of osimertinib merits further 
investigation. 
Why are you being asked to take part in this study? 
You have been asked to take part in this study because you have been diagnosed with non-small 
cell lung cancer that has an EGFR mutation, with any of the following characteristics:  
 You have not been treated with any EGFR TKI. (cohort 1) 
 Your lung cancer has progressed after treatment with other EGFR TKIs and now it has 
the EGFR T790M mutation.  (cohort 2) 
 Your lung cancer has progressed while being treated with osimertinib and there are no 
more than 5 sites of your disease that have progressed and are suitable for treatment with 
LAT (surgery, radiation therapy or radiofrequency ablation). (cohort 3) 
How many people will take part in this study?  
Up to 100 people will take part in this study. 


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PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
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File in Section 4:  Protocol Consent 
 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
All research studies have specific criteria for entry to allow for valid interpretation of the study 
results and safety of participants, known as eligibility criteria. Before you begin this study, you 
will need to have the following exams and tests to make sure you are eligible for this study. The 
exams and tests are part of regular cancer care and may be done even if you do not join the 
study. You may have already had these tests done as part of a NCI protocol, including the 
screening protocol.  If you have recently undergone some of these tests, they may not need to be 
repeated. 
 History and physical examination, including obtaining information about how you 
function in your daily activities 
 Standard blood tests to measure your liver and kidney function, white blood cells, red 
blood cells and platelets, blood electrolytes and how quickly you form blood clots.  If you 
are a woman able to get pregnant, you will also have a pregnancy test done. You will not 
be able to participate in the study if you are pregnant. 
 Scans of your tumor 
 Eye exam 
 Electrocardiogram (ECG) 
 Echocardiogram 
 Review of your tumor sample from previous surgery or biopsy to confirm diagnosis and 
for genetic testing.  If sufficient material does not exist, you will be asked to undergo a 
biopsy. 
If you meet the eligibility criteria for this study you will be offered the option of participating 
and you will be asked to sign this informed consent document before participating in the study. 
During the study 
Cohorts 1 and 2 
Once you have signed the consent, you will begin taking osimertinib by mouth once a day, on 
every day of a 28-day course.  You will continue to take osimertinib until you have intolerable 
side effects or if your disease worsens.  If your disease worsens, you will be assessed for your 
suitability for LAT.  If you have no more than 5 disease sites that can be treated with LAT, you 
will undergo the most appropriate procedure (surgery, RFA, or radiation therapy).  If your 
disease is not suitable for LAT, you will be permanently removed from study treatment. 


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CONTINUATION: page 4 of 17 pages 
 
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Cohort 3 
If you enrolled in the study having already progressed on osimertinib, you will be asked to 
undergo a biopsy, will be evaluated for eligibility for LAT and if you are eligible, you will 
undergo the most appropriate LAT procedure before re-starting osimertinib. 
All Cohorts 
After LAT, you start osimertinib again, taking it daily by mouth until your disease worsens or 
you have intolerable side effects. If your disease worsens at the same site where you had an LAT 
procedure done before, you will be considered for further LAT procedure at that site and have an 
option to be re-started on osimertinib after the 2nd LAT procedure at the same site.  
Osimertinib can be taken with or without food at the same time each day.   If a dose of 
osimertinib is missed, you may make up the dose unless the next dose is due within 12 hours. 
The tablet should be swallowed whole with water. The tablet should not be crushed, split or 
chewed. If you are unable to swallow the tablet, it may first be dispensed in 50 mL of non-
carbonated water. The tablet should be dropped in the water, without crushing, stirred until 
dispersed and immediately swallowed. An additional half a glass of water should be added to 
ensure that no residue remains and then immediately swallowed.  
You will be asked to keep a medication diary to record your doses.  Please bring the diary and 
your remaining tablets with you at every study visit. 
Study tests/procedures 
We will also collect several samples and perform several tests during the study. Some will be to 
monitor your safety and the progress of your disease.  Some will be for additional research 
studies we plan to conduct.  
Clinical Assessments 
You will have a physical examination, an ECG, and routine blood tests on day -1 and day 7 of 
your first course, then on day -1 of all subsequent courses.  
Scans to assess the response of your disease to the study therapy will be performed every 8 
weeks. 
An echocardiogram will be performed every four months. 


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Research Assessments 
The following samples will be collected at baseline (before you have had your first dose of study 
drug) and day 7 of course 1 and on day -1 of subsequent courses: 
 Blood sample:  We will ask you to provide up to 50mL (approximately 3.5 tablespoons) 
of blood at the above time points.  The maximum amount of blood taken from you is 
based on your age and will not be more than the blood volume limit set for research by 
the NIH. 
 Urine sample: We will ask you to provide up to 45 mL of urine at each sampling time 
point, if feasible. We may also provide you with a container to collect urine for a 24hr 
period at home, or during your stay in the NIH Clinical Center. 
 Saliva sample: We will ask you to provide a saliva sample, if possible, each time you 
provide us with your blood and urine samples. We will provide you with a container with 
specific instructions to get your saliva samples.  
The above samples will be analyzed for alterations in genes and proteins.  
We will also collect tumor tissue at the beginning of the study before you have taken any study 
medication (if we have enough tissue left from your sample at screening, we will use that), and 
after your disease worsens for the first time.  We may also collect a sample after your disease has 
worsened for the second time, but this is optional, and we will ask your permission to do so later 
on in the consent. 
If you undergo surgery as your form of LAT, the tumor sample will be obtained at that time.  If 
you are not undergoing surgery at the time the sample is needed, you will have to undergo a 
biopsy, a description of which is provided later.  
When you are finished taking the drugs (treatment) 
Approximately 30 days after you have finished taking the study drug, you will be asked to the 
return to the NIH for a medical history and physical exam, an ECG, routine blood tests for 
safety. 
After you are no longer coming to the Clinical Center for visits, we will contact you by phone 
every year to check on your health. 
Standard of Care Treatment: 
Treatments covered under this study may include a single medication or a combination of 
medications, surgery or radiation to treat your cancer. These treatments will not be experimental. 
Your doctors will describe your treatment plan to you in detail before asking you to sign this 


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CONTINUATION: page 6 of 17 pages 
 
PATIENT IDENTIFICATION 
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consent form. You may be asked to sign a separate consent form for any treatment procedures 
not outlined in this consent. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 3 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Acceptable forms of birth control for women include:  
• abstinence  
 intrauterine device (IUD) 
• hormonal [injections or implants].  
Note: use oral hormonal contraception alone is not recommended as the study 
medication may reduce its effectiveness.  
• tubal ligation 
• vasectomy 
Acceptable forms of birth control for men: 
• condoms (should be used even if your female partner is on another form of contraception) 
You should also refrain from donating sperm for 6 months after your last dose 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
Risks from osimertinib 
The medication used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drug. 


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Here are important points about side effects: 
 The study doctors do not know if you will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go 
away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
 The study doctor may be able to treat some side effects. 
 The study doctor may adjust the study drugs to try to reduce side effects. 
The table below shows the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
Likely 
Less Likely 
Rare but Serious 
 Nausea 
 Diarrhea 
 Rash, Acne 
 Dry Skin, Itching 
 Infection of the skin 
around a fingernail or 
toenail 
 Eye Discomfort: burning / 
itching  /  irritation / 
smarting/ redness with or 
without discharge 
 Blurred vision 
 Light sensitivity 
 
 Pneumonia 
 Pneumonitis, an 
inflammation of lung tissue 
 Pleural Effusion, a 
condition of excess fluid in 
the pleural cavity, the 
fluid-filled space that 
surrounds the lungs 
 Interstitial Lung Disease 
(ILD), a variety of 
conditions characterized by 
the scarring of lung tissue 
 Heart function: changes in 
how well your heart pumps 
with each beat 
 Change in heart rhythm 
 Increased levels of calcium 
in the blood 
 Vision Changes 
 Septic Shock, a severe 
infection where toxins can 
cause a full-body 
inflammatory response 
 Death 


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PATIENT IDENTIFICATION 
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The risks you might experience other than the drug side effects are: 
Biopsies 
Risks associated with the biopsies include pain and bleeding at the biopsy site. We may need to 
perform a CT scan to guide the collection of tissue which would involve risks from radiation as 
described below. 
Radiation risks: You will be asked to undergo CT-guided biopsy before initiating treatment even 
if you had undergone a biopsy before. In case a biopsy at this time is not clinically safe and you 
had a biopsy done before, tissue will be obtained from the previous biopsy for the mutation 
testing needed for your eligibility for this protocol. A 2nd biopsy is also required after your first 
progression on osimertinib to detect the T790M mutation in EGFR to guide your therapy and 
also for research purposes. Another optional CT-guided biopsy may be requested when you 
finally come off protocol because of disease progression. One or more of these CT-guided 
biopsies may be for research purposes only and may or may not affect your future treatment.  
Therefore, the study may involve exposure to radiation from up to 3 CT scans.  This radiation 
exposure is not required for your medical care and is for research purposes only.   
The amount of radiation you will receive in this study is 2.4 rem which is below the guideline of 
5 rem per year allowed for research subjects by the NIH Radiation Safety Committee.  The 
average person in the United States receives a radiation exposure of 0.3 rem per year from 
natural sources, such as the sun, outer space, and the earth's air and soil.  If you would like more 
information about radiation, please ask the investigator for a copy of the pamphlet, An 
Introduction to Radiation for NIH Research Subjects. 
While there is no direct evidence that the amount of radiation exposure received from 
participating in this study is harmful, there is indirect evidence it may not be completely safe.  
There may be a very slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation.  Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study.  It is best to 
avoid radiation exposure to unborn or nursing infants since they are more sensitive to radiation 
than adults. 
Blood draw 
Risks associated with blood draw, which include pain and bruising, lightheadedness, and rarely, 
fainting 


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Privacy 
Psychological or Social Risks Associated with Loss of Privacy in Genetic Research 
1. Psychological or Social Risks Associated with Return of Incidental or Secondary Findings 
As part of the research study, it is possible that you could learn that you have genetic risks 
for another disease or disability. This may be upsetting and, depending on what you learn, 
might create a need to make challenging decisions about how to respond.  
 
Although your genomic information is unique to you, you share some genomic similarities 
with your children, parents, brothers, sisters, and other blood relatives. Therefore, learning 
your research results could mean something about your family members and might cause you 
or your family distress.  
2. Privacy Risks Associated with Return of Incidental or Secondary Findings 
Your privacy is very important to us and we will use many safety measures to protect your 
privacy. However, in spite of all of the safety measures that we will use, we cannot guarantee 
that your identity will never become known. While neither the public nor the controlled-
access databases developed for this project will have information such as your name, address, 
telephone number, or social security number, it may be possible to identify you based on the 
information in these databases and other public information (including information you tell 
people or post about yourself).  The risk of this happening is currently very low.  
 
Although your genetic information is unique to you, you do share some genetic information 
with your children, parents, brothers, sisters, and other blood relatives. Consequently, it may 
be possible that genetic information from them could be used to help identify you.  Similarly, 
it may be possible that genetic information from you could be used to help identify them.  
Patterns of genetic variation also can be used by law enforcement agencies to identify a 
person or his/her blood relatives.   
 
It is possible also that someone could get unauthorized access or break into the system that 
stores information about you.  Every precaution will be taken to minimize this risk.  There 
also may be other privacy risks that we have not foreseen. 
3. Protections against misuse of genetic information 
Since some genetic variations can help to predict future health problems for you and your 
relatives, this information might be of interest to health care providers, life insurance 
companies, and others.  However, Federal and State laws provide some protections against 
discrimination based on genetic information.  For example, the Genetic Information 
Nondiscrimination Act (GINA) makes it illegal for health insurance companies, group health 
plans, and most employers to discriminate against you based on your genetic information.  
However, GINA does not prevent companies that sell life insurance, disability insurance, or 
long-term care insurance from using genetic information as a reason to deny coverage or set 
premiums.  GINA also does not apply to members of the United States military, individuals 


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PATIENT IDENTIFICATION 
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covered by the Indian Health Service, or veterans obtaining health care through the Veteran’s 
Administration.  Lastly, GINA does not forbid insurance medical underwriting based on your 
current health status though the Affordable Care Act limits consideration of pre-existing 
conditions by insurers. 
Risks of local ablative therapy (LAT)  
You will be required to sign separate consent forms at the time of LAT.  Surgery, radiation 
therapy, or radiofrequency ablation have their own risks and these will be explained to you if and 
when you are eligible for that.  You have the option of declining the LAT part of the study at that 
time. Prior osimertinib treatment may have unknown risks associated with subsequent LAT 
procedure, including radiation.  
 
Incidental findings 
Your tissue (tumor and normal tissue) and blood that is collected will be used to look for specific 
changes in the DNA in tumors that could be used to develop new ways of diagnosing and 
treating cancer.   DNA (also called deoxyribonucleic acid) are the molecules inside cells that 
carry genetic information and pass it from one generation of cells to the next – like an instruction 
manual. Normal tissue contains the DNA (instructions) that you were born with, DNA in tumor 
cells has changed – or mutated – and we think that change in the DNA is what causes tumors to 
form and to grow.  In order to determine which parts of the DNA have mutated, we will compare 
the DNA in your tumor cells to DNA from your normal cells.  We will then analyze all of the 
results from similar tumors to see if there are any changes in the DNA that are common to a 
particular type of tumor.  In order to examine the tumor and normal tissue we may use several 
different techniques depending on the type of tissue we collect.  These could include growing 
cell lines (cells which keep dividing and growing in the laboratory, sometimes for years allowing 
us to continually study those cells), growing your tissue for a short time in culture in the 
laboratory and growing your tumor tissue in mouse models and looking in great detail at the 
parts of the genes that produce specific proteins.  When we are examining these pieces of your 
DNA, it is possible that we could identify possible changes in other parts of your DNA that are 
not related to this research.  These are known as “incidental medical findings”. These include:  
 Changes in genes that are related to diseases other than cancer  
 Changes in genes that are not known to cause any disease. These are known as normal 
variations.  
 Changes in genes that are new and of uncertain clinical importance. This means that we 
do not know if they could cause or contribute to a disease or if they are normal variations.  
However, the analyses that we will perform in our laboratory are for research purposes only. 
They are not nearly as sensitive as the tests that are performed in a laboratory that is certified to 
perform genetic testing. Changes that we observe unrelated to our research may or may not be 
valid.  Therefore, we do not plan to inform you of the results of testing on your tissue and blood 


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that is performed in our research lab.  However, in the unlikely event that we discover a finding 
that could be clinically relevant, we will contact you to ask if you would like to submit a blood 
sample to be tested at a certified lab and meet with a credentialed genetics healthcare provider 
for genetics education and counseling (either in clinic or via phone conference).  The genetics 
healthcare provider will explain to you the nature of the result, implications for you and your 
family members, the need to confirm the results with an outside certified laboratory, the time 
frame for analysis, and implications of results including risks, benefits, and limitations.  
At the start of the study, we will give you the option to complete a form to name a person (a 
designee) that you would like to receive information about your genetic findings. If we find a 
change in a gene that is important to you or your family’s health, but you are deceased or have 
diminished mental capacity at the time results are available, we will offer your designee to come 
to NIH (at our expense) to have genetic education and counseling to explain this result. If your 
designee does not want to come to NIH, we will help the designee find a local genetic healthcare 
provider who can explain the result (at the designee’s expense). 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if LAT and re-initiation of treatment with osimertinib can increase 
the time before your disease gets worse.   We do not know if you will receive personal, medical 
benefit from taking part in this study.  These potential benefits could include shrinking of your 
tumor or lessening of your symptoms, such as pain, that are caused by the cancer.  Because there 
is not much information about this strategy of LAT and re-initiation of osimertinib, we do not 
know if you will benefit from taking part in this study, although the knowledge gained from this 
study may help others in the future who have cancer.   
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
 Getting treatment or care for your cancer without being in a study 
 Taking part in another study 
 Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 


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Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
 if he/she believes that it is in your best interest 
 if your disease comes back after LAT or if you are not eligible for LAT 
 if you have side effects from the treatment that your doctor thinks are too severe 
 if new information shows that another treatment would be better for you 
 if AstraZeneca is no longer able to supply osimertinib 
In this case, you will be informed of the reason therapy is being stopped. 
If your doctor decides to stop your therapy because your disease has come back, and that disease 
is later found to be a non-cancerous diagnosis such as infection or inflammation, you may be 
able to restart treatment as long as you continue to meet the study’s enrollment requirements and 
have not stopped taking the study drug for more than one month. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the pharmaceutical 
company or designated representatives. If you withdraw your consent and leave the trial, any 
samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  


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 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
 The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
 National Institutes of Health Intramural Institutional Review Board 
 Qualified representatives from Astra Zeneca, the pharmaceutical company who produces 
osimertinib. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
Your individual genomic data and health information will be put in a controlled-access database.  
This means that only researchers who apply for and get permission to use the information for a 
specific research project will be able to access the information.  Your genomic data and health 
information will not be labeled with your name or other information that could be used to 
identify you.  Researchers approved to access information in the database have agreed not to 
attempt to identify you. 
Certificate of Confidentiality 
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
 will be used for auditing or program evaluation internally by the NIH; or  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 16-C-0092 
 
CONTINUATION: page 14 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
 is necessary for your medical treatment and you have consented to this disclosure;  
 is for other research.  
 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest  
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using osimertinib 
developed by Astra Zeneca through a joint study with your researchers and the company.   The 
company also provides financial support for this study.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 16-C-0092 
 
CONTINUATION: page 15 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Biopsy Procedure  
A mandatory tumor biopsy will be obtained before starting treatment and after first progression. 
You will be asked about another tumor biopsy at second progression. This biopsy will be 
optional. 
If your doctor determines it is safe we will obtain a piece of your tumor (biopsy) using a needle. 
This process will be guided by a CT scan or bronchoscopy and is minimally invasive. You will 
be given local anesthesia (numbing medicine). The biopsy will be taken through a needle put 
through the skin into your tumor. After the procedure the nurses will watch your blood pressure 
and other vital signs. 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 16-C-0092 
CONTINUATION: page 16 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Udayan Guha, M.D., Building 10, Room 4-5330, Telephone:  240-760-
6241. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 16-C-0092 
CONTINUATION: page 17 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby consent to take part in this 
study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby give permission for my 
child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian 
Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the 
study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JANUARY 28, 2019 THROUGH FEBRUARY 4, 2020.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name