A Phase II Study to Evaluate Neoadjuvant Osimertinib Therapy in Patients With Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Stage I Non-Small Cell Lung Cancer, Stage IA Non-Small Cell Lung Cancer, Stage IB Non-Small Cell Lung Cancer, Stage II Non-Small Cell Lung Cancer, Stage IIA Non-Small Cell Lung Cancer, Stage IIB Non-Small Cell Lung Cancer, Stage IIIA Non-Small Cell Lung Cancer
Sponsor: University of California, San Francisco



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Protocol Signature Page
Protocol No.: 17658
Version Date:04/12/2022
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee (DSMC).
2. I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants.
3. I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol.
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website.
5. I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations.
UCSF Principal Investigator
______________________________________________________________________
Printed Name
____________________________________________
_______________________
Signature
Date

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Abstract
Title
A phase II study to evaluate neoadjuvant osimertinib therapy in patients with 
surgically resectable, EGFR-mutant non-small cell lung cancer
Patient 
population
Patients with stage I-IIIA, EGFR-mutant lung adenocarcinoma population
Rationale for 
Study
Somatic activating mutations in epidermal growth factor receptor (EGFR) 
are present in 15-20% of non-small cell lung cancer (NSCLC) patients [2, 
3]. The EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, and 
afatinib have each demonstrated significant improvement in progression-
free survival compared to standard platinum doublet-based chemotherapy 
when used in the first line setting for advanced EGFR-mutant NSCLC [4-6]. 
Despite this clinical advance, tumor resistance to EGFR TKI treatment is a 
major clinical challenge. Approximately 20-30% of patients exhibit innate 
resistance and fail to respond to initial treatment; moreover, 98% of patients 
who respond to initial EGFR TKI treatment exhibit an incomplete response 
[4-6].
To date, efforts to understand the basis of EGFR TKI resistance have 
largely focused on uncovering mechanisms of acquired resistance. A 
second site T790M resistance mutation in EGFR accounts for over 50% of 
acquired resistance to first- and second-generation EGFR TKIs [7-17]. The 
third-generation EGFR TKI osimertinib has shown efficacy against lung 
cancers harboring the EGFRT790M mutation [18, 19]. However, even in 
patients whose tumors harbor EGFRT790M, the objective response rate  is 
only 60-70% and complete responses (CRs) are rare [20]. Further, all 
patients treated with osimertinib eventually develop disease progression 
(PD) and succumb to their cancer [18, 19]. While mechanisms of acquired 
resistance to osimertinib are being explored [21, 22], the basis of 
incomplete response and residual disease that occurs after initial third-
generation EGFR TKI therapy is poorly understood.
We hypothesize that neoadjuvant treatment with osimertinib in stage I-IIIa 
EGFR-mutant lung cancers will result in significant tumor reduction and 
major pathological responses (MPRs). Furthermore, the neoadjuvant design 
of this trial will permit comprehensive molecular analyses on tumor 
specimens pre-treatment and after initial response to osimertinib. This will 
allow us to define mechanisms of incomplete initial response to osimertinib 
and identify rational companion therapies that when combined with 
osimertinib in the first line setting could result in more durable and CRs for 
patients.
Primary 
Objective
To evaluate the efficacy of osimertinib as neoadjuvant therapy in patients 
with surgically resectable EGFR-mutant NSCLC. The primary endpoint of 
the study will be MPR rate defined as ≤10% viable tumor present 
histologically in the resected tumor specimen.

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Secondary 
Objectives
1. To evaluate the safety of osimertinib given as neoadjuvant therapy in 
early stage EGFR-mutant NSCLC patients
2. To evaluate whether neoadjuvant osimertinib treatment increases the 
frequency of tumors that are unresectable due to adverse events (AEs) or 
PD.
3. To evaluate secondary measures of clinical efficacy in early stage EGFR-
mutant NSCLC patients treated with osimertinib induction therapy. 
Secondary endpoints of efficacy will include radiographic decrease in 
maximum tumor diameter, complete pathologic response rate, 5-year 
disease-free survival (DFS), and 5-year overall survival (OS).
Study Design
This is a phase II multi-institution (UCSF and participating sites), single-
arm, open-label clinical trial of neoadjuvant osimertinib in Stage I-IIIa 
EGFR-mutant lung cancer patients who are planning to undergo surgical 
resection of their lung cancer.
A total of 27 evaluable subjects will be enrolled in the study. This will provide 
87% power to detect a MPR rate of 50% among patients receiving 
osimertinib induction therapy as compared to a null hypothesis response 
rate of 22%, which has been observed for neoadjuvant chemotherapy in 
unselected NSCLC populations [23, 24], at the 5% significance level.
Patients will receive the study drug for a minimum of 1 cycle prior to surgery 
(28 days). ORR will be determined by CT scan prior to surgery. 
Investigators will have the option to give a second cycle of study drug prior 
to surgery if clinically indicated.
Number of 
patients
27 patients will be enrolled.
Duration of 
Therapy
Patients may continue treatment for up to 70 days from the time of study 
entry.
Duration of 
Follow-up
Follow-up for individual participants will be up to 5 years.
Duration of 
study
The study will reach completion 48 months from the time the study opens 
to accrual.
Study Drugs
Osimertinib 80 mg per os (PO) daily
Safety 
Assessments
Analyses will be performed for all patients  who have received at least one 
dose of study drug. The study will use the Common Terminology Criteria 
for Adverse Events (CTCAE) v4.03 for reporting of non- hematologic AEs 
and modified criteria for hematologic AEs. The number of patients whose 
surgery is not performed as planned will also be reported.

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Efficacy 
Assessments
The primary measure of efficacy will be MPR as determined by central 
review. Secondary measures of efficacy will be radiographic decrease in 
maximum tumor diameter, 5-year DFS, 5-year OS, pathological response 
rate (pCR), and depth of response (DpR).
Unique 
Aspects of this 
Study
This is the first study to evaluate the safety and efficacy of a 3rd generation 
EGFR TKI in the neoadjuvant setting.

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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CITI
Collaborative Institute Training Initiative
CLIA
Clinical Laboratory Improvement Amendments
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CRO
Contract research organization
CT
computerized tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
ctDNA
circulating tumor DNA
DFS
disease-free survival
DpR
Depth of Response
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
FDA
Food and Drug Administration
GCP
Good Clinical Practices
HBV
hepatitis B virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HGB
Hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
ILD
interstitial lung disease
IND
investigational new drug
IP
investigational product
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MPR
Major Pathological Response
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NF-kB
nuclear factor kappa-light-chain-enhancer of activated B cells

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NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
Overall survival
PD
progressive disease/disease progression
PDX
patient-derived xenograft
PD-1
programed cell death protein 1 
PI
Principal investigator
PK
Pharmacokinetic
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
SAE
serious adverse event
SD
stable disease
SIV
Site initiation visit
SOP
Standard operating procedure
SPE
Single patient exception
TAM
tumor-associated macrophage
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal

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Table of Contents
Protocol Signature Page .......................................................................................................................................2
Protocol Signature Page – Participating Sites........................................................................................................3
Abstract................................................................................................................................................................4
List of Abbreviations.............................................................................................................................................7
Table of Contents .................................................................................................................................................9
1 Introduction.....................................................................................................................................................13
1.1 Background on Indication .................................................................................................................................13
1.1.1 Treatment of early stage Non-Small Cell Lung Cancer ................................................................13
1.1.2 Use of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Early Stage, EGFR-mutant Non-
Small Cell Lung Cancers........................................................................................................................13
1.2 Background on the Compounds ........................................................................................................................14
1.2.1 Osimertinib..................................................................................................................................14
1.3 Rationale for the Proposed Study......................................................................................................................15
1.3.1 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) tumor cell survival is induced by 
epidermal growth factor receptor tyrosine kinase inhibitor treatment...............................................16
1.3.2 Tumor-associated macrophages (TAMs).....................................................................................16
1.3.3 Concurrent tumor genomic alterations influence osimertinib response ....................................18
1.3.4 Rationale for osimertinib neoadjuvant clinical trial ....................................................................19
1.4 Correlative Studies ............................................................................................................................................20
1.4.1 Exome and transcriptome sequencing........................................................................................20
1.4.2 Immune profiling.........................................................................................................................20
1.4.3 Derivation of patient-derived xenografts and organoids ............................................................21
1.4.4 Peripheral Blood circulating tumor DNA Collection ....................................................................21
2 Objectives of the Study....................................................................................................................................21
2.1 Primary..............................................................................................................................................................21
2.2 Secondary..........................................................................................................................................................21
2.3 Exploratory........................................................................................................................................................21
2.4 Endpoints...........................................................................................................................................................21
2.4.1 Primary Endpoint.........................................................................................................................21
2.4.2 Secondary Endpoints...................................................................................................................22
2.4.3 Exploratory Endpoints .................................................................................................................22
3 Study Design....................................................................................................................................................22
3.1 Characteristics...................................................................................................................................................22
3.2 Number of Participants .....................................................................................................................................23
3.3 Eligibility Criteria ...............................................................................................................................................23
3.3.1 Inclusion Criteria..........................................................................................................................23

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3.3.2 Exclusion Criteria.........................................................................................................................25
3.4 Duration of Therapy ..........................................................................................................................................27
3.5 Duration of Follow Up .......................................................................................................................................27
3.6 Randomization Procedures ...............................................................................................................................27
3.7 Study Timeline...................................................................................................................................................27
3.7.1 Primary Completion.....................................................................................................................27
3.7.2 Study Completion........................................................................................................................27
4 Study Drugs .....................................................................................................................................................28
4.1 Description, Supply and Storage of Investigational Drugs ................................................................................28
4.1.1 Osimertinib..................................................................................................................................28
4.2 Drug Accountability...........................................................................................................................................31
4.3 Drug Ordering ...................................................................................................................................................31
4.4 Packaging and Labeling of Study Drugs ............................................................................................................31
5 Treatment Plan................................................................................................................................................31
5.1 Dosage and Administration...............................................................................................................................31
5.1.1 Other Modalities or Procedures..................................................................................................32
5.2 Dose Modifications and Dosing Delays .............................................................................................................32
5.3 Monitoring and Toxicity Management..............................................................................................................35
5.3.1 Other toxicities ............................................................................................................................35
6 Study Procedures and Observations.................................................................................................................38
6.1 Schedule of Procedures and Observations ........................................................................................................38
6.1.1 Pretreatment Period....................................................................................................................39
6.1.2 Treatment Period ........................................................................................................................40
6.1.3 Study Procedures, D15 following surgery....................................................................................43
6.1.4 End-of-Treatment Study Procedures...........................................................................................43
6.1.5 Long Term/Survival Follow-up Procedures..................................................................................43
6.1.6 Discontinuation of Therapy .........................................................................................................43
6.2 Specimen Acquisition for Exploratory/Correlative Studies/Specimen Banking .................................................43
6.2.1 Peripheral Blood..........................................................................................................................43
6.2.2 Specimen acquisition from screening biopsies............................................................................44
6.2.3 Specimen acquisition from surgical resection.............................................................................44
6.2.4 Banking of leftover specimens ....................................................................................................44
6.3 Usage of Concurrent/Concomitant Medications...............................................................................................44
6.4 Dietary Restrictions ...........................................................................................................................................45
6.5 Prohibited Medications Other anticancer therapy............................................................................................45
6.6 Contraceptive Counseling..................................................................................................................................47
7 Reporting and Documentation of Results.........................................................................................................47

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7.1 Antitumor Effect – Solid Tumors .......................................................................................................................47
7.2.1 Definitions ...................................................................................................................................48
7.2.2 Disease Parameters.....................................................................................................................48
7.2.3 Methods for Evaluation of Measurable Disease..........................................................................49
7.2.4 Response Criteria.........................................................................................................................49
7.2 Evaluation of Safety ..........................................................................................................................................50
7.3 Definitions of Adverse Events............................................................................................................................50
7.3.1 Adverse Event..............................................................................................................................50
7.3.2 Adverse reaction..........................................................................................................................51
7.3.3 Serious.........................................................................................................................................52
7.3.4 Life threatening ...........................................................................................................................52
7.3.5 Overdose .....................................................................................................................................52
7.3.6 Maternal and Paternal Exposures ...............................................................................................53
7.3.7 Disease progression.....................................................................................................................53
7.3.8 New cancers ................................................................................................................................53
7.3.9 Lack of efficacy ............................................................................................................................54
7.3.10 Deaths........................................................................................................................................54
7.4 Recording of an Adverse Event..........................................................................................................................54
7.5 Follow-up of Adverse Events .............................................................................................................................55
7.6 Adverse Events Monitoring ...............................................................................................................................55
7.7 Expedited Reporting..........................................................................................................................................55
8 Statistical Considerations and Evaluation of Results.........................................................................................58
8.1 Sample Size and Accrual Rate Considerations...................................................................................................58
8.1.1 Sample Size and Power Estimate.................................................................................................58
8.1.2 Replacement Policy .....................................................................................................................58
8.1.3 Accrual estimates ........................................................................................................................58
8.2 Interim Analyses and Stopping Rules ................................................................................................................59
8.3 Analyses Plans...................................................................................................................................................59
8.3.1 Analysis Population .....................................................................................................................59
8.3.2 Primary Analysis (or Analysis of Primary Endpoints)...................................................................59
8.3.3 Secondary Analysis (or Analysis of Secondary Endpoints)...........................................................60
8.3.4 Other Analyses/Assessments ......................................................................................................61
8.4 Evaluation of Safety ..........................................................................................................................................62
9 Study Management .........................................................................................................................................62
9.1 Pre-study Documentation .................................................................................................................................62
9.2 IRB Approval......................................................................................................................................................62
9.3 Informed Consent..............................................................................................................................................63
9.4 Changes in the Protocol.....................................................................................................................................63
9.5 Handling and Documentation of Clinical Supplies.............................................................................................63
9.6 Case Report Forms ............................................................................................................................................63

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9.7 Oversight and Monitoring Plan.........................................................................................................................64
9.8 Multicenter Communication .............................................................................................................................64
9.9 Record Keeping and Record Retention..............................................................................................................64
9.10 Coordinating Center Documentation of Distribution ......................................................................................65
9.11 Regulatory Documentation.............................................................................................................................65
10 Protection of Human Subjects........................................................................................................................66
10.1 Protection from Unnecessary Harm ................................................................................................................66
10.2 Protection of Privacy .......................................................................................................................................66
References..........................................................................................................................................................67
Appendix 1 Schedule of Study Procedures and Assessments...............................................................................70
Appendix 2 Performance Status Criteria .............................................................................................................72
Appendix 3 Data and Safety Monitoring Plan for a Multicenter Study (Phase II or III study)................................73
Appendix 4 UCSF Policy/Procedure for Required Regulatory Documents for UCSF Multicenter Investigator-
Initiated Oncology Clinical Trials with an Investigator held IND...........................................................................77
Appendix 5 Required Regulatory Documents for Sub-sites Participating in a UCSF Investigator Initiated 
Multicenter Trial (Checklist)................................................................................................................................79
Appendix 6 Prohibited Medications....................................................................................................................80
Appendix 7 Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy’s Law .................83

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1 Introduction
1.1 Background on Indication
Lung cancer is the leading cause of cancer-related mortality in the United States. Molecular 
profiling of NSCLC has identified multiple driver mutations responsive to targeted therapy. The 
most common of these targetable somatic activating mutations is in the EGFR, present in 15-
20% of patients [2, 26], leading to constitutive activation of EGFR signaling. The vast majority of 
patients with tumors harboring these mutations will respond to treatment with first or second-
generation EGFR TKIs such as erlotinib, gefitinib, and afatinib. In this patient population, 
response rates from 56-80% have been reported [4, 27, 28].
Despite this high initial response rate, less than 2% of patients will experience a CR to initial 
EGFR TKI therapy and on average patients will progress within the first year of treatment [4, 27, 
28]. The EGFR T790M “gatekeeper” mutation is the most common mechanism of acquired 
resistance to EGFR TKIs. The third generation EGFR TKI osimertinib is Food and Drug 
Administration (FDA)-approved for T790M-mutated NSCLC progressive after prior EGFR TKI 
therapy, with a 71% overall response rate (ORR) in a phase three study. However, as with 
treatment with earlier generation TKIs, the CR rate was low at only 1% and responses were not 
durable, with a median progression-free survival of 10.1 months [20].
While mechanisms of acquired resistance to osimertinib are being explored [21, 22], the 
molecular basis of incomplete response and residual disease that occurs after initial 3rd 
generation EGFR TKI therapy is poorly understood.
1.1.1 Treatment of early stage Non-Small Cell Lung Cancer
In patients with resectable stage I and II NSCLC, the standard of care is surgical resection, 
followed by consideration for adjuvant chemotherapy depending on pathologic staging. Adjuvant 
chemotherapy (with a platinum doublet) is recommended in patients with T3 or node positive 
disease, and should be considered in patients with T2 node negative disease in which there are 
other high risk features (such as poor differentiation, vascular invasion, size >4 cm, visceral 
pleural involvement, and wedge resection or unknown lymph node pathologic status). 
Concurrent or sequential chemoradiation should be considered in patients with positive margins 
after resection.
In patients with resectable stage IIIA disease, standard of care is to proceed with surgical 
resection followed by adjuvant chemotherapy, with radiation therapy if with positive margins or if 
found to have N2 nodal involvement upon pathologic staging. Patients with N2 positive stage 
IIIA disease are generally not felt to have upfront resectable disease and will instead undergo a 
course of neoadjuvant therapy (chemotherapy with or without radiation therapy) prior to 
reconsideration for surgical resection or upfront definitive chemoradiation therapy (National 
Comprehensive Cancer Network Guidelines – Non-Small Cell Lung Cancer, Version 7, 2017).
1.1.2 Use of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Early 
Stage, EGFR-mutant Non-Small Cell Lung Cancers
Induction therapy with platinum-based chemotherapy given prior to surgical resection for 
patients with resectable lymph node-positive NSCLC is a safe and acceptable practice [29], as 
discussed above. The role of EGFR TKI therapy as induction therapy for patients with EGFR-
mutant NSCLC remains incompletely explored. In an unselected study of 50 patients with stage 
I or II NSCLC treated with gefitinib, 17 of 21 patients found to have activating EGFR mutations 
in their resected tumor specimens had a radiographic response to treatment [30]. In a separate 
study of an enriched population of 60 patients non-squamous patients with early stage lung 
cancer treated with erlotinib for 21 days prior to surgery, patients with EGFR-activating 

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mutations (n=7), 40% (3 of 7) had a pathological response with >50% tumor necrosis at the time 
of resection. In contrast, only 20% (8 of 35 patients) with WT EGFR exhibited >50% necrosis in 
their tumors at the time of resection [25]. While these results suggest that neoadjuvant therapy 
may be beneficial to patients with EGFR-activating mutations prior to surgery, a prospective trial 
in pre-selected EGFR-mutant lung cancer patients has not been performed.
It has been reported that up to 60% of patients harbor pre-existing EGFR T790M resistance 
mutations within their lung cancers prior to initiating EGFR TKI, which correlates with worse 
clinical outcomes for patients treated with erlotinib therapy [31]. The contribution of pre-existing 
EGFR T790M expressing cells to incomplete initial response to therapy is unknown.
1.2 Background on the Compounds
1.2.1 Osimertinib
Investigators should be familiar with the current osimertinib Investigator’s Brochure.
Osimertinib (AZD9291, AstraZeneca) is an oral, potent, irreversible EGFR TKI selective for 
EGFR-activating mutations and the T790M resistance mutation with a significant selectivity 
margin against wild-type EGFR. As a result, osimertinib can effectively block EGFR signaling 
both in EGFR single mutant cells with activating EGFR mutations and in double mutant cells 
bearing the resistance T790M mutation. Osimertinib is currently FDA-approved for treatment of 
EGFR T790M mutated NSCLC after progression on prior EGFR TKI therapy.
In the phase 1 dose escalation study of osimertinib (AURA), no dose-limiting toxicities were 
reported in any of the dose escalation cohorts (20, 40, 80, 160, and 240mg) and a non-tolerated 
dose has not been defined. Based on the totality of the safety, pharmacokinetic (PK) and 
preliminary efficacy data, 80 mg once daily was selected as the recommended phase II dose.
Osimertinib has been studied in NSCLC patients with EGFR T790M positive tumors following 
progression on prior EGFR TKI therapy in the AURA studies, including the AURA phase 1 
extension component and the AURA2 phase 2 study. Of 398 patients in these pooled studies, 
the ORR was 66.1% (95% CI: 61.2, 70.7). This included 0.5% patients with a CR and 65.6% 
with a partial response (PR). The estimated progression-free survival was 9.7 months (95% CI: 
8.3, NC) [32]. Osimertinib is also efficacious for first-line treatment of patients with EGFR-
mutated NSCLC, with a 77% ORR and median PFS that was not yet reached after a median of 
16.6 months of follow up in phase 1 extension cohorts. [33]
Osimertinib has also been studied in the first line setting for patients with metastatic EGFR 
mutations (exon 19 deletion, or L858R) in comparison to erlotinib or gefitinib (FLAURA study) 
[34]. The median progression-free survival was significantly longer with osimertinib than with 
standard EGFR TKIs (18.9 months vs. 10.2 months; hazard ratio for PD or death, 0.46; 95% CI 
[0.37 to 0.57]; P<0.001). The objective response rate was similar in the two groups: 80% with 
osimertinib and 76% with standard EGFR TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). 
The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib 
versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR TKIs. Data on OS were immature at 
the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) 
with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR TKIs (hazard ratio for death, 
0.63; 95% CI [0.45 to 0.88], P=0.007 [nonsignificant in the interim analysis]). AEs of grade 3 or 
higher were less frequent with osimertinib than with standard EGFR TKIs (34% vs. 45%).
Osimertinib has an overall 9-fold selectivity over wild-type EGFR towards EGFR bearing 
traditional activating mutations and towards T790M-mutated EGFR. There was minimal off- 
target kinase activity, including minor activity against ACK1, BLK, ErbB2, ErbB4, BRK, MLK1, 
and MNK2. Metabolism is primarily via CYP3A4/5, with strong CYP 3A4inhibitors found to 

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increase net osimertinib exposure. Osimertinib and its major metabolites are also substrates for 
P-gp and BCRP and may increase exposure to co-administered BCRP substrates.
Oral absorption is greater than 80% with a median Tmax of 6-8 hours. Absorption was not 
affected by food intake or by gastric pH. The major route of excretion is fecal, with minor urinary 
excretion. Less than 1% of overall clearance is accounted for by renal clearance, with clearance 
not affected by mild to moderate renal dysfunction in population PK analyses. Given limited data 
in patients with several renal dysfunction, osimertinib should be used with caution in this 
population. Osimertinib showed similar steady state clearance in patients with normal hepatic 
function and mild hepatic dysfunction; however, appropriate dosing has not been established in 
moderate and severe hepatic dysfunction.
Common adverse effects include rash (45.7%), low-grade diarrhea (45.5%), dry skin (25.5%), 
and paronychia (21.7%). AEs of Grade 3 or higher were reported in 36.3% of patients in phase 
II studies and serious AEs (SAEs) were reported in 26.0% of patients. There was a very low rate 
of AEs leading to dose reduction (3.9%) and high mean dose intensity (97.7%) consistent with 
good overall tolerability. Potential AEs of note include risk of interstitial lung disease 
(ILD)/pneumonitis, which occurs in 3.3% of treated patients. QTc prolongation is seen, with a 
predicted increase of 14.2 ms. An association between osimertinib and CHF/reduction in LVEF 
has been reported.
In this study, patients will be treated at the FDA-approved dose of osimertinib 80 mg PO daily.
Please see the osimertinib investigator’s brochure and package insert for full details.
1.3 Rationale for the Proposed Study
Despite high initial response rates to EGFR TKIs, patients with EGFR-mutant NSCLC treated 
with these agents will ultimately develop PD, on average in less than one year. Much of the 
research into EGFR TKI resistance has focused on mechanisms of acquired resistance present 
at the time of PD. For patients who received first and second generation EGFR TKIs, the most 
common of these mechanisms is the T790M gatekeeper mutation, occurring in 50-60% of 
patients who progress on these agents, with less commonly occurring mechanisms including 
amplification of alternative signaling pathways such as MET and HER2 [35]. The third 
generation EGFR TKI osimertinib has activity against T790M mutant NSCLC and is FDA 
approved in this setting; however, resistance will ultimately develop leading to progression of 
disease. Specific EGFR mutations, such as the EGFR C797S mutation [21, 22] have been 
identified as contributing to acquired resistance to osimertinib. 
Less is known about the phenomenon of persistent disease, which is the most common 
outcome in patients treated with all generations of EGFR TKIs, with CR rates less than 2% with 
these agents. The persistence of disease in the face of EGFR TKI therapy may contribute to 
selection for resistant subclones and ultimately to PD.

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1.3.1 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) tumor cell 
survival is induced by epidermal growth factor receptor tyrosine kinase inhibitor 
treatment
Prior work has uncovered a cancer cell population 
termed ‘drug tolerant persisters’ that withstood initial 
treatment via an IGF1R-mediated epigenetic 
program that could be pharmacologically reversed 
with chromatin-directed or IGF1R targeted therapy 
[36]. Subsequent clinical trials did not show a 
significant effect of either chromatin-directed or 
IGF1R targeted therapy on response to concurrent 
EGFR kinase inhibitor treatment in lung cancer 
patients [37, 38]. Although this hypothesis remains 
promising, additional studies are required. Other 
work exploring initial response to targeted therapy in 
cancer cells showed that EGFR inhibition provokes 
STAT3 survival signaling [39]. We further 
investigated signaling events that occur in response 
to EGFR oncogene inhibition in lung 
adenocarcinoma cells to enable their adaptation and 
survival during initial therapy. We found that NF-kB 
signaling is rapidly engaged upon initial EGFR 
inhibitor treatment to promote tumor cell survival and 
residual disease. EGFR oncogene inhibition induced 
an EGFR-TRAF2-RIP1-IKK complex that stimulated 
an NF-kB-mediated transcriptional survival program 
(Fig. 1) [1]. Validation of these findings in patients 
could unveil NF-kB activation as a critical adaptive 
survival mechanism engaged by EGFR oncogene 
inhibition and provide rationale for EGFR and NF- kB co-inhibition to eliminate residual disease 
and enhance patient responses. Beyond adaptive NF-kB activation, pre-treatment tumor 
heterogeneity may in part explain incomplete responses to osimertinib. Sequist et al. found that 
the allele frequency of the EGFR T790M mutation correlated with increased response to an 
alternative third-generation EGFR TKI rociletinib [22]. This suggests that co-occurring events 
that bypass EGFR oncogene dependence could be driving incomplete response to therapy.
1.3.2 Tumor-associated macrophages (TAMs) 
Tumor-associated macrophages (TAMs) promote NF-kB signaling in non-small cell lung cancer 
cells, the upregulation of which promotes survival of epidermal growth factor receptor-mutant 
non-small cell lung cancer in response to treatment with epidermal growth factor receptor 
tyrosine kinase inhibitors
NF-kB is a transcription factor that regulates numerous biological processes, including cell 
proliferation and apoptosis, as well as a critical mediator of both innate and adaptive immune 
cell activity [40].

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Crosstalk between tumor cells and TAMs within the tumor microenvironment may contribute 
both to NSCLC development and to tumor cell survival in response to treatment with EGFR 
TKIs. These myeloid-derived cells serve diverse functions in host defense and tissue repair. 
TAMs subsequently influence diverse elements of tumor progression, including angiogenesis, 
modulation of local immune response, and promotion of metastasis. In order to carry out these 
roles, TAMs exist within the microenvironment in multiple functional states, broadly 
characterized as either M1 or M2 polarization states. M1 polarized macrophages serve a pro-
inflammatory role including promotion of T cell cytotoxicity and secretion of pro-inflammatory 
cytokines, and ultimately serve an antitumor role. Conversely, M2 polarized macrophages have 
reduced antigen presenting capabilities, restrain the cytotoxic T cell response, and thereby 
produce a microenvironment which is more permissive of tumor progression. Co-culture of 
macrophages or macrophage-conditioned media with EGFR-mutant lung adenocarcinoma cell 
lines makes tumor cells relatively resistant to osimertinib treatment (Figs 2 and 3). Shifts in 
programmed cell death protein 1 (PD-1) and PD-L1 expression have also been linked to NF-kB 
activity [41]. We hypothesize that osimertinib treatment will induce a pro-tumor immune 
microenvironment that allows for tumor cell persistence through inducing TAM infiltration, or 
through effects on adaptive immune cells, including CD4+ TREGs, or through altering PD-1 and 
PD-L1 expression.

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1.3.3 Concurrent tumor genomic alterations 
influence osimertinib response
These data suggest a potential role for genetic 
epistasis in controlling tumor progression and 
EGFR inhibitor response in EGFR-mutant 
NSCLC patients. If this hypothesis is true, then 
the presence of specific co-occurring genetic 
alterations would be enriched in non-responder 
versus responder patients. We found that primary 
resistance of EGFRT790M-positive NSCLCs to 
initial osimertinib treatment was associated with 
the presence of alterations in cell cycle genes 
such as CDK4/6 (5/13, 38% vs. 0/14, 0%, p = 
0.02), and a trend towards alterations in MET 
(3/13, 23% vs. 0/14, 0%, p = 0.09) and TP53 
(8/13, 69% vs. 5/14, 36%, p=0.12) prior to 
treatment (Fig. 2A,B) [42]. While mechanisms of 
acquired osimertinib resistance have been 
reported [21, 43, 44], these data uncover 
potential clinically-relevant mechanisms that may 
limit the initial response to osimertinib treatment 
(i.e. promote primary resistance). The findings 
suggest that multiple co- alterations in specific 
signaling pathways that promote biological 
processes critical for cancer growth may help limit 
EGFR inhibitor response, even in cancers with 
EGFRT790M. This finding of polygenic driver 
alterations in the EGFRT790M-positive cases 
may help explain why clinical responses to 
EGFRT790M-directed therapies such as 
osimertinib occur in only 60-70% of 
EGFRT790M-positive NSCLC patients and are 
almost always incomplete [19, 45]. Altogether, 
the data argue that EGFR-mutant NSCLC clinical 
outcomes are impacted by the widespread 
presence of combinations of functional genetic 
alterations that are present and undergo selection 
before and during EGFR inhibitor treatment and tumor progression.
1.3.4 Rationale for osimertinib neoadjuvant clinical trial
Access to patient tissue during the initial acute period of EGFR TKI treatment will be critical to 
defining the molecular and cellular mechanisms that underlie incomplete responses to EGFR 
TKI therapy. The availability of such tissue is incredibly limited, as EGFR TKI treatment is not 
standardly given prior to surgical resection of early stage NSCLCs.
Induction therapy with platinum-based chemotherapy given prior to surgical resection for 
patients with resectable lymph node-positive NSCLC is a safe and acceptable practice [29]. The 
role of EGFR TKI therapy as induction therapy for patients with EGFR-mutant NSCLC remains 
incompletely explored. In an unselected study of 50 patients with stage I or II NSCLC treated 
with gefitinib, 17 of 21 patients found to have activating EGFR mutations in their resected tumor 
specimens had a radiographic response to treatment [30]. In a separate study of an enriched 

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population of 60  non-squamous patients with early stage lung cancer treated with erlotinib for 
21 days prior to surgery, patients with EGFR-activating mutations (n=7), 40% (3 of 7) had a 
pathological response with >50% tumor necrosis at the time of resection. In contrast, only 23% 
(8 of 35 patients) with WT EGFR exhibited >50% necrosis in their tumors at the time of 
resection [25]. While these results suggest that neoadjuvant therapy may be beneficial to 
patients with EGFR-activating mutations prior to surgery, a prospective trial in pre-selected 
EGFR-mutant lung cancer patients has not been performed.
We hypothesize that neoadjuvant treatment with osimertinib, an EGFR TKI that targets T790M 
in addition to common activating mutations in EGFR, will improve patient responses to induction 
therapy. Furthermore, the neoadjuvant design of this trial will allow us to perform 
comprehensive molecular analyses on tumor specimens pre-treatment and after initial response 
to osimertinib. We anticipate that this information will allow us to define mechanisms of 
incomplete initial response to osimertinib and facilitate development of rational companion 
therapies that when combined with osimertinib in the first line setting could result in more 
complete and durable responses for patients.
1.4 Correlative Studies
Biopsies for tissue sampling will be obtained as 
described in detail in study procedures and as 
summarized here. A fresh tissue biopsy will be 
required prior to enrollment, permitting a baseline 
analysis.
Peripheral blood samples will be drawn for 
correlative studies at enrollment, serially during 
therapy, and following surgical resection. This 
tissue and blood collection will allow for serial 
assessment of correlative studies, in order to 
better understand mechanisms of disease 
persistence and resistance during treatment with 
EGFR TKI therapy.
Tissue and peripheral blood sample analysis will 
be carried out in collaboration with the Bivona 
Lab (UCSF) and the Chan Zuckerberg Biohub. 
Organoid generation will be carried out through 
collaboration with the Kuo Lab (Stanford 
University). Patient-derived xenografts (PDXs) generation will be carried out at the UCSF Tissue 
Core. Circulating tumor DNA (ctDNA) analysis will be performed in collaboration with Guardant 
Health or the Chan Zuckerberg Biohub.
1.4.1 Exome and transcriptome sequencing
We will perform RNA sequencing and whole exome sequencing analysis on isolated cancer cell 
populations (Fig. 5) from pre- treatment tumor biopsy specimens, as well as tumor tissue 
acquired at the time of surgical resection (post- osimertinib). Gene Set Enrichment Analysis will 
be performed to identify osimertinib-induced changes in common cancer related pathways, 
including: RAS-RAF- MAPK, PI3K-AKT, WNT- β -catenin, JAK-STAT, HGF-MET, and IGF-1R, 
as well as emerging pathways of resistance (i.e. NF-kB and Hippo- YAP) [1, 46, 47]. We will 
determine whether there is a statistically significant increase in oncogenic/survival pathway 
related gene expression signatures in the post-osimertinib compared to the pre-treatment 
sample using established methods [48]. We will compare MPR rates in tumors that exhibit 

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specific oncogenic/survival pathway activation post-osimertinib treatment compared to tumors 
that do not. Immunohistochemistry (IHC) analysis will be performed on pre-treatment and post-
surgical specimens to confirm pathway activation identified by transcriptional analysis (i.e. 
phosphorylated-ERK (indicative of MAPK signaling), phosphorylated-AKT (indicative of PI3K 
signaling) or nuclear NF-kB (RELA), or beta-catenin expression).
1.4.2 Immune profiling
We will assess for shifts in the cellular make-up of the tumor microenvironment induced by 
osimertinib treatment by performing single cell dissociation and fluorescence associated cell 
sorting (FACS) on fresh pre-treatment tumor biopsies and post-osimertinib tumor resection 
specimens. Using FACS gating strategies established and validated by the Krummel lab at 
UCSF [49], we will isolate CD45+ immune cells and determine how osimertinib treatment alters 
the proportions of cells that make up the lymphoid (CD4+ and CD8+ T cells, Tregs, NK cells, B 
cells) and myeloid (macrophages, neutrophils, mast cells, dendritic cells) compartments. We will 
then use RNA-Seq to assess the transcriptional profiles of populations of TAMs, CD4+ and 
CD8+ T Cells (Fig. 5). We hypothesize that osimertinib treatment will induce a pro-tumor 
immune microenvironment that allows for tumor cell persistence. Specifically, we will assess the 
polarization of TAMs by assessing the mRNA expression profiles of genes classically 
associated with TH1-skewed (i.e. TNF-α, IL-6, IL-12p40, and IL-1β, and Nos2) and TH2-skewed 
polarization (i.e. ARG1, TGFB, CD163, CD206), many of which are targets of NF-kB 
transcriptional activation[50]. We will also investigate whether osimertinib affects T-cell 
phenotypes. CD4+ T cells will be assessed for the expression of genes indicative of TREG, 
TH1, TH2, or TH17 activity (i.e. GATA3, T-bet, FOXP3, IFNgamma, IL-4, IL-13, IL-10, and IL-
17a)[50], and CD8+ T cells will be assessed for expression of cytotoxic effector molecules 
(IFNgamma, GRZA, GRZB, and PRF1)[50]. Finally, tumor cells and infiltrating immune cells will 
be assessed for shifts in PD-1 and PD-L1 expression (by RNA-Seq and IHC), a phenomenon 
that has been linked to NF-kB activity[41], and which may indicate changes in anti-tumor 
immunity induced by osimertinib. When possible, we will perform single cell RNA-sequencing on 
tumor biopsy and resection specimens at the Chan Zuckerberg Biohub.
1.4.3 Derivation of patient-derived xenografts and organoids
When adequate tissue is available, PDXs and organoids derived directly from patients’ resected 
tumors will be generated, as previously described (23). PDX-bearing mice will be treated with 
osimertinib or osimertinib in combination with therapies (acquired through commercial vendors) 
that target the putative resistance mechanisms identified, including tumor cell intrinsic or 
extrinsic targets. PDXs that are generated will be shared with AstraZeneca.
1.4.4 Peripheral Blood circulating tumor DNA Collection
Serial peripheral blood and plasma samples will be stored for ctDNA analysis, and changes in 
peripheral immune cells.
2 Objectives of the Study
2.1 Primary

To evaluate the efficacy of osimertinib as neoadjuvant therapy in patients with surgically 
resectable EGFR-mutant NSCLC.
2.2 Secondary

To evaluate the safety of osimertinib given as neoadjuvant therapy in early stage EGFR-
mutant NSCLC patients.

To evaluate whether neoadjuvant osimertinib treatment increases the frequency of 

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tumors that are unresectable due to AEs or PD.

To evaluate secondary measures of clinical efficacy in early stage EGFR-mutant NSCLC 
patients treated with osimertinib induction therapy.
2.3 Exploratory

To evaluate long-term measures of efficacy in patients treated with osimertinib 
neoadjuvant therapy.

To explore tissue and cell-free biomarkers that may be predictive of response or primary 
resistance to osimertinib neoadjuvant therapy.
2.4 Endpoints
2.4.1 Primary Endpoint

To determine the MPR rate, defined as ≤ 10% viable tumor present histologically in the 
resected tumor specimen as has been previously defined.
2.4.2 Secondary Endpoints

Radiographic decrease in maximum tumor diameter

DpR

5-year DFS

5-year OS

Complete pCR

Treatment-emergent AEs, laboratory abnormalities and ECG abnormalities as 
determined by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 
4.03 by investigator

Rate of conversion to inoperable status due to treatment-related toxicity or PD

Rate of surgical complications occurring prior to the end of treatment visit
2.4.3 Exploratory Endpoints

Evaluate for adverse pathologic outcomes including pathologic upstaging as compared 
to clinical staging by pre-operative scans, rate of LVI, and rate of positive margins on 
resection specimens.

Evaluate genomic and transcriptional changes on baseline and resected tumor 
specimens.

Evaluate changes in immune cell infiltration on baseline and resected tumor specimens.

Serial peripheral blood collection for exploratory biomarker assessment

Changes in ctDNA
3 Study Design
3.1 Characteristics
This is a Phase 2, single arm, open-label, multicenter study evaluating the safety and efficacy of 
osimertinib administered orally daily to patients with stage I-IIIA, EGFR-mutant NSCLC who are 
planning to undergo surgical resection of their cancer.
Patients will undergo a research biopsy for correlative studies during screening prior to starting 
osimertinib treatment. Treatment will consist of osimertinib 80 mg by mouth daily in 28 day 
cycles given as neoadjuvant therapy. Patients may receive a second cycle of osimertinib at 
investigator’s discretion. Patients will undergo serial assessments for anti-tumor efficacy and 
drug safety. The last dose of study drug will occur 3-7 days prior to planned surgical resection, 
which will occur within 14 days of the patient’s most recent disease assessment scan.

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Study Schema:
3.2 Number of Participants
27 evaluable patients will be enrolled in the study.
3.3 Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.
3.3.1 Inclusion Criteria
1.
Males and females ≥18 years of age.
2.
Histologically or cytologically confirmed NSCLC, performed on a biopsy that occurred 
within the last 90 days. This biopsy can be deferred if the procedure is deemed to 
represent an unacceptable safety risk to the patient by the Principal Investigator and as 
long as the patient has a prior biopsy showing non-small cell lung cancer.
3.
Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor 
samples by Clinical Laboratory Clinical Laboratory Improvement Amendments (CLIA)-
approved test.
4.
Patients treated with osimertinib or another EGFR TKI  (including erlotinib, afatinib, 
gefitinib, & rocelitinib) are eligible if they received no more than 28 days of treatment, 
and if there is no evidence of grade 2 or greater treatment adverse events possibly 
related to treatment with the EGFR TKI.
5.
PET-CT (computerized tomography) within the last 60 days showing radiographic stage I 
to IIIa lung cancer (mediastinal staging biopsy is allowed but not required). 
6.
Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 
60 days showing no evidence of metastatic disease.
7.
Documentation that the patient is a candidate for surgical resection of their lung cancer 
by an American Board of Thoracic Surgery certified surgeon. 

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8.
The patient must have a tumor size >1 cm in its longest diameter. 
9.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
10. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of 
starting study treatment, with the exception of alopecia and grade 2 prior platinum-
therapy–related neuropathy is allowed 
11. Adequate organ function:
Hepatic Function:

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 
× upper limit of normal (ULN).

Bilirubin ≤1.5× ULN, (Patients with documented Gilbert’s syndrome and 
conjugated bilirubin within the normal range may be allowed into the study. In 
this event, it will be documented that the patient was eligible based on 
conjugated bilirubin levels).
Electrolytes: Potassium, magnesium, and calcium within normal range, patients 
may receive supplements to meet this requirement.
Hematologic Function:

Leukocytes >3,000/mcL

Hemoglobin (Hgb) ≥9 g/dL, with no blood transfusions in the 28 days prior 
to study entry

Absolute neutrophil count >1,500/mcL

Platelets >100,000/mcL
Renal Function: CrCl > 50 mL/min for patients with SCr > 1.5 x ULN. 
12. Ability to swallow oral medications
13. Women of childbearing potential must have a negative serum pregnancy test within 3 
days prior to the first dose of study treatment and agree to use highly effective 
contraception, during the study and for 90 days following the last dose of osimertinib
Women of Childbearing Potential (WoCBP): Women between menarche and 
menopause who have not been permanently or surgically sterilized and are 
capable of procreation. 
Women NOT of Childbearing Potential: Women who are permanently or 
surgically sterilized or postmenopausal (definitions below): 
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy 
and/or bilateral salpingectomy but excludes bilateral tubal occlusion. Tubal 
occlusion is considered a highly effective method of birth control but does not 
absolutely exclude possibility of pregnancy. (The term occlusion refers to both 
occluding and ligating techniques that do not physically remove the oviducts). 

Women who have undergone tubal occlusion should be managed on 
trials as if they are WoCBP (e.g. undergo pregnancy testing etc., as 
required by the study protocol) 

Women will be considered postmenopausal if they are amenorrhoeic for 
12 months without an alternative medical cause. The following age-
specific requirements apply: 
o
Women under 50 years old will be considered postmenopausal if they 
have been amenorrhoeic for 12 months or more following cessation of 
exogenous hormonal treatments and with luteinizing hormone and 
follicle-stimulating hormone levels in the postmenopausal range 
o
Women over 50 years of age will be considered postmenopausal if 
they have been amenorrhoeic for 12 months or more following 

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cessation of all exogenous hormonal treatments 
Acceptable contraception methods are: 

Total sexual abstinence (abstinence must be for the total duration of the 
trial and the follow-up period) 

Vasectomized sexual partner plus male condom (with participant 
assurance that partner received post-vasectomy confirmation of 
azoospermia) 

Tubal occlusion plus male condom 

Intra-uterine device – provided coils are copper-banded, plus male 
condom 

Intra-uterine system (IUS) levonorgestrel IUS (e.g., Mirena), plus male 
condom 

Medroxyprogesterone injections (Depo-Provera) plus male condom 

Etonogestrel implants (e.g., Implanon, Norplant) plus male condom 

Normal and low dose combined oral contraceptive pills, plus male 
condom 

Norelgestromin/ethinylestradiol transdermal system plus male condom 

Intravaginal device (e.g., ethinylestradiol and etonogestrel) plus male 
condom 

Cerazette (desogestrel) plus male condom (Cerazette is currently the only 
highly efficacious progesterone based pill) 
Unacceptable Contraception Methods 
The following methods are considered not to be highly effective and are therefore 
not acceptable contraceptive methods:

Triphasic combined oral contraceptives 

All progesterone only pills except, Cerazette 

All barrier methods, if intended to be used alone 

Non-copper containing intra-uterine devices 

Fertility awareness methods 

Coitus interruptus 
14. Men with a female partner of childbearing potential must have either had a prior 
vasectomy agree to use effective contraception as described in the full protocol for at 
least 14 days prior to administration of the first dose of study treatment, during the study, 
and for 120 days following the last dose of osimertinib. Men also can not donate sperm 
within this time period.  
3.3.2 Exclusion Criteria
Any of the following criteria will exclude patients from study participation: 
1.
Leptomeningeal carcinomatosis or other CNS metastases. 
2.
Stage IIIB, or distant metastases (including malignant pleural effusion) identified on PET-
CT scan or biopsy (PET abnormalities that are negative for malignancy on biopsy will be 
considered on a case by case basis). 
3.
Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required 
steroid treatment, or any evidence of clinically active ILD. 
4.
Patients who are known to be serologically positive for human immunodeficiency virus 
(HIV)
5.
Active second malignancy, i.e. patient known to have potentially fatal cancer present for 
which he/she may be (but not necessarily) currently receiving treatment. Patients with a 

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history of malignancy that has been completely treated, with no evidence of that cancer 
currently, are permitted to enroll in the trial provided all chemotherapy for prior malignancy 
was completed >12 months prior and/or bone marrow transplant >2 years prior. 
6.
Patients who are currently receiving treatment with contraindicated QTc prolonging 
medications  or potent CYP3A4 inducers (at least 3 weeks prior) (Appendix 6), if that 
treatment cannot be either discontinued or switched to a different medicationprior to first 
day of study treatment. Listing of contraindicated QTc prolonging and CYP3A4 
inducing/inhibiting medications is provided in Tables 4.1, 4.2, and 4.3, with washout 
periods. All patients must try to avoid concomitant use of any medications, herbal 
supplements and/or ingestion of foods with known inducer effects.
7.
Any of the following cardiac abnormalities or history: 

Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 
electrocardiograms (ECGs), using the screening clinic ECG machine derived 
QTc value. 

Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG e.g. complete left bundle branch block, third degree heart block and 
second degree heart block. 

Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, electrolyte abnormalities (including: Serum/plasma 
potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < 
LLN) , congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age in first degree relatives or any 
concomitant medication known to prolong the QT interval.
8.
Treatment with prohibited medications (concurrent anticancer therapy including 
chemotherapy, radiation, hormonal treatment [except corticosteroids and megesterol 
acetate], or immunotherapy) ≤ 14 days prior to treatment with osimertinib.
9.
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, or known active infection including chronic active hepatitis 
B virus (HBV), hepatitis C virus, and HIV. Screening for chronic conditions is not 
required. Patients with chronic HBV with negative HBV viral load on appropriate antiviral 
therapy will be permitted, if able to continue appropriate antiviral therapy throughout 
treatment period.
10. Active tuberculosis.
11. Signs or symptoms of infection within 2 weeks prior to first day of study.
12. Therapeutic oral or IV antibiotics within 2 weeks prior to first day of study treatment:

Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) are eligible.
13. Class II to IV heart failure as defined by the New York Heart Association functional 
classification system.
14. Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF <50% must be on a stable medical regimen that is optimized in 
the opinion of the treating physician, in consultation with a cardiologist if appropriate, to 
be eligible.
15. Patients who have experienced untreated and/or uncontrolled cardiovascular conditions 
and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, 
myocardial infarction within the previous 3 months; coronary angioplasty, or stenting or 
bypass grafting within the past 6 months; cardiac ventricular arrhythmias requiring 
medication; any history of 2nd or 3rd degree atrioventricular conduction defects);

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16. Females who are pregnant or breastfeeding;
17. Presence of active gastrointestinal (GI) disease (including GI bleeding or ulceration) or 
other condition that could affect GI absorption (e.g., malabsorption syndrome, history of 
biliary tract disease), including refractory nausea or vomiting, or chronic GI disease 
which may affect absorption or tolerance to oral medications.
18. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a 
similar chemical structure or class to osimertinib.
19. Involvement in the planning and/or conduct of the study (applies to both Investigator staff 
and/or staff at the study site).
20. Participation in another clinical study with an investigational product (IP) during the last 3 
months or within five half-lives of the compound, whichever is longer.
21. Uncontrolled medical, psychological, familial, sociological, or geographical conditions 
that interfere with the patient’s safety, ability to provide informed consent, or ability to 
comply with the protocol. 
3.4 Duration of Therapy
Patients may receive up to 2 cycles of therapy prior to surgery. Surgery must occur within 14 
days of final scans. Patients will continue the study drug following final scans and then 
discontinue the study drug between 3 and 7 days prior to surgery, and thus may ultimately 
receive up to two weeks additional therapy with study drug beyond end of cycle 1 (or cycle 2) 
while awaiting surgery. No treatment with the study drug will be given after surgery.
Criteria for treatment with Cycle #2: 

No Grade 3 or higher AEs with Cycle #1 

No evidence of PD by RECIST 1.1 criteria at end of Cycle #1 scan. 

Additional reduction in tumor size deemed to be potentially beneficial by thoracic surgeon 
planning to perform resection. 
Treatment may be stopped for any of the following reasons:

The patient or legally authorized representative withdraws consent.

Any AE that in the opinion of the investigator would pose an unacceptable safety risk to 
the patient.

Closure of the study.
3.5 Duration of Follow Up
Patients will be followed for safety assessments 30 days following the Day 15 post-operative 
visit, or removal from study, or until death, whichever occurs first. Patients removed from study 
for unacceptable treatment-related AE(s) will be followed until resolution or stabilization of all 
treatment related AEs to Grade 2 or lower. Patients whose disease is not resectable at the time 
of scheduled surgery will be managed per standard of care for patients with unresectable 
EGFR-mutant NSCLC. All patients will be followed for disease relapse and OS for up to 5 years.
3.6 Randomization Procedures
There is no randomization in this study.
3.7 Study Timeline
3.7.1 Primary Completion
Accrual in this study is expected to require 36 months. Data collection will be complete 60 
months after enrollment of the last patient.

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3.7.2 Study Completion
In total, this study is expected to reach completion approximately 96 months from the time 
accrual opens.
4 Study Drugs
4.1 Description, Supply and Storage of Investigational Drugs
4.1.1 Osimertinib
Osimertinib is provided as beige, film-coated tablets, containing either 40 or 80 mg osimertinib 
expressed as a free base. Osimertinib tablets are packed in high-density polyethylene bottles 
with desiccant, sealed with a child-resistant closure and induction-sealed membranes.
Osimertinib tablets contain osimertinib mesylate, mannitol, microcrystalline cellulose, low- 
substituted hydroxypropyl cellulose and sodium stearyl fumarate. The tablet film-coat contains 
polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, yellow iron oxide, red iron 
oxide and black iron oxide.
Classification
Osimertinib is a small molecule EGFR TKI, FDA-approved for patients with metastatic EGFR-
mutated NSCLC with a T790M mutation, who have progressed on prior EFR TKI therapy.
Mechanism of Action
Irreversible EGFR TKI for specific mutated forms of EGFR, including T790M, L858R, and exon 
19 deletion. Biochemical studies showed osimertinib to be a potent and selective inhibitor of 
mutant EGFRs binding at approximately 9-fold lower concentrations as compared to wild-type 
EGFR (IC50 of 12 nM for mutant EGFR and 185 nM for wild-type). In a screen against 265 
other protein kinase, osimertinib had significant activity, as defined by >60% inhibition at 1nM, 
against only 18 other kinases, including ACK1, BLK, ErbB2, ErbB4, BRK, MLK1, and MNK2. In 
cellular assays, osimertinib potently inhibited both EGFR-mutant cell lines and cell lines bearing 
an additional T790M mutation (IC50 6 nM to 54nM), with weaker inhibition of wild-type EGFR 
cell lines (IC50 480 nM to 1.8 μ). This correlated with reduced cell proliferation upon osimertinib 
exposure and to tumor regression in EGFR-mutant mice bearing xenograft tumors both with and 
without the T790M mutation. Tumor regression was accompanied by pharmacodynamic 
inhibition of pEGFR and downstream biomarkers pAKT and pERK.
Metabolism
PKs were linear over a 20 to 240 mg dose range and steady state is reached at approximately 
15 days treatment. Osimertinib showed a high volume of distribution and is predicted to bind 
plasma proteins. The mean half-life of osimertinib was 48 hours. In animal studies, tissue 
distribution was widespread, with highest concentrations at the uvea and retinal pigment 
epithelium, renal cortex, pituitary, spleen, bile ducts, lung, and Hadarian gland.
Metabolism is primarily via the CYP3A4/5. Two pharmacologically active metabolites (AZ7550 
and AZ5104) are generated with similar kinase selectivity and accounted for less than 10% of 
exposure compared to osimertinib. Renal clearance accounts for less than 1% of overall 
clearance. Excretion is primarily fecal (68%), with minor urinary excretion (14%). PKs have been 
studied in patients with moderate renal impairment (CrCl 30-59 mL/min) and with mild hepatic 
impairment (AST greater than ULN with normal bilirubin, or total bilirubin 1-1.5xULN with any 
AST). PKs in patients with more severe renal or hepatic impairment are unknown.

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Contraindications
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 electronic case report form (eCRF).
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 website: https://www.crediblemeds.org/.  The website 
categorizes drugs based on the risk of inducing Torsades de Pointes (TdP).  
During screening the drugs that patients are currently prescribed should be checked oppsite the 
ArizonaCert website.
Drugs with a known risk of Torsades de Pointes 
The following drugs prolong the QT interval and are clearly associated with a known risk of TdP, 
even when taken as recommended.  These drugs must have been discontinued prior to the start 
of administration of study treatment in accordance with guidance provided in Table 3 and should 
not be co-administered with study treatment (osimertinib) and for a period of two weeks after 
discontinuing study treatment.  The list of drugs may not be exhaustive and is subject to 
change as new information becomes available.  As such, investigators are recommended 
to search the website to provide the most up to date information.  
Table 4.1 Drugs prolonging the QT interval
Contraindicated drug
Withdrawal period prior 
to osimertinib start
Clarithromycin, droperidol, erythromycin, procainamide, 
aclarubicin, anagrelide, ciprofloxacin, cocaine, 
levofloxacin, ondansetron, papaverine hydrochloride, 
sulpiride, sultropride, terfenadine terlipressin
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
Arsenic trioxide
6 weeks*
Pentamidine 
8 weeks
Amiodarone, chloroquine
1 year
*Estimated value as PKs of arsenic trioxide has not been studied
Metabolism of osimertinib is primarily carried out by CYP3A4/5. A drug-drug interaction study of 
osimertinib evaluated in patients showed that there is potential for osimertinib being a victim 
when co-administered with strong inducers of CYP3A4 (osimertinib concentrations are 
decreased when co-dosed with rifampicin)

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The following potent inducers of CYP3A4 must not be used during this study for any patient 
receiving osimertinib.
Table 4.2 Drugs inducing CYP3A4
Contraindicated drugs
Withdrawal period prior 
to osimertinib start
Carbamazepine, phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine
3 weeks 
St John’s Wort
Phenobarbitone 
5 weeks 
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.
Osimertinib and its metabolites are substrates for P-gp and BCRP. Osimertinib may increase 
the concentration of sensitive BCRP and Pgp substrates (concentration of the sensitive BCRP 
substrate, rosuvastatin and sensitive Pgp substrate, fexofenadine, are increased).
Table 4.3 Exposure may be increased by osimertinib treatment
Warning of possible interaction
Advice
Rosuvastatin
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan
Dabigatran
Aliskiren
Digoxin
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.
With the exception of contraindicated drugs listed above, therapies considered necessary for 
the patient’s well-being may be given at the discretion of the investigator and should be 
documented on the eCRF. Other concomitant medications, except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life-threatening medical 
problems, should be avoided.
Herbal and complementary therapies are not permitted as potential drug-drug interaction cannot 
be definitively excluded.
No other anti-cancer therapies (including chemotherapy, radiation, hormonal treatment [except 
corticosteroids and megestrol acetate], antibody or other immunotherapy or other experimental 
drugs) of any kind are permitted.
Availability
Osimertinib is absorbed orally, with a median time to maximum concentration (Cmax) of 6 hours 
(range 3-24 hours). Oral bioavailability was similar in the fasting state and following a high-fat 
meal. Absorption is not affected by gastric pH.
Storage and handling
All study drugs should be kept in a secure place under appropriate storage conditions. The IP 
label on the bottle and the Investigator Brochure specifies the appropriate storage
Osimertinib should be stored in its original packaging at 25°C (77°F); excursions to 15-30°C are 
permitted.

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Side Effects
Table 4.4 Adverse Reactions as Reported in the AURA Studies (Phase II and Phase III) 
[51]
Category 
Adverse 
Event 
CIOMS Descriptor 
(Overall Frequency) 
Frequency of CTCAE 
Grade 3 or Higher
Pulmonary 
ILD
Common (3.2%)
1.3%
Gastrointestinal
Diarrhea
Very common (44%)
1%
Stomatitis
Very common (15%)
0%
Ocular
Keratitis
Uncommon (0.9%)
0%
Dermatologic
Rash
Very common (41%)
0.7%
Dry skin 
Very common (29%) 
0%
Paronychia 
Very common (27%) 
0%
Pruritus 
Very common (15%) 
0%
Cardiac 
QTc interval 
prolongation 
Uncommon (0.7%) 
0.7% 
Hematologic 
Platelet count 
decreased 
Very common (54%) 
2.1% 
Leucocytes 
decreased 
Very common (66%) 
2.4% 
Neutrophils 
decreased 
Very common (32%) 
4.3% 
Complete and updated AE information is available in the Investigational Drug Brochure and 
product package insert.
4.2 Drug Accountability
The Investigational Pharmacist will manage drug accountability records.
4.3 Drug Ordering
UCSF will obtain osimertinib directly from AstraZeneca as study supply.
4.4 Packaging and Labeling of Study Drugs
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws. 
5 Treatment Plan
5.1 Dosage and Administration
Treatment will be administered on an outpatient basis. 

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Table 5.1 Regimen Description
Study Drug
Premedication; 
precautions
Dose 
(mg/day)
Route
Schedule
Cycle 
Length
Osimertinib1
Can be taken with or 
without food 
80 mg
Oral
Daily
4 weeks (28 
days)
Osimertinib is administered as an 80 mg tablet orally once daily. Osimertinib can be taken 
without regard to food. Osimertinib 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. Each dose 
should be taken with 8 oz (240 mL) of water.
The patients will be requested to maintain a medication diary for each dose of medication. The 
medication will be returned to clinic staff at the end of each cycle. Any change in dosing 
schedule, dose interruptions, or dose reductions should be recorded.
5.1.1 Other Modalities or Procedures
Surgery/Anesthesia: Surgical resection of the patients lung cancer will be carried out in 
accordance with the institutions standard practice and surgical guidelines. The last dose of 
study drug prior to surgery will be taken by the study participant between 3 and 7 days prior to 
surgery. The attending anesthesiologist for the case will be notified and informed of the QTc 
prolonging potential of the study drug. Drugs that are known to cause or possibly cause QTc 
prolongation (See crediblemeds.org) should be avoided. Anesthesiologists should be made 
aware that this list includes Sevoflurane and Propofol, which should be avoided as anesthetics if 
possible.
5.2 Dose Modifications and Dosing Delays
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity including a 
DLT, not attributable to the disease or disease-related processes under investigation, dosing will 
be interrupted and supportive therapy administered as required in accordance with local 
practice/guidelines.  
If a toxicity resolves or reverts to ≤CTCAE grade 2 within 3 weeks of onset, treatment with 
osimertinib may be restarted at the same dose (80 mg) or a lower dose (40 mg) using the rules 
below for dose modifications (Table 5.2) and with discussion and agreement with Principal 
Investigator (PI). There will be no individual modifications to dosing schedule in response to 
toxicity, only potential dose reduction or dose interruption. 
On resolution of toxicity within 3 weeks:  If an AE subsequently requires dose interruption, 
osimertinib may restart at the same dose or the reduced dose, on resolution/improvement of the 
AE at the discretion of the Investigator.
Table 5.2 Dose Modifications and Dosing Delays
Dose Level
Osimertinib (PO daily)
Each Cycle 28 Days
0
80 mg
-1
40 mg
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation.

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The following dose modification rules will be used with respect to potential toxicity. Toxicity will 
be assessed according to the NCI CTCAE Version 4.03.
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity including a 
DLT, not attributable to the disease or disease-related processes under investigation, dosing will 
be interrupted and supportive therapy administered as required in accordance with local 
practice/guidelines. 
If toxicities do not resolve to less than or equal to Grade 2 after 2 weeks despite supportive 
care, then the participant should be withdrawn from the study.
Table 5.3 Dose Modifications and Dosing Delays Tables for General Adverse Events
Grade of Event
Management/Next Dose for Osimertinib 
≤ Grade 1
No change in dose 
Grade 2
Hold until ≤Grade 1 if clinically significant, otherwise no change in 
dose
Resume at same dose level 
Grade 3
Hold* until <Grade 2 
Resume at one dose level lower, if indicated**
Grade 4
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy
**Patients who do not tolerate 40 mg PO daily dose will be taken off protocol therapy
***Alopecia/hair color changes are excluded from requirement for dose delays or modifications
Dose Modifications and Dosing Delays Tables for Specific Adverse Events
Table 5.4 Adverse Event: Diarrhea
Grade of Event
Management/Next Dose for Osimertinib
≤ Grade 1
No change in dose
Grade 2
Hold until <Grade 1 if clinically significant, otherwise no change in 
dose
Resume at same dose level
Grade 3
Hold* until <Grade 2
Resume at one dose level lower**
Grade 4
Off protocol therapy
Recommended management: Loperamide antidiarrheal therapy, see section 5.3.1
*Patients requiring a delay of >2 weeks should go off protocol therapy
**Patients who do not tolerate 40 mg PO daily dose will be taken off protocol therapy

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Table 5.6 Adverse Event: Dermatologic
Grade of Event
Management/Next Dose
≤ Grade 1
No change in dose 
Grade 2
No change in dose 
Grade 3
Hold* until <Grade 2 
Resume at one dose level lower 
Grade 4
Hold* until <Grade 2 
Resume at one dose level lower 
Please see Section 5.3.1 for recommendations regarding supportive care to be undertaken in patients 
experiencing dermatologic AEs on study 
*Patients requiring a delay of >2 weeks should go off protocol therapy
**Patients who do not tolerate dose level -1 dosing should go off protocol therapy
5.3 Monitoring and Toxicity Management
Each patient receiving osimertinib will be evaluable for safety. The safety parameters include all 
laboratory tests and hematological abnormalities, physical findings, ECG findings, 
echocardiography findings, and spontaneous reports of AEs reported to the investigator by 
patients.
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI 
CTCAE v4.03. Dose adjustments will be made according to the system showing the greatest 
degree of toxicity.
We will monitor for potential adverse effects including but not limited to fatigue, nausea, 
vomiting, dehydration, cytopenias, and signs and symptoms of infection. In addition we will 
monitor specifically for the following AEs of special interest (Please see the corresponding 
subsections in Section 6.2 for acute toxicity management and dose modifications).

Rash/Dry Skin

Diarrhea 

Ejection Fraction Changes 

Prolonged QTc 

Pneumonitis/ILD 

Liver Chemistry Elevations 

Hyperglycemia 
Management of any grade 3 or higher toxicity should be discussed with the PI of the study.
5.3.1 Other toxicities
Toxicity will be managed according to local guidelines.
Rash and Dry Skin
Rash, acneiform rash, and dry skin are common AEs experienced on osimertinib therapy. The 
following guidelines are provided to facilitate supportive care in patients experiencing these 
findings. These skin adverse effects may occur at any time but are most likely to start within two 
weeks of starting treatment. 

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We recommend application of over-the-counter moisturizing cream to face, hands, and feet 
twice daily from the start of treatment with osimertinib. 
For Grade 1 or 2 rash and acne we recommend initiation of emollient cream and/or a topical 
moderate strength steroid BID and/or a topical antibiotic BID. For grade 2 rash/acne, a six-
week course of oral antibiotics can be considered. For grade 3 or greater rash/acne, we 
recommend a topical moderate strength antibiotic BID in combination with a 6-week course of 
oral antibiotic. 
For grade 1 or 2 dry skin consider over the counter moisturizing cream or ointment BID to 
face/hands/feet with ammonium lactate 12% cream or salicylic acid 6% cream BID to the body. 
For grade 3 or greater dry skin add a topical moderate strength steroid to eczematous areas 
of the body. 
For patients experiencing grade 1 pruritus consider a topical moderate strength steroid or 
topical antipruritic BID to localized areas. For patients with grade 2 pruritus consider an oral 
antihistamine. For grade 3 or greater pruritus, consider addition of a GABA agonist (such as 
gabapentin).
Diarrhea
Initiate dietetic measures including discontinuing lactose-containing products, frequent small 
meals, increased fluid intake with 8 to 10 glasses of clear liquids per day, and a low fat regimen 
enriched with rice, bananas, and applesauce. 
For grade 1 or 2 diarrhea, initiate pharmacologic treatment with loperamide as per the 
following dosage schedule: Loperamide 4 mg at first onset, followed by 2 mg with each loose 
motion until diarrhea-free for 12 hours (maximum dosage 16 mg/24 hours). Grade 1 intermittent 
diarrhea may not require treatment. Adjunct anti-diarrheal therapy is permitted and should be 
recorded when used. Use electrolyte replacement as appropriate. In patients with ≥ grade 3 
diarrhea, consider IV fluids and more frequent electrolyte monitoring as indicated, with 
consideration for prophylactic antibiotics if diarrhea is persistent beyond 24 hours, there is fever, 
or ≥ grade 3 neutropenia.
Left Ventricle Ejection Fraction Changes 
Osimertinib and its active metabolites may inhibit HER2 and a low rate of LVEF decrease from 
baseline has been reported in patients treated with osimertinib. Patients will be evaluated for 
abnormal LVEF at baseline. Subsequently, 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, with cardiologic consultation at the 
investigator’s discretion. Patients with asymptomatic reduction in LVEF which persists for 
greater than 4 weeks, or with symptomatic congestive heart failure, should permanently 
discontinue treatment with osimertinib.
Prolonged QTc 
In light of the potential for QT changes associated with osimertinib, electrolyte abnormalities 
(hypokalaemia, hypomagnesaemia, hypocalcaemia) must be correct to be within normal ranges 
prior to first dose and electrolyte levels monitored during study treatment.
Electrocardiograms will be performed throughout the study as described. Readings for QTc 
prolongation will be based on the average of a single ECG for each time point. For patients 
found to have grade 3 or greater QTc prolongation, test serum potassium, calcium, phosphorus, 
and magnesium and correct per routine clinical practice to within normal limits. Review 
concomitant medications for medications that may cause prolongation of the QTc and 
discontinue if clinically feasible. Patients should have regular ECGs until return of QTc to 

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baseline. If the toxicity does not resolve to < grade 1 within 21 days the patient will be 
permanently withdrawn from the study treatment.  Further recommendations regarding dose 
adjustments and management are found in Table 5.5. 
Pneumonitis/ILD 
Pneumonitis/ILD can occur in patients treated with osimertinib. Patients with new or worsening 
dyspnea, cough, or new pulmonary radiological abnormality while receiving treatment, without 
clinically evident alternative etiology, should hold osimertinib, undergo a high resolution CT scan 
of the chest and the investigator should be notified. It is strongly recommended to perform a full 
diagnositic workup, to exclude alternative causes such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic edema or pulmonary hemorrhage.  The results of full diagnostic 
workup (including high-resolution computed tomography (HRCT), blood and sputum culture, 
haematological parameters) will be captured by eCRF.  In the presence of confirmatory HRCT 
scans where other causes of respiratory symptoms have been excluded, a diagnosis of 
intersititial lung disease should be considered and study treatment 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. Permanently 
discontinue osimertinib for any grade ILD/pneumonitis. 
Liver Chemistry Elevations 
Patients with combined increases in transaminases (AST or ALT to greater than 3x the ULN) 
and total bilirubin (to greater than 2x the ULN) should be reviewed for compatibility with Hy’s law 
(Appendix 7). An appropriate diagnostic evaluation for alternative etiologies should be 
completed within a three-week period. Patients with both an increased in AST or ALT to greater 
than 3x the ULN AND subsequent or coincident elevation in total bilirubin to greater than 2x 
ULN, without an alternative explanation upon clinical evaluation (i.e. cholestasis, viral hepatitis, 
another drug exposure), are found to meet the criteria for Hy’s Law and should be reported as 
an SAE. 
Hyperglycemia 
Treatment with osimertinib may result in hyperglycemia in some patients, most commonly in the 
first week of treatment. Regular monitoring of fasting or non-fasting blood glucose (FBG) will be 
completed as described in the study procedures in section 6.1. If a patient has a non-fasting 
glucose level of > 140 mg/dL (ULN for glucose within 2 hours of eating), then they must have a 
fasting glucose drawn and followed with fasting glucose for all future monitoring. Investigators 
should use discretion on an individual patient basis regarding need for more frequent 
monitoring: for example, patients with pre-existing diabetes or glucose intolerance. These 
patients should perform home monitoring at least once weekly during the first two cycles of 
treatment. Patients should be educated to contact the site if they have any positive urine 
glucose test or a home blood glucose reading of >160 mg/dL (>8.9 mmol/L) and any time they 
experience symptoms that have correlated with osimertinib-induced hyperglycemia, including 
increases in nausea, vomiting, anorexia, diarrhea, fatigue, polydipsia, polyuria, and polyphagia. 
Upon reports of positive home tests and/or symptoms suggesting hyperglycemia, local 
laboratory FBG tests should be performed. 
The following guidelines serve as recommended management guidelines for hyperglycemia; 
however, management of individual patients is deferred to the treating physician’s judgement.

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Table 5.7 Management Guidelines for Hyperglycemia
FBG Result
Antihyperglycemic 
Interventiona
Osimertinib Dose 
Modification
Grade 2
(>160 to 250 mg/dL;
>8.9 to 13.9 mmol/L)

If asymptomatic,b repeat test 
within 1 week; if results in 
this range at least twice in 1 
week, start 
antihyperglycemicc and 
continue home monitoring;

If symptomatic,b start 
antihyperglycemic and 
continue home monitoring.

Osimertinib may continue 
without interruption or dose 
reduction.
Grade 3
(>250 to 500 mg/dL;
>13.9 to 27.8 mmol/L)

Start antihyperglycemic and 
continue home monitoring.

If asymptomatic,b osimertinib 
may continue without 
interruption or dose 
reduction;

If symptomatic,b interrupt 
osimertinib until 
resolution/improvement in 
symptoms and FBG <250 
mg/dL (<13.9 mmol/L).c
Grade 4
(>500 mg/dL;
>27.8 mmol/L)

Start antihyperglycemic and 
continue home monitoring.

Consider adding a second 
antihyperglycemic agent.d

Interrupt osimertinib dosing 
until resolution/improvement 
in symptoms and FBG <250 
mg/dL (<13.9 mmol/L).c
FBG, fasting blood glucose
a Oral antihyperglycemic agent (e.g., metformin), which may need to be maintained for duration of 
osimertinib treatment. Use of insulin or agents that increase insulin production (e.g., sulphonyl ureas) is 
generally not recommended because the mechanism of osimertinib-induced hyperglycemia is not due to 
a deficit in insulin production.
b Increased nausea, vomiting, anorexia, diarrhea, and fatigue have been most common symptoms of 
hyperglycemia.
c Per Investigator discretion, osimertinib may be restarted at the same dose. A reduced dose may also 
be considered if glucose levels prove difficult to control.
d Additional anti-hyperglycemia agents such as SGLT2 inhibitors (e.g., dapagliflozin) or pioglitazone, 
which increase glucose uptake or increase glucose excretion, may be added to metformin.
6 Study Procedures and Observations
6.1 Schedule of Procedures and Observations
The study-specific assessments are detailed in this section and outlined in the schedule of study 
procedures and assessments. Screening assessments must be performed within 30 days prior 
to the first dose of IP. Any results falling outside of the reference ranges may be repeated at the 
discretion of the investigator. All on-study visit procedures are allowed a window of ± 3 days 
unless otherwise noted. Treatment or visit delays for public holidays or weather conditions do 
not constitute a protocol violation. 

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A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF will be given to the participant and a copy 
will be filed in the medical record. The original will be kept on file with the study records. 
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center (HDFCCC) Clinical Trial Management System (CTMS). The 
system is password protected and meets HIPAA requirements.
6.1.1 Pretreatment Period
6.1.1.1 Pre-Screening Assessments 
If EGFR mutation status is unknown, archived FFPE NSCLC specimen may be tested by local 
laboratory (UCSF or laboratories affiliated with participating sites) or investigator’s choice of 
CLIA- approved laboratory.
Assessment of cardiac function for changes in cardiac contractility must adhere to the ‘Special 
warnings and special precautions for use’ in the current approved TAGRISSO core data 
sheet.
6.1.1.2 Screening Assessments
The Screening procedures and assessments must be completed withing 30 days prior to Day 1 
Visit, except for, pregnancy testing, which must be completed within 3 days prior to Day 1. 

IR-guided core biopsy tumor specimen of a soft tissue lesion within 30 days prior to starting 
study drug for correlative studies. A repeat biopsy is permitted if quantity of tissue is 
insufficient. This biopsy can be deferred if the procedure is deemed to represent an 
unacceptable safety risk to the patient by the principal investigator.

If there was not enough archival tissue for a pre-screening EGFR mutation testing, this 
research biopsy will be used to obtain tissue for EGFR mutation testing as well as the 
correlative studies. EGFR mutation tests will be done at a local laboratory (UCSF or 
laboratories affiliated with participating sites) or investigator’s choice of CLIA-approved 
laboratory. 

If there is enough archival tissue left over, it will be sent to Guardant (Redwood City) for 
DNA analysis.

A physical examination will be performed and include an assessment of the following: 
general appearance, skin, head and neck (including ears, eyes, nose and throat), 
respiratory, cardiovascular, abdomen, lymph nodes, thyroid, musculoskeletal (including 
spine and extremities) and neurological systems. 

Vital signs 

Complete medical history, including history of prior treatments and any residual toxicity 
relating to prior treatment. 

Baseline conditions assessment

Performance status (ECOG)

Baseline medications taken within 30 days of Day 1.

Complete blood cell count (CBC) with differential and platelet count

Blood chemistry assessment, including:
o
Alkaline phosphatase (ALP), AST/ALT, total bilirubin, calcium, phosphorus, blood 
urea nitrogen (BUN), creatinine, total protein, albumin, fasting or non-fasting 
glucose, potassium, magnesium, sodium, chloride, bicarbonate.

Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR)

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
Urinalysis

For female patients, serum or urine pregnancy test within 3 days prior to the start of 
study drug

Contraceptive counseling

Confirmation of no evidence of metastatic disease by PET-CT and brain imaging (MRI or 
CT) within 60 days of Day 1.

Disease assessment by CT of the chest, abdomen, pelvis (MRI acceptable if 
contraindications to CT) within 30 days of Day 1.

Cardiac assessment (MUGA or TTE). Allowed within 30 days of Day 1.

Electrocardiogram (ECG)
o
Twelve-lead ECGs 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. For each time point, single ECG 
recording should be taken at about 5 minute intervals. A standardized ECG 
machine should be used and the patient should be examined using the same 
machine throughout the study if possible.
o
The investigator or designated physician will review each of the ECGs and may 
refer to a local 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, details of rhythm, ECG intervals and an overall 
evaluation will be recorded.

Peripheral blood collection for exploratory biomarker analysis
For each participant, the Pre-Treatment Period ends upon receipt of the first dose of the study 
treatments or final determination that the participant is ineligible for the study.
6.1.2 Treatment Period
6.1.2.1 Study Procedures, Cycle 1, Day 1 

Screening laboratory tests completed within 3 days of Cycle 1 Day 1 do not need to be 
repeated. 

Physical examination 

Vital signs 

Performance status 

Evaluation of AEs 

Concomitant medications 

CBC with differential and platelet count 

Blood chemistry assessment, including: 
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate 

Coagulation assessment, including PT/PTT/INR 

Urinalysis 

Serum or urine pregnancy test 

Electrocardiogram (ECG) 

Patient medication diary will be provided to patients 

Osimertinib tablets will be dispensed to patient 

Peripheral blood collection for exploratory biomarker analysis. 
6.1.2.2 Study Procedures Cycle 1, Day 15

Physical examination

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
Vital signs

Performance status

Evaluation of AEs

Concomitant medications

CBC with differential and platelet count

Blood chemistry assessment, including:
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate

Coagulation assessment, including PT/PTT/INR

Electrocardiogram (ECG)
6.1.2.3 Study Procedures Cycle 1, Day 28 – if not receiving optional second cycle of osimertinib

Physical examination

Vital signs

Performance status

Evaluation of AEs 

Concomitant medications 

CBC with differential and platelet count 

Blood chemistry assessment, including: 
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate 

Coagulation assessment, including PT/PTT/INR 

Optional post-treatment research biopsy within 30 days of C1D28 for patients who are 
determined to both be unable to undergo surgical resection of their tumor and who will 
not be proceeding with Cycle 2 of osimertinib therapy. 

Peripheral blood collection for exploratory biomarker analysis.

Urinalysis is optional or as clinically indicated

Serum or urine pregnancy test is optional or as clinically indicated 

Electrocardiogram (ECG) 

Disease assessment (includes measurable disease per RECIST) and imaging including 
CT of the chest, abdomen, pelvis (MRI if contraindications to CT). 

Cardiac assessment (MUGA or TTE) 

Review of patient diary for Cycle 1 

Patients will undergo surgical resection of their lung cancer within 14 days after the 
C1D28 restaging systemic scan. 

Osimertinib tablets will be dispensed, for up to a 14 day supply to be taken by patient 
until 3-7 days prior to surgery 

Patients must be assessed by a study investigator within approximately 14 days prior to 
surgery. 
6.1.2.4 Study Procedures Cycle 2, Day 1 – if receiving optional second cycle of osimertinib

Physical examination 

Vital signs 

Performance status 

Evaluation of AEs 

Concomitant medications 

CBC with differential and platelet count 

Blood chemistry assessment, including: 
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 

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albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate 

Coagulation assessment, including PT/PTT/INR 

Peripheral blood collection for exploratory biomarker analysis. 

Urinalysis 

Serum or urine pregnancy test 

Electrocardiogram (ECG) 

Disease assessment (includes measurable disease per RECIST) ) and imaging 
including CT of the chest, abdomen, pelvis (MRI if contraindications to CT).

Cardiac assessment (MUGA or TTE). For patients receiving the second of cycle of 
osimertinib, TTE is optional except for patients with pre-existing risk factors as clinically 
indicated  

Review of patient diary for prior cycle 

Osimertinib tablets will be dispensed 
6.1.2.5 Study Procedures Cycle 2, Day 15 – if receiving optional second cycle of osimertinib 

Physical examination 

Vital signs 

Performance status 

Evaluation of AEs 

Concomitant medications 

CBC with differential and platelet count 

Blood chemistry assessment, including: 
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate 

Coagulation assessment, including PT/PTT/INR 
6.1.2.6 Study Procedures Cycle 2, Day 28 – if receiving optional second cycle of osimertinib 

Physical examination 

Vital signs 

Performance status 

Evaluation of AEs 

Concomitant medications 

CBC with differential and platelet count 

Blood chemistry assessment, including: 
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate 

Coagulation assessment, including PT/PTT/INR 

Electrocardiogram (ECG) 

Cardiac assessment (MUGA or TTE) 

Disease assessment (includes measurable disease per RECIST) and imaging including 
CT of the chest, abdomen, pelvis (MRI if contraindications to CT). 

Optional post-treatment research biopsy within 30 days of C2D28 for patients who are 
unable to undergo surgical resection of their tumor. 

Peripheral blood collection for exploratory biomarker analysis 

Review of patient diary for Cycle 2 

Patients will undergo surgical resection of their lung cancer within 14 days of C2D28 
systemic restaging scan. 

Osimertinib tablets will be dispensed, for up to 14 day supply to taken by patient until 3-7 
days prior to surgery 

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6.1.2.7 Study Procedures on day of surgery 

CBC with differential and platelet count 

Blood chemistry assessment, including: 
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate 

Coagulation assessment, including PT/PTT/INR 

Peripheral blood collection for exploratory biomarker analysis (ctDNA analysis and 
PBMCs) 

Electrocardiogram (ECG) 
6.1.3 Study Procedures, D15 following surgery 
Peripheral blood collection for exploratory biomarker analysis (ctDNA analysis and 
PBMCs)
6.1.4 End-of-Treatment Study Procedures 
To be completed at 30 days of post-operative D15 study visit. 

Physical examination 

Vital signs 

Performance Status 

Evaluation of AEs 

Concomitant medications 

CBC with differential and platelet count 

Blood chemistry assessment, including: 
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate 

Coagulation assessment, including PT/PTT/INR 

Urinalysis 

Serum or urine pregnancy test 

Electrocardiogram (ECG) 

Peripheral blood collection for exploratory biomarker analysis 
6.1.5 Long Term/Survival Follow-up Procedures 
Patients will continue to be followed as per standard of care every three months (+/- 2 weeks) 
following the end-of-treatment visit for a period of up to one 5 years, or until death or closure of 
the study. This follow up will include assessment of survival status and subsequent therapies for 
NSCLC. Standard of care tumor scans (CT chest/abdomen/pelvis or PET/CT) will occur every 6 
months, unless local requirements or investigator opinion warrant more frequent scans. After 
the first year, assessment of survival status and subsequent therapies will occur via telephone 
or via routine clinic visits every six months (+/- 2 weeks) for 5 years post-surgery. 
6.1.6 Discontinuation of Therapy
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests. Reasons for withdrawing a patient include, but are not limited to, PD, the 
occurrence of an AE or a concurrent illness, a patient’s request to end participation, a patient’s 
non-compliance or simply significant uncertainty on the part of the Investigator that continued 
participation is prudent. There may also be administrative reasons to terminate participation, 
such as concern about a patient’s compliance with the prescribed treatment regimen.

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6.3 Usage of Concurrent/Concomitant Medications
Osimertinib is metabolized by CYP3A4 and CYP3A5 enzymes.
A drug-drug interaction study of osimertinib evaluated in patients showed that there is potential 
for osimertinib being a victim when co-administered with strong inducers of CYP3A4 
(osimertinib concentrations are decreased when co-dosed with rifampicin).
The following potent inducers of CYP3A4 must not be used during this study for any patient 
receiving osimertinib.
D1 Drugs Inducing CYP3A4
Contraindicated Drugs
Withdrawal period prior to 
osimertinib start
Carbamazepine, phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentin
3 weeks
St John’s Wort
Phenobarbitone
5 weeks
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.
Please contact AstraZeneca with any queries you have on this issue.
Medicines Whose Exposures May be Affected by Osimertinib That are Allowed With 
Caution 
Osimertinib may increase the concentration of sensitive breast cancer resistance protein 
(BCRP) substrates (concentration of the sensitive BCRP substrate, rosuvastatin, is increased).
D2 Exposure, Pharmacological Action and Toxicity May be Increased by 
Osimertinib
Warning of possible interaction
Advice
Rosuvastatin
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan
Dabigatran
Aliskiren
Digoxin
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.
6.4 Dietary Restrictions 
Osimertinib can be taken with or without food, with at least 240 mL (8 oz.) of water. 
6.5 Prohibited Medications Other anticancer therapy 
Systemic anticancer therapy (chemotherapy, targeted therapy, biologic therapy, or radiation 
therapy), other than the osimertinib treatment, must not be given to patients while they are 
enrolled in the treatment portion of the trial. If such agents are required then the patient must be 
permanently discontinued from the treatment portion of the study. 
Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. 
Potent CYP3A inducers 

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Potent inducers of CYP3A4/5 are prohibited. Patients receiving concomitant medications known 
to potently induce CYP3A4/5 that are deemed medically necessary should be excluded from the 
study. Please see section 4.1.1 and 6.3 for additional details. 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study, as a potential drug-drug 
interaction is always possible. These herbal medications include, but are not limited to: St. 
John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. 
Medications that may prolong the QT interval or have a known risk of inducing Torsades 
de Pointes 
Medications known to produce QTc prolongation should be avoided during treatment of patients 
with osimertinib. See section 4.1 for lists of QTc prolonging medications. Please note potential 
QTc prolonging medications contain common supportive medications, such as anti-emetics 
(ondansetron [and other 5HT3 antagonists], metoclopramide, hydroxyzine), antibiotics 
(azithromycin, ciprofloxacin, metronidazole) and anti-depressants (escitalopram). 
Medications to consider for nausea that are not associated with QT prolongation include: 

Steroids (dexamethasone, methylprednisolone) 

Benzodiazepines 

Aprepitant 

Select anticholinergic agents (scopolamine) 

Trimethobenzamide 

Cannabinoids 
If a drug that has the potential to cause QTc prolongation is indicated to control AEs (e.g. 5HT3 
inhibitor for nausea/vomiting), then additional ECGs should be performed to monitor for potential 
QTc changes.
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 website: https://www.crediblemeds.org/. The website 
categorizes drugs based on the risk of inducing Torsades de Pointes (TdP). 
During screening, the drugs that patients are currently prescribed should be checked opposite 
the ArizonaCert website.
Drugs with a known risk of Torsades de Pointes 
The following drugs prolong the QT interval and are clearly associated with a known risk 
of TdP, even when taken as recommended. These drugs must have been discontinued 
prior to the start of administration of study treatment in accordance with guidance 
provided in Table 3 and should not be co-administered with study treatment 
(osimertinib) and for a period of two weeks after discontinuing study treatment. The list 
of drugs may not be exhaustive and is subject to change as new information 
becomes available. As such, investigators are recommended to search the 
website to provide the most up to date information. 
Drugs with a known risk of TdP 
Drug name 
Withdrawal period prior 
to study treatment start 

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Aclarubicin, anagrelide, ciprofloxacin, clarithromycin, 
cocaine, droperidol, erythromycin, levofloxacin, 
ondansetron, papaverine hydrochloride, procainamide, 
sulpiride, sultopride, terfenadine terlipressin 
2 days 
Cilostazol, Cisapride, disopyramide, dofetilide, 
domperidone, flecainide, gatifloxacin, grepafloxacin, 
ibutilide, moxifloxacin, oxaliplatin, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol, sparfloxacin, 
thioridazine 
7 days 
Azithromycin bepridil, citalopram, chlorpromazine, 
dronedarone, escitalopram, fluconazole, halofantrine, 
haloperidol, levomepromazine, levosulpiride, mesoridazine 
14 days 
Donepezil, terodiline 
3 weeks 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide*, Ibogaine 
6 weeks 
Pentamidine 
8 weeks 
Astemizole, Probucol, vandetanib 
4 months 
Amiodarone, chloroquine 
1 year 
* Estimated value as pharmacokinetics of arsenic trioxide has not been studied
Other TdP risk Categories 
Patients receiving drugs that prolong QT interval or may increase the risk of TdP from other TdP 
risk categories can be enrolled, notwithstanding other exclusions and restrictions, if these drugs 
are considered essential for patient management and the patient has been stable on therapy. 
Close monitoring with ECGs and electrolytes is recommended. 
Patients with congenital long QT syndrome (CLQTS) are excluded from this study. 
Guidance regardless of TdP risk category 
Following study treatment initiation if it is considered essential for patient management to give 
drugs known to prolong QTc interval, regardless of TdP risk category, close monitoring with 
ECGs and electrolytes is recommended.
6.6 Contraceptive Counseling
1. 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 
are described in Section 3.3.1. 

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7 Reporting and Documentation of Results 
7.1 Antitumor Effect – Solid Tumors 
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria. 
7.2.1 Definitions 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study drug. 
Evaluable for objective response 
Only those patients who have measurable disease present at baseline, 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 PD prior to the end of Cycle 1 will also be 
considered evaluable.) 
7.2.2 Disease Parameters 
Measurable disease 
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters. 
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy. 
Target lesions 
All measurable lesions, up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ), representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline. Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
Non-target lesions
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. It is possible to record multiple non-target lesions involving the same organ as a single 
item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”). Bone lesions may be measureable if ≥1 cm on MRI. Measurements of these 
lesions are not required, but the presence or absence of each will be noted throughout follow-
up. 
Non-measurable disease (Tumor Markers) 
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan). 

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Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques are all non- 
measurable (e.g. PSA, CA-125, CA19-9, CEA). 
7.2.3 Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations will 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 will 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 when both methods have been used to assess 
the antitumor effect of a treatment. 
Conventional CT and MRI 
CTs should be performed with cuts of 10 mm or less in slice thickness contiguously. 
Cytology, Histology 
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 
(SD) is mandatory to differentiate between response or SD and PD. 
7.2.4 Response Criteria 
Evaluation of Target Lesions 
Complete Response
Disappearance of all target lesions, confirmed as permitted by observation on two separate 
observations conducted not less than 4 weeks apart. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm (the sum may not be “0” if 
there are target nodes). There can be no appearance of new lesions. 
By nature of neoadjuvant study design, responses will be unconfirmed in many patients in this 
study, as resection will often occur less than 4 weeks after scans. 
Partial Response
At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions, taking as 
reference the baseline SLD. There can be no appearance of new lesions. 
Progressive Disease
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or the 
appearance of one or more new lesions. 
Stable Disease
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest SLD since the treatment started. 
Evaluation of Non-Target Lesions 
Complete Response

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Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10 
mm short axis). 
Incomplete Response/Stable Disease
Persistence of one or more non-target lesion(s). 
Progressive Disease
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
PD/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started) or surgical resection. The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
Table 7.1 Response Criteria
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this 
Category Also Requires
CR
CR
No
CR
>4 weeks confirmation**
CR
PR
Non-CR/
Non-PD
Non-PD
No
No
PR
PR
>4 weeks confirmation**
SD
Non-PD
No
SD
Documented at least once >4 
weeks from baseline
PD
Any
Any
Any
PD*
Any
Yes or No
Yes or No
Yes
PD
PD
PD
No prior SD, PR or CR
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD
**Due to neoadjuvant nature of this study, radiographic responses will often be unconfirmed due to 
surgical resection prior to repeat scans
Disease-Free Survival 
DFS is defined as the duration of time from surgical resection to time of disease recurrence. 
7.2 Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE v4.03 for reporting of non-hematologic AEs and modified criteria for 
hematologic AEs. 
7.3 Definitions of Adverse Events 
7.3.1 Adverse Event
An AE (also known as an adverse experience) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related. More 
specifically, an AE (can be any unfavorable and unintended sign (e.g., an abnormal laboratory 

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finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. An AE can arise from any use of the drug (e.g., off-label use, use in 
combination with another drug) and from any route of administration, formulation, or dose, 
including an overdose. 
AEs based on signs and symptoms 
All AEs spontaneously reported by the participant or revealed by observation will be collected 
and recorded in the CRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to the recording  list of signs and symptoms. However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis and 
each sign or symptom will be recorded separately. 
AEs based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, QTc, 
LVEF, and DLCO should only be reported as AEs if they fulfill any of the SAE criteria or are the 
reason for discontinuation of treatment with the IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible, the reporting Investigator uses the 
clinical rather than the laboratory term (e.g., anemia versus low Hgb value). In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters should 
be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to PD, should not be reported as 
an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE.
7.3.2 Adverse reaction 
An adverse reaction is defined as any AE caused by the use of a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. 
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility 
that the drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
indicates that there is evidence to suggest a causal relationship between the drug and the AE. A 
suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
7.3.2.2 Unexpected 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has 
been observed, or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 

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from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 
AEs that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure. For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure. 
Some AEs are listed in the Investigator Brochure as occurring with the same class of drugs, or 
as anticipated from the pharmacological properties of the drug, even though they have not been 
observed with the drug under investigation. Such events would be considered unexpected until 
they have been observed with the drug under investigation. For example, although angioedema 
is anticipated to occur in some patients exposed to drugs in the ACE inhibitor class and 
angioedema would be described in the investigator brochure as a class effect, the first case of 
angioedema observed with the drug under investigation should be considered unexpected for 
reporting purposes. 
7.3.3 Serious 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 

Death 

Life-threatening AE 

Inpatient hospitalization or prolongation of existing hospitalization 

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 

Congenital anomaly/birth defect 
Important medical events that may not result in death, are life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined earlier in this section. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE unless it meets the criteria shown above. On the 
other hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be a SAE when it satisfies the criteria shown above. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to the study sponsors in accordance with the agreed 
process. 
7.3.4 Life threatening 
An AE or suspected adverse reaction is considered life threatening if, in the view of either the 
investigator or sponsor, its occurrence places the patient or participant at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 

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7.3.5 Overdose 
A maximum tolerated dose has not been established for osimertinib.  An overdose is any dose 
which exceeds the daily dose that is defined in the clinical study protocol.
There is no specific treatment in the event of osimertinib overdose, and symptoms of 
overdose are not established. In the event of an overdose, physicians should follow general 
supportive measures and should treat symptomatically. 
For overdoses associated with a SAE, the standard agreed reporting timelines apply. 
7.3.6 Maternal and Paternal Exposures
Maternal Exposure 
If a participant becomes pregnant during the course of the study, osimertinib should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should be followed up and documented even if the participant was 
discontinued from the study.
If any pregnancy occurs in the course of the study and within 6 weeks of the last dose of 
osimertinib, then the Investigator or other site personnel informs the appropriate sponsor 
representatives within 1 day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
The same timelines apply when outcome information is available. 
Paternal Exposure 
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should if possible be followed up and documented. 
To capture information about a pregnancy from the partner of a male participant, the male 
participant’s partner’s consent must be obtained to collect information related to the pregnancy 
and outcome; the male participant should not be asked to provide this information. A consent 
form specific to this situation must be used. The outcome of any conception occurring from the 
date of the first dose until 6 months after dosing ends should be followed up and documented. 
7.3.7 Disease progression 
PD can be considered as a worsening of a participant’s condition attributable to the disease for 
which the IP is being studied. It may be an increase in the severity of the disease under study 
and/or increases in the symptoms of the disease. The development of new, or progression of 
existing metastasis to the primary cancer under study should be considered as PD and not an 
AE. Events, which are unequivocally due to PD, should not be reported as an AE during the 
study. 
7.3.8 New cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the serious criteria. New primary cancers are those that are not the primary 

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reason for the administration of the study treatment and have developed after the inclusion of 
the patient into the study. They do not include metastases of the original cancer. Symptoms of 
metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be PD. 
7.3.9 Lack of efficacy 
When there is progression or deterioration related to NSCLC, there may be uncertainty as to 
whether this is lack of efficacy or an AE. In such cases, unless the Sponsor or the reporting 
physician considers that the study treatment contributed to the deterioration of the condition, or 
local regulations state to the contrary, the deterioration should be considered to be a lack of 
efficacy and not an AE. 
7.3.10 Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study follow-up 
period after the administration of the last dose of study treatment, must be reported as follows: 

Death that is clearly the result of PD should be reported to the study monitor at the next 
monitoring visit and should be documented in the eCRF but should not be reported as 
an SAE. 

Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the study monitor as a SAE within 24 
hours (see Section 7.2.2.3 for further details). The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should 
assign main and contributory causes of death. This information can be captured in the 
eCRF. 

Deaths with an unknown cause should always be reported as a SAE. A post mortem 
maybe helpful in the assessment of the cause of death, and if performed, a copy of the 
post-mortem results should be forwarded to the study sponsors within the usual 
timeframes. 
7.4 Recording of an Adverse Event 
All grade 3 and above AEs will be entered into OnCore®, whether or not the event is believed to 
be associated with use of the study drug. Data about these events and their severity will be 
recorded using the NCI CTCAE v4.03.
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below:
Relationship 
Attribution
Description
Unrelated
The AE is clearly NOT related to the 
intervention
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention
Possible
The AE may be related to the intervention
Probable
The AE is likely related to the intervention
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention
Signs or symptoms reported as AEs will be graded and recorded by the Investigator according 
to the CTCAE. When specific AEs are not listed in the CTCAE, they will be graded by the 
Investigator as none, mild, moderate or severe according to the following grades and definitions:

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Grade 0:
No AE (or within normal limits) 
Grade 1:
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2:
Moderate; minimal, local, or noninvasive intervention (e.g., packing, 
cautery) indicated; limiting age-appropriate instrumental activities of daily 
living (ADL) 
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL
Grade 4;
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
7.5 Follow-up of Adverse Events 
All AEs will be followed with appropriate medical management until resolved. Patients removed 
from study for unacceptable AEs will be followed until resolution or stabilization of the AE. For 
AEs that do not require permanent discontinuation after stopping administration of the study 
drug, a re-challenge of the participant may be conducted if considered both safe and ethical by 
the investigator. 
7.6 Adverse Events Monitoring 
All AEs, whether or not unexpected, and whether or not considered to be associated with the 
use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all AEs and determine reportability requirements to the UCSF 
DSMC and UCSF’s IRB; and, when the study is conducted under an Investigational New Drug 
(IND) Application, to the FDA if it meets the FDA reporting criteria.
All AEs entered into OnCore® will be reviewed by the HDFCCC Site Committee on a monthly 
basis. The Site Committee will review and discuss the selected toxicity, the toxicity grade, and 
the attribution of relationship of the AE to the administration of the study drug(s). 
In addition, all AEs and suspected adverse reactions considered “serious” that are entered into 
OnCore® will be reviewed and monitored by the DSMC on an ongoing basis.  They will be 
discussed at DSMC meetings, which take place every six (6) weeks. 
For a detailed description of the Data and Safety Monitoring Plan (DSMP) for a Multicenter 
Phase 2 or 3 Institutional Study at the HDFCCC, please refer to Appendix 3 DSMP* for Phase 
II/III Multicenter Institutional Studies. 
7.7 Expedited Reporting 
Reporting to the DSMC
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event. The contact may be by 
phone or e-mail. 
Reporting to UCSF IRB

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The PI must report events meeting the UCSF IRB definition of “Unanticipated Problem” (UP) 
within 10 business days of his/her awareness of the event. 
Expedited Reporting to the FDA
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report via an IND safety report any suspected adverse reaction that is 
SUSAR (Suspected unexpected serious adverse reaction). The Sponsor-Investigator needs to 
ensure that the event meets all three definitions: 

Suspected adverse reaction (as defined in 7.2.2.1) 

Unexpected (as defined in 7.2.2.2) 

Serious (as defined in 7.3.3.3) 
If the AE does not meet all three of the definitions, it should not be submitted as an expedited 
IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Reporting to Pharmaceutical Companies providing Study Drug 
AstraZeneca/MedImmune retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
All SAEs will be reported, whether or not considered causally related to the IP or to the study 
procedure(s). The investigator and/or Sponsor are responsible for informing the Ethics 
Committee and/or the Regulatory Authority of the SAE as per local requirements. 
The following variables will be collected for AEs, for reporting to AstraZeneca 

AE (verbatim) 

The date when the AE started and stopped 

CTCAE Grade 

Whether the AE is serious or not 

Investigator causality rating against the IP (yes or no), comparator/combination drug 
(yes/no) 

Action taken with regard to IP/comparator/combination agent 

AE caused participant’s withdrawal from study (yes or no)

Outcome 
In addition, the following variables will be collected for SAEs: 

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
Date AE met criteria for SAE

Date Investigator became aware of SAE 

AE is serious due to 

Date of hospitalization 

Date of discharge 

Probable cause of death 

Date of death 

Autopsy performed 

Causality assessment in relation to Study procedure(s) 

Causality assessment in relation to Other medication 

Causality assessment in relation to Additional Study Drugs 

Description of AE 
The investigator and/or sponsor must inform the FDA, via a MedWatch form, of any serious or 
unexpected AEs that occur and will concurrently forward all such reports to AstraZeneca. A 
copy of the MedWatch report must be emailed to AstraZeneca at the time the event is reported 
to the FDA. It is the responsibility of the sponsor to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting requirement timelines and 
to ensure that these reports are also submitted to AstraZeneca at the same time. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA. 
SAEs that do not require expedited reporting to the FDA still need to be reported to 
AstraZeneca preferably using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
language for SAEs. This information should be reported on a monthly basis and under no 
circumstance less frequently than quarterly. 
*A cover page should accompany the MedWatch form indicating the following: 

Investigator Sponsored Study (ISS) 

The investigator IND number assigned by the FDA 

The investigator’s name and address 

The trial name/title and AstraZeneca ISS reference number 
*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 PD, as determined 
by the PI. 
*Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox: 
. If a non-serious AE 
becomes serious, this and other relevant follow-up information must also be provided to 
AstraZeneca and the FDA. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
IP. All SAEs will be documented. The investigator is responsible for informing the IRB and/or the 
Regulatory Authority of the SAE as per local requirements. 
Non-serious AEs and SAEs will be collected from the time consent is given, throughout the 
treatment period and up to and including the 30 day follow-up period. After withdrawal from 
treatment, participants must be followed-up for all existing and new AEs for 30 calendar days 
after the last dose of trial drug and/or until event resolution. All new AEs occurring during that 
period must be recorded (if SAEs, then they must be reported to the FDA and AstraZeneca). All 

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study-related toxicities/SAEs must be followed until resolution, unless in the Investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease. 
8 Statistical Considerations and Evaluation of Results
Table 8.1 Study Endpoints
Objective
Endpoint 
Primary
To evaluate the efficacy of 
osimertinib as neoadjuvant 
therapy in patients with surgically 
resectable EGFR-mutant NSCLC.
To determine the MPR rate, defined as ≤ 10% 
viable tumor present histologically in the 
resected tumor specimen.
Secondary 
To evaluate the safety and 
tolerability of osimertinib given as 
neoadjuvant therapy in early 
stage EGFR-mutant NSCLC 
patients. 
To evaluate secondary measures 
of clinical efficacy in early stage 
EGFR-mutant NSCLC patients 
treated with osimertinib induction 
therapy. 

Radiographic decrease in maximum tumor 
diameter

5-year DFS 

5-year OS 

DpR 

Complete pathological response rate 

Treatment-emergent AEs, laboratory 
abnormalities and ECG abnormalities as 
determined by NCI-CTC version 4.0 by 
investigator. 

Rate of inability to undergo surgical resection 
due to treatment-related AE. 

Rate of surgical complications occurring prior 
to end of treatment visit. 
Exploratory 
To evaluate long-term measures 
of efficacy in patients treated with 
osimertinib neoadjuvant therapy. 
To explore tissue and cell-free 
biomarkers that may be predictive 
of response or primary resistance 
to osimertinib neoadjuvant 
therapy. 

Evaluate rates of adverse pathologic 
features on resection specimens. 

Evaluate genomic and transcriptional 
changes on baseline and resected tumor 
specimens. 

Evaluate changes in immune cell infiltration 
on baseline and resected tumor specimens. 
Changes in ctDNA.
8.1 Sample Size and Accrual Rate Considerations
8.1.1 Sample Size and Power Estimate
27 evaluable patients will provide 87% power to detect a MPR rate of 50% as compared to a 
null rate of 22%, at the 5% significance level.
8.1.2 Replacement Policy
All patients who receive a dose of osimertinib will be analyzed for safety and efficacy. 
Participants who discontinue from study participation prior to surgical resection may be replaced 
after discussion with the PI. Patients removed from study for unacceptable treatment related 
AE(s) will be followed until resolution or stabilization of all treatment related AEs to grade 2 or 
lower; however, they will not be replaced.
8.1.3 Accrual estimates 
This is a multi-institution study (UCSF and participating sites). Thoracic oncology sees 
approximately 300 new early stage lung adenocarcinoma patients per year with ~ 25% of these 
patients harboring EGFR-activating mutations We predict that ~ 25 patients per year will be 
eligible for this study. UCSF and participating sites currently have no competing trials for this 

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patient population. We expect to fully accrue this study within 36 months of opening for patient 
enrollment. 
8.2 Interim Analyses and Stopping Rules 
An interim safety analysis will be performed following enrollment of 9 patients (33% of planned 
study population). A 97% disease control rate has been previously reported to osimertinib in the 
first-line setting in advanced EGFR-mutated NSCLC.[35] Even in the setting of standard of care 
resection, there is a high rate of pathologic upstaging relative to initial clinical staging. For 
example, among patients enrolled in CALGB9761 with clinical stage I NSCLC and PET scans 
negative for additional disease, 38.3% were subsequently upstaged on pathology.[52] 
We would therefore consider conversion to unresectable status in two or more patients to reach 
threshold for early study discontinuation. In patients with evidence of clinical benefit (SD or PR) 
to osimertinib therapy on preoperative imaging, pathologic upstaging will not be considered an 
indication for study discontinuation unless it occurs at a rate greater than previously reported to 
standard of care (i.e., in 4 or more patients), as overall presence of disease response on 
imaging renders isolated occult lymph node progression unlikely. 
Safety of the study will be continuously assessed by the PI and the DSMC. The study may be 
stopped early if there is deemed to be an unacceptable safety risk by either the PI or the DSMC. 
8.3 Analyses Plans 
8.3.1 Analysis Population 
All patients who receive a dose of osimertinib will be analyzed for safety and efficacy. 
Participants who discontinue from study participation prior to surgical resection may be replaced 
after discussion with the Study PI. 
Demographic and baseline characteristics will be summarized. In general, frequency distribution 
and percentage will be used to summarize categorical measurements, while mean with 
standard deviation and median with interquartile range will be used to describe symmetric and 
skewed continuous measurements, respectively. Univariate analysis among variables will be 
assessed using the two-sample t-test, Wilcoxon-rank-sum test, or Chi-square test, as 
appropriate. 
8.3.2 Primary Analysis (or Analysis of Primary Endpoints) 
MPR rate (primary endpoint) will be determined in patients who receive at least one dose of 
study drug.
Patients who receive one dose of study drug and become ineligible for surgery either because 
of disease progression or adverse event will be deemed not to have achieved MPR.  
In patients who undergo surgical resection or their lung tumor resection specimens will be 
processed at the local institution following CAP and CLIA guidelines. Immediate sampling of the 
tumor and overnight fixation in 10% buffered formalin for paraffin embedding, usually within 20-
24 hours after fixation. For histopathological evaluation, at least one sample per every 1-cm of 
diameter will be submitted for FFPE processing and pathology analysis. The local institutional 
study pathologist will assess each case for MPR, using percentage of viable tumor cells (cutoff 
as + MPR is ≤ 10% of viable tumor cells) as has been reported [24]. The pathological response 
should be reported as average percentage of viable tumor cells by slide examined. 
Pathology slides (H&E and IHC and special stains) will be forwarded to the designated central 
pathologists for the study and MPR will be determined as described above.

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In order to more fully evaluate the specimens associated with this trial, the central review 
pathologists will score the material using criteria as follows: 
Pathological CR: Residual viable tumor: 0% MPR: Residual viable tumor: ≤ 10% 
Pathological response (not meeting major response criteria) 11-49% residual viable tumor. No 
pathological response: 50% or greater residual viable tumor. 
Predominant reaction type: Necrosis, Fibrosis 
Tumors that exhibit ≤ 10% viable tumor will meet the criteria for an MPR as has been 
previously described [24]. The MPR rate will be reported with 95% confidence intervals. 
As needed, a sub-set of tissues will be independently evaluated by both pathologists for 
assessment of inter-pathologist reproducibility for this scoring. 
Whenever possible, the following will be included: 

Concurrent submission of pre-treatment biopsy or FNA sample. This can help inform 
pathologic evaluation in that pre-treatment necrosis can be assessed, within the context 
of potential sampling bias. 

Whenever feasible, all post-treatment surgical tumor samples will be submitted for 
pathologic examination (full lesion block-in), after tissue procurements have been 
completed. 

Samples will be identified, accrued and sent for central review in groups of no less than 
10 cases to minimize criteria drift. If fewer than 10 cases are sent in any individual batch, 
the cases will be held until a minimum of 10 cases are available for review. 
8.3.3 Secondary Analysis (or Analysis of Secondary Endpoints)
5-Year DFS: DFS will be calculated as 1+ the number of days from date of surgical resection to 
documented radiographic relapse/progression or death due to any cause over a period of 60 
months. The Kaplan-Meier analysis will be used to calculate the median DFS with 95% 
confidence interval.  5-year DFS rate will be calculated as the percentage of patients who are 
disease free at 5 years.  This will be calculated using the Kaplan-Meier method.
Assuming alpha of 0.05 and a set sample size of 27, as well as a null hypothesis of 50% 5-year 
DFS [53], we will have a power of 80% to detect a 25% increase in 5-year DFS.
Objective Response Rate: The objective response rate is defined as the best overall response 
recorded from the start of the treatment until time of surgery. The frequency and percentages of 
patients with a best ORR of CR, PR, SD, or PD will be determined. The objective response rate 
will be reported with 95% confidence intervals.
Pathologic Complete Response Rate (pCR): The pCR is defined as absence of (0%) viable 
tumor present histologically in the resected tumor specimen. Scoring for pathologic response is 
described above.
5-Year Overall survival (OS) rate: 5-year OS rate will be calculated using the Kaplan-Meier 
method . OS will be defined as the 1+ the number of days from surgical resection to death due 
to any cause over a period of 60 months. The Kaplan-Meier analysis will be used to calculate 
the median OS with 95% confidence interval.

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Depth of Response (DpR): DpR will be defined as the percentage change in tumor burden by 
RECIST criteria at best response versus baseline imaging. DpR will be summarized using 
descriptive statistics and correlated with patient outcomes using hazard ratios via the Cox 
proportional hazards model.
Safety and Tolerability: AE terms recorded on the CRFs will be mapped to preferred terms 
using the MedDRA. Seriousness, severity grade and relationship to study treatment will be 
assessed by the investigator. Severity grade will be defined by the NCI CTCAE v4.03. Listings 
of AEs will be provided. Rate of conversion from operable to non-operative will be recorded as 
rate of patients initially assessed as surgically resectable, who are subsequently unable to 
undergo surgical resection due to either treatment-related AEs or PD. Rate of surgical 
complications occurring prior to the end of treatment visit will be recorded.
8.3.4 Other Analyses/Assessments 
Exploratory Analysis:

We will record rates of adverse pathologic features including rates of positive margins, 
LVI, and pathologic upstaging (e.g., by T or N status) as compared to clinical staging 
based on pre-operative scans, for comparison to historical controls.

We will perform RNA sequencing and whole exome sequencing analysis on isolated 
cancer cell populations from pre-treatment tumor biopsy specimens, as well as tumor 
tissue acquired at the time of surgical resection (post-osimertinib). Gene Set Enrichment 
Analysis will be performed to identify osimertinib-induced changes in common cancer 
related pathways, including: RAS-RAF-MAPK, PI3K-AKT, WNT- β catenin, JAK-STAT, 
HGF-MET, and IGF-1R, as well as emerging pathways of resistance (i.e. NF-kB and 
Hippo-YAP) [1, 46, 47]. We will determine whether there is a statistically significant 
increase in oncogenic/survival pathway related gene expression signatures in the post-
osimertinib compared to the pre-treatment sample using established methods [48]. We 
will compare MPR rates in tumors that exhibit specific oncogenic/survival pathway 
activation post-osimertinib treatment compared to tumors that do not. IHC analysis will 
be performed on pre-treatment and post-surgical specimens to confirm pathway 
activation identified by transcriptional analysis (i.e. phosphorylated-ERK (indicative of 
MAPK signaling), phosphorylated-AKT (indicative of PI3K signaling) or nuclear NF-kB 
(RELA), or - β -catenin expression). Samples will be scored in a continuous manner and 
difference among time points will be determined by a two-tailed T-test. 

We will assess for shifts in the cellular make-up of the tumor microenvironment induced 
by osimertinib treatment by performing single cell dissociation and fluorescence 
associated cell sorting (FACS) on fresh pre-treatment tumor biopsies and post-
osimertinib tumor resection specimens. Using FACS gating strategies established and 
validated by the Krummel lab at UCSF [49], we will isolate CD45+ immune cells and 
determine how osimertinib treatment alters the proportions of cells that make up the 
lymphoid (CD4+ and CD8+ T cells, Tregs, NK cells, B cells) and myeloid (macrophages, 
neutrophils, mast cells, dendritic cells) compartments. We will then use RNA-Seq to 
assess the transcriptional profiles of populations of TAMs, CD4+ and CD8+ T Cells (Fig. 
5). We hypothesize that osimertinib treatment will induce a pro-tumor immune 
microenvironment that allows for tumor cell persistence. Specifically, we will assess the 
polarization of TAMs by assessing the mRNA expression profiles of genes classically 
associated with TH1-skewed (i.e. TNF-α, IL-6, IL-12p40, and IL-1β, and Nos2) and TH2-
skewed polarization (i.e. ARG1, TGFB, CD163, CD206), many of which are targets of 
NF-kB transcriptional activation[50]. We will also investigate whether osimertinib affects 

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T-cell phenotypes. CD4+ T cells will be assessed for the expression of genes indicative 
of TREG, TH1, TH2, or TH17 activity (i.e. GATA3, T-bet, FOXP3, IFNγ, IL-4, IL-13, IL-
10, and IL-17a)[50], and CD8+ T cells will be assessed for expression of cytotoxic 
effector molecules (IFN, GRZA, GRZB, and PRF1)[50]. Finally, tumor cells and 
infiltrating immune cells will be assessed for shifts in PD-1 and PD-L1 expression (by 
RNA-Seq and IHC), a phenomenon that has been linked to NF-kB activity[41], and which 
may indicate changes in anti-tumor immunity induced by osimertinib. Comparisons will 
be made to PBMCs when possible. Assessment of TIL and TAM infiltration into the 
tumor microenvironment, and of TAM polarization will be confirmed by IHC analysis for 
relevant macrophage attributes including CD68, CD163, CD206, iNOS, HLA-DR, as well 
as for CD4, CD8, and PD-L1, as well as for cancer-associated fibroblasts. Comparisons 
will be made to PBMCs when possible. Samples will be scored in a continuous manner 
and difference among time points will be determined by a two-tailed T-test. 

We will assess peripheral blood samples for ctDNA analysis. Descriptive statistics and 
graphical methods will be used to analyze the data. 
8.4 Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the NCI CTCAE v4.03. 
9 Study Management 
9.1 Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the IRB for 
the protocol, written informed consent form, participant recruitment materials, and any other 
written information to be provided to participants before any protocol related procedures are 
performed on any participants. 
The clinical investigation will not begin until either FDA has determined that the study under the 
IND Application is allowed to proceed or the Investigator has received a letter from FDA stating 
that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP- International Conference on Harmonization 
(ICH) guidelines, and all applicable regulatory requirements. The IRB must comply with the 
regulations in 21 CFR §56 and applicable regulatory requirements. 
9.2 IRB Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB. Prior to obtaining IRB approval, the protocol must be approved by 
the HDFCCC Site Committee and by the PRC. The initial protocol and all protocol amendments 
must be approved by the IRB prior to implementation. 

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9.3 Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants must 
sign the IRB-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file. 
9.4 Changes in the Protocol 
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after implementation.
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites. 
9.5 Handling and Documentation of Clinical Supplies 
The UCSF PI and each participating site will maintain complete records showing the receipt, 
dispensation, return, or other disposition of all investigational drugs. The date, quantity and 
batch or code number of the drug, and the identification of patients to whom study drug has 
been dispensed by patient number and initials will be included. The sponsor- investigator will 
maintain written records of any disposition of the study drug. 
The PI shall not make the investigational drug available to any individuals other than to qualified 
study patients. Furthermore, the PI will not allow the investigational drug to be used in any 
manner other than that specified in this protocol. 
9.6 Case Report Forms
The PI and/or his/her designee will prepare and maintain adequate and accurate participant 
case histories with observations and data pertinent to the study. Study specific CRFs will 
document safety and treatment outcomes for safety monitoring and data analysis. All study data 
will be entered into OnCore® via standardized CRFs in accordance with the CTMS study 
calendar, using single data entry with a secure access account. The Clinical Research 
Coordinator (CRC) will complete the CRFs as soon as possible upon completion of the study 
visit; the Investigator will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
UCSF personnel. All source documentation should be kept in separate research folders for each 
patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 

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The PI will be responsible for ensuring the accurate capture of study data. At study completion, 
when the CRFs have been declared to be complete and accurate, the database will be locked. 
Any changes to the data entered into the CRFs after that time can only be made by joint written 
agreement among the Study Chair, the Trial Statistician, and the Protocol Project Manager. 
Each participating site will complete study specific CRFs for safety monitoring and data 
analysis. Each site will enter the study data into OnCore® via standardized CRFs in accordance 
with the CTMS study calendar, using single data entry with a secure access account. The 
participating site’s CRC will complete the CRFs; the Investigator will review and approve the 
completed CRFs – this process must be completed within 3 business days of the visit. Study 
data from the participating site will be reported and reviewed in aggregate with data from 
patients enrolled at the coordinating center, UCSF. All source documentation and CTMS data 
will be available for review/monitoring as needed.
9.7 Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes: 

Semiannual auditing (depending on trial accrual)

Review of serious adverse events

Minimum of biennial regulatory auditing
For more information regarding the Data Safety and Monitoring Plan, see Appendix 3.
9.8 Multicenter Communication
The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites.  
The following issues will be discussed as appropriate:

Enrollment information. 

Adverse events (i.e., new adverse events and updates on unresolved adverse events 
and new safety information).

Protocol Violations.

Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The data (i.e., copies of source documents) from the 
participating sites will be downloaded into the PC console of OnCore prior to the remote 
monitoring visits in order for the DSMC to monitor the participating site’s compliance with the 
protocol and applicable FDA regulations.
9.9 Record Keeping and Record Retention 
The PI is required to maintain adequate records of the disposition of the drug, including dates, 
quantity, and use by participants, as well as written records of the disposition of the drug when 
the study ends. 

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The PI is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include the 
CRFs and supporting data including, for example, signed and dated consent forms and medical 
records including, for example, progress notes of the physician, the individual's hospital chart(s), 
and the nurses' notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed, or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 
9.10 Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
9.11 Regulatory Documentation
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF IRB. Prior to implementing this protocol at the participating sites, approval for the 
UCSF IRB approved protocol must be obtained from the participating site’s IRB.
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants:

Participating Site IRB approval(s) for the protocol, appendices, informed consent form, 
and HIPAA authorization

Participating Site IRB approved consent form

Participating Site IRB membership list

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number

Curriculum vitae and medical license for each investigator and consenting professional

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
Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site

Participating site laboratory certifications and normals.
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment. For more information on participating site required 
documents, see Appendix 5.
10 Protection of Human Subjects
10.1 Protection from Unnecessary Harm
Each clinical site is responsible for protecting all participants involved in human 
experimentation. This is accomplished through the IRB mechanism and the process of informed 
consent. The IRB reviews all proposed studies involving human experimentation and ensures 
that the participant’s rights and welfare are protected and that the potential benefits and/or the 
importance of the knowledge to be gained outweigh the risks to the individual. The IRB also 
reviews the informed consent document associated with each study in order to ensure that the 
consent document accurately and clearly communicates the nature of the research to be done 
and its associated risks and benefits.
10.2 Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.

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22. Piotrowska, Z., et al., Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type 
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25. Schaake, E.E., et al., Tumor response and toxicity of neoadjuvant erlotinib in patients with 
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27. Sequist, L.V., et al., Phase III study of afatinib or cisplatin plus pemetrexed in patients with 
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28. Zhou, C., et al., Erlotinib versus chemotherapy as first-line treatment for patients with 
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multicentre, open-label, randomised, phase 3 study. Lancet Oncol, 2011. 12(8): p. 735-42. 
29. Marulli, G., et al., Outcomes and prognostic factors of non-small-cell lung cancer with lymph 
node involvement treated with induction treatment and surgical resection. Interact 
Cardiovasc Thorac Surg, 2014. 19(2): p. 256-62; discussion 262. 
30. Rizvi, N.A., et al., Molecular characteristics predict clinical outcomes: prospective trial 
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31. Costa, C., et al., The impact of EGFR T790M mutations and BIM mRNA expression on 
outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the 
randomized phase III EURTAC trial. Clin Cancer Res, 2014. 20(7): p. 2001-10. 
32. Osimertinib Investigator's Brochure. January 2016. Edition 6. 
33. Ramalingam, S., et al., Osimertinb as first-line treatment for EGFR mutation-positive 
advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. 
ESMO abstract LBA 1_PR, 2016. 
34. Soria, J.C., et al., Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung 
Cancer. N Engl J Med, 2017. 
35. Stewart, E.L., et al., Known and putative mechanisms of resistance to EGFR targeted 
therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res, 2015. 
4(1): p. 67-81. 
36. Sharma, S.V., et al., A chromatin-mediated reversible drug-tolerant state in cancer cell 
subpopulations. Cell, 2010. 141(1): p. 69-80. 
37. Goldberg, S.B., et al., A phase I study of erlotinib and hydroxychloroquine in advanced non-
small-cell lung cancer. J Thorac Oncol, 2012. 7(10): p. 1602-8. 
38. Ramalingam, S.S., et al., Randomized phase II study of erlotinib in combination with 
placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for 
advanced-stage non-small-cell lung cancer. J Clin Oncol, 2011. 29(34): p. 4574-80.
39. Lee, H.J., et al., Drug resistance via feedback activation of Stat3 in oncogene-addicted 
cancer cells. Cancer Cell, 2014. 26(2): p. 207-21.
40. DiDonato, J.A., F. Mercurio, and M. Karin, NF-kappaB and the link between inflammation 
and cancer. Immunol Rev, 2012. 246(1): p. 379-400.
41. Lim, S.O., et al., Deubiquitination and Stabilization of PD-L1 by CSN5. Cancer Cell, 2016. 

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30(6): p. 925-939.
42. Blakely, C.M., et al., Evolution and clinical impact of co-occurring genetic alterations in 
advanced-stage EGFR-mutant lung cancers. Nat Genet, 2017.
43. Ho, C.C., et al., Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment 
with Osimertinib. J Thorac Oncol, 2016.
44. Ou, S.H., N. Agarwal, and S.M. Ali, High MET amplification level as a resistance mechanism 
to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment 
post-osimertinib progression. Lung Cancer, 2016. 98: p. 59-61.
45. Mok, T.S., et al., Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung 
Cancer. N Engl J Med, 2016.
46. Lin, L., et al., The Hippo effector YAP promotes resistance to RAF- and MEK-targeted 
cancer therapies. Nat Genet, 2015.
47. Subramanian, A., et al., Gene set enrichment analysis: a knowledge-based approach for 
interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 2005. 102(43): p. 
15545-50.
48. Blakely, C.M., et al., Hormone-induced protection against mammary tumorigenesis is 
conserved in multiple rat strains and identifies a core gene expression signature induced by 
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49. Broz, M.L., et al., Dissecting the tumor myeloid compartment reveals rare activating antigen-
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50. DeNardo, D.G., et al., CD4(+) T cells regulate pulmonary metastasis of mammary 
carcinomas by enhancing protumor properties of macrophages. Cancer Cell, 2009. 16(2): p. 
91-102.
51. Osimertinib Investigator's Brochure. October 2016. Edition 7.
52. D'Cunha, J., et al., Poor correspondence between clinical and pathologic staging in stage 1 
non-small cell lung cancer: results from CALGB 9761, a prospective trial. Lung Cancer, 
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53. Kelly, K., et al., Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell 
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33(34): p. 4007-14.

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Appendix 1 Schedule of Study Procedures and Assessments
Period/Procedure
Pre-
screening1
Screening
Cycle 1
Cycle 24
Day of 
Surgery
D15 Post-
op 
Lab Draw
End of 
Treatment
Long Term 
Follow Up
Study Day/Visit Day1
Within 60 
days of D1
-30 to 0
1
15
283
1
15
28
15D post-op
30D after 
D15 post-op
Every 3/6 
mo
after EOT
Informed consent
X
EGFR mutation testing 
(if status unknown)
X
X5
Baseline conditions 2
X
Contraceptive counseling
X
AE assessment
X
X
X
X
X
X
X12
Concomitant medications
X
X
X
X
X
X
X
X
Tumor tissue for correlative 
studies5
X
X13
X13
X
Survival status and other 
therapies
X17
Treatment/Drug Administration
Osimertinib Dispensing
X
X14
X
X
Clinical procedures
Physical exam
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Medical history
X
X
X
X
X
X
X
X
Disease assessment
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
Biopsy or archived tissue 
procurement
X5
X13
X13
Laboratory procedures
CBC w/ Diff6
X
X
X
X
X
X
X
X
X
Blood Chemistry7
X
X
X
X
X
X
X
X
X
Coagulation8
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X19
X
X
Pregnancy test (HCG)9
X
X
X19
X
X
Blood for ctDNA and PBMCs
X
X
X
X
X
X
X
X
X
Imaging procedures
Imaging (CT) C/A/P
X10
X
X
X
X18

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Period/Procedure
Pre-
screening1
Screening
Cycle 1
Cycle 24
Day of 
Surgery
D15 Post-
op 
Lab Draw
End of 
Treatment
Long Term 
Follow Up
Study Day/Visit Day1
Within 60 
days of D1
-30 to 0
1
15
283
1
15
28
15D post-op
30D after 
D15 post-op
Every 3/6 
mo
after EOT
PET-CT
X16
MRI Brain
X16
ECG/EKG
X
X
X
X
X
X
X
MUGA or TTE
X
X15
X15
X
1 Window for each study visit is +/- 3 days. Screening procedures allowed within 30 days prior to day 1.
2 Baseline conditions assessment per DSMC policy (Baseline Conditions VI Form)
3 C1D28 visit only for patients not receiving second cycle of osimertinib
4 Optional second cycle as per investigator discretion. Those receiving second cycle osimertinib do not attend the C1D28 visit
5 Screening biopsy within 30 days prior to C1D1. Tissue from screening biopsy and surgical resection will be used for correlative studies (see Section 1.4). If there 
is not enough tissue for pre-screening EGFR mutation testing, tissue from this biopsy will also be collected for EGFR mutation testing. This biopsy can be deferred 
if the procedure is deemed to represent an unacceptable safety risk to the patient by the principal investigator.
6 Including CBC with differential and platelet count
7 Including ALP, ALT/AST total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting or non-fasting glucose, potassium, sodium, chloride, 
bicarbonate. Magnesium required at screening only.
8 Including PT/PTT/INR
9 In women of child-bearing potential. At screening to be done within 3 days of C1D1.
10 Imaging within 28 days prior to C1D1. If CT contraindicated, MRI acceptable
11 If not be receiving second cycle of osimertinib
12 Including documentation of AEs leading to inability to proceed with surgical resection and of surgical complications
13Optional research biopsy for patients who will be unable to undergo surgical resection, within 30 days of C1D28 or C2D28
14Dispensing of up to 14 days’ supply osimertinib for treatment until pre-surgical washout period if will be proceeding to resection after first cycle of osimertinib.
15 TTE is only required if the patient is proceeding to surgical resection following first cycle of osimertinib therapy. For patients receiving the second of cycle of 
osimertinib, TTE is optional except for patients with pre-existing risk factors as clinically indicated. .
16PET-CT and brain MRI (standard of care procedures) must be done within 60 days of C1D1 as part of inclusion criteria (see Section 3.3.1)
17 During the first year after the EOT visit, assessment of survival status and subsequent care for NSCLC will occur every 3 months. From the first year following 
EOT visit up to the 5 years post-surgery, assessment of survival status and subsequent therapies will occur every 6 months via telephone or routine clinic visits.
18 LTFU imaging will be performed every 6 months as standard of care. LTFU may be performed with greater frequency per the investigator’s discretion or local 
institutional requirements
19 Urinalysis and pregnancy test are optional at C1D28 or as clinically indicated. 

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Appendix 2 Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance without 
restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease 
80
Normal activity with effort; some 
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)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
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
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed >50% of the time
Capable of only limited self- care, 
confined to bed or chair more than 
50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden 
Completely disabled
Cannot carry on any self-care 
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 3 Data and Safety Monitoring Plan for a Multicenter Study 
Phase II or III Trial
Data and Safety Monitoring Plan for a Multicenter Study Phase II or III Trial
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes: 

Semiannual auditing (depending on accrual).

Review of serious adverse events.

Minimum of a biennial regulatory auditing visit.
Monitoring and Reporting Guidelines
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the trial and for auditing its safety and 
progress at all participating sites.  The Study Chair will conduct continuous review of data and 
participant safety at monthly UCSF Site Committee meetings.  The discussions are documented 
in the UCSF Site Committee meeting minutes.  
All institutional Phase II or III therapeutic trials are designated with a moderate risk assessment. 
The data is audited by a DSMC Monitor/Auditor on a semiannual basis with a random selection 
of twenty percent of the participants (or at least three participants if the calculated value is less 
than three).   The DSMC Monitor/Auditor will audit a maximum of 5 cycles of treatment in the 
participants selected for review or until the selected participants discontinue study participation 
or the trial is closed with the IRB.  Additionally, the assigned DSMC Monitor/Auditor will review 
no more than 10 total participant charts during the course of auditing this trial.  DSMC 
Monitor/Auditors will send a follow-up report to the study team within 20 business days after the 
monitoring visit is complete for the PI and the study team to resolve all action items from this 
report within 20 business days.  An abbreviated regulatory review (i.e., reviewing protocol and 
consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) will occur at each participant 
monitoring review; however, a full regulatory review will occur on a biennially basis by the 
DSMC for regulatory compliance.
The participating site’s source documents are audited remotely via either review of redacted 
source documents downloaded by the site into the CRA console of OnCore and/or via access to 
the site’s electronic medical records.  The DSMC Monitor/Auditor will audit no more than three 
participant charts at each participating site during the course of auditing this trial.
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.  

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Multicenter communication
The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites.  
The following issues will be discussed as appropriate:

Enrollment information. 

Adverse events (i.e., new adverse events and updates on unresolved adverse events 
and new safety information).

Protocol Violations.

Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The data (i.e., copies of source documents) from the 
participating sites will be downloaded into the PC console of OnCore prior to the remote 
monitoring visits in order for the DSMC to monitor the participating site’s compliance with the 
protocol and applicable FDA regulations.
Review and Oversight Requirements
Adverse Event Monitoring 
All Grade 3-5 adverse events (AEs), regardless of being unexpected or considered to be 
associated with the use of the study drug will be entered into OnCore®, UCSF’s Clinical 
Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation 
Program (CTEP) of the National Cancer Institute.  Adverse events are further given an 
assignment of attribution or relationship to the investigational agent(s) or study 
procedure.  Attribution categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or 
study procedure.

Probable – The adverse event is likely related to the investigational agent(s) or 
study procedure.

Possible – The adverse event may be related to the investigational agent(s) or 
study procedure.

Unrelated – the adverse event is clearly not related to the investigational agent(s) 
or study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the UCSF Site Committee meetings.  All adverse events entered into OnCore® will be 
reviewed on a monthly basis at the UCSF Coordinating Center Site Committee 
meetings.  All grade 3-5 adverse events must be reported to the UCSF Coordinating 
Center by the participating sites within 10 business days of becoming aware of the event 

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or during the next scheduled monthly conference call, whichever is sooner.  The UCSF 
Site Committee will review and discuss the selected toxicity, the toxicity grade, and 
attribution assignment from the UCSF Coordinating Center and the participating sites. 
Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria:

Death.

Life-threatening (i.e., results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Permanent or significant disability/incapacity.

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience 
that suggests a significant hazard, contraindication, side effect, or precaution 
that may require medical or surgical intervention to prevent one of the 
outcomes listed above.

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.  
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All Serious adverse events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be 
reported to the UCSF Coordinating Center within one business days of becoming aware 
of the event.  The SAEs are reviewed and audited by the UCSF Data and Safety 
Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which 
take place every six weeks.  The date the SAE was sent to all required reporting 
agencies will be documented in OnCore®. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or 
definitely related either to the investigational drug or any research related procedure, the 
Study Chair at the UCSF Coordinating Center or the assigned designee must be notified 
within 1 business day from the participating site(s) and the Study Chair must then notify 
the DSMC Chair or Vice Chair and the DSMC Director within 1 business day of this 
notification.  

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Appendix 4 UCSF Policy/Procedure for Required Regulatory 
Documents for UCSF Multicenter Investigator-Initiated Oncology 
Clinical Trials with an Investigator held IND
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator 
Initiated Oncology Clinical Trials at the HDFCCC where the PI holds the IND. 
Background 
The ICH-GCP Guidelines define Essential Regulatory Documents as those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of data 
produced. These documents serve to demonstrate compliance with standards of GCP and with 
all applicable regulatory requirements. Filing essential documents in a timely manner can greatly 
assist in the successful management of a clinical trial. 
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as 
paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) 
in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
Procedures 
1.
HDFCCC Essential Regulatory Documents 
Documents Filed in iRIS: 

IRB approvals for initial submission of application, all modifications, and continuing annual 
renewals 

Current and prior approved protocol versions with signed protocol signature page(s) 

IRB approval letters and ICF(s) 

Current and prior versions of the Investigator Brochure (IB). 

SAE Reporting 

Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting fax 
documentation 
Documents Filed in OnCore®: 

Package Insert (if the study drug is commercial) or Investigator Brochure 

PRC-approved protocols, protocol amendments and Summary of Changes (SOC) 

Patient handouts 

Screening/enrollment log 

DSMC monitoring reports 

OnCore® CRF completion manual 
Documents Filed in Regulatory Binder: 

Completed FDA 1572 document with PI’s signature 

For all PIs and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure 
Forms, CVs, MD Licenses, Drug Enforcement Agency Licenses, and Staff Training 
Documents (i.e., Collaborative Institute Training Initiative (CITI), etc.) 

Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center 

SAE reports to IRB and sponsor. 

MedWatch reporting to FDA and sponsor 

Delegation of Authority Form 

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
Drug Destruction SOP 

For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
2.
Additional Essential Documents for Multicenter Trials for the Coordinating Center (filed 
in Regulatory Binder or OnCore) 

IRB approval letters, IRB roster, ICF, and HIPAA Consent Form for the Participating 
Site(s) 

For all PIs and Sub-Investigators listed on the 1572 at the Participating Site(s) – Financial 
Disclosure Forms, CVs, MD Licenses, and Staff Training documents (i.e. CITI, etc.) (for 
IND Application) 

SIV minutes and correspondence with Participating Site(s). 

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s) 

Protocol Violations and SPE reports to IRB with supporting fax documentation for 
Participating Site(s) 

Drug Destruction SOP for the Participating Site(s) 

DSMC monitoring reports for the Participating Site(s) 

For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, 
lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating 
Site(s) 

Copy of the DSMP Monitoring Plan for all participating site(s) in Multicenter studies or 
Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the 
study) 

SAE forms submitted to both the IRB and the sponsor for the Participating Site(s) 
27 April 2012

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Appendix 5 Required Regulatory Documents for Sub-sites 
Participating in a UCSF Investigator Initiated Multicenter Trial 
(Checklist)
Directions: 
1) Fax the documents listed below to the UCSF Coordinating center at 415-514-6995 or 
2) Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found 
1572 
PI and Sub investigators: 
CV and Medical license 
Financial disclosure form 
NIH or CITI human subject protection training certification 
Laboratories 
CLIA and CAP 
CV of Lab Director and Lab Licenses 
Laboratory reference ranges 
Local IRB 
IRB Approval letter 
Reviewed/Approved documents 

Protocol version date: __________

Informed consent version date: __________

Investigator Brochure version date: __________

HIPAA 
Current IRB Roster 
Other 
Delegation of Authority Log 

Include NIH or CITI human subject protection training certificates or GCP training 
certification 
Pharmacy 

Drug destruction SOP and Policy 
Protocol signature page 
Executed sub contract 

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Appendix 6 Prohibited Medications
Drug
Trade name (if applicable)
Aclarubicin 
Aliskiren 
Amiodarone 
Anagrelide 
Arsenic trioxide 
Astemizole 
Azithromycin bepridil 
Carbamazepine 
Chloroquine 
Chlorpromazine 
Cilostazol 
Ciprofloxacin
Cisapride 
Citalopram 
Clarithromycin
Cocaine
Dabigatran
Daunorubicin 
Digoxin 
Disopyramide 
Norpace 
Dofetilide 
Tikosyn 
Domperidone 
Dronedarone 
Donepezil 
Droperidol 
Doxorubicin 
Erythromycin 
Escitalopram
Flecainide 
Fluconazole 
Flecainide 
Gatifloxacin 

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Grepafloxacin 
Halofantrine 
Haloperidol 
Ibogaine 
Ibutilide 
Corvert 
Levofloxacin
Levomepromazine 
Levomethadyl
Orlaam 
Levosulpiride 
Mesoridazine 
Methadone 
Moxifloxacin 
Ondansetron 
Oxaliplatin 
Papaverine hydrochloride
Pentamidine 
Phenobarbital 
Phenobarbitone 
Phenytoin 
Dilantin 
Pimozide 
Probucol 
Procainamide 
Propofol 
Quinidine 
Rifabutin 
Rifampicin 
Rifapentin 
Rosuvastatin 
Roxithromycin 
Sevoflurane
Sotalol 
Sparfloxacin 
St John’s Wort 
Sulfasalazine 
Sulpiride
Sultopride 
Terfenadine 

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Terlipressin 
Terodiline 
Thioridazine 
Mellaril 
Topotecan 
Vandetanib 

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Appendix 7 Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries. Specific guidance on the managing of liver abnormalities can be found in 
Section 5.3.1 of the protocol. 
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 participates, together with Sponsor clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. HL 
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). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal 
(ULN) together with total bilirubin (TBL) ≥ 2xULN at any point during the study following the start 
of study medication irrespective of an increase in Alkaline Phosphatase (ALP). 
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the IMP, 
can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug. 
For PHL and HL, 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. 
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, the investigator will: 
Determine whether the patient meets PHL criteria (see Definitions within this Appendix for 
definition) by reviewing laboratory reports from all previous visits 

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Promptly enter the laboratory data into the laboratory CRF 
Follow-up 
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. 
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 
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 CRF Modules as information becomes available 
If at any time the PHL case meets serious criteria, report it as an SAE using standard reporting 
procedures 
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. 
No later than 3 weeks after the biochemistry abnormality was initially detected, Investigator 
reviews available data and agrees on whether there is an alternative explanation for meeting PHL 
criteria other than DILI caused by the IMP. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed 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 
CRF 

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 

If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 

Report an SAE (report term ‘Hy’s Law’) according to standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
As there is no alternative explanation for the HL case, a causality assessment of ‘related’ should 
be assigned. 
If there is an unavoidable delay of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 

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
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review, amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment 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 found 
to be the disease under study (e.g. chronic or progressing malignant disease, severe 
infection or liver disease), or did the patient meet PHL criteria prior to starting study 
treatment and at their first on study treatment visit.
If No: follow the process described in Potential Hy’s Law Criteria met 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 above in this Appendix
A ‘significant’ change in the patient’s condition refers to a 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. The determination of whether there has 
been a significant change will be at the discretion of the Investigator.