Gene Profile in EGFRm Locally Advanced or Metastatic NSCLC Patients Post Osimertinib 1L Treatment Failure: A Real-world, Multi-center Study (GPS)
Phase: PHASE4
Conditions: Advanced NSCLC
Sponsor: AstraZeneca

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 1 of 75 
 
 
Clinical Study Protocol  
Study Intervention 
No Drug 
Study Code 
<<D5161R00037>> 
Version 
2.0 
Date 
20-01-2023 
Gene Profile in EGFRm Locally Advanced or Metastatic NSCLC 
patients post Osimertinib 1L treatment failure: A real-world, multi-
center Study (GPS) 
Sponsor Name: China AstraZeneca Marketing Company 
Legal Registered Address: AstraZeneca, No.199, Liangjing Rd, Shanghai, 201203, China 
Regulatory Agency Identifier Number(s) Not Applicable 
 
This CSP has been subject to a peer review according to AstraZeneca Standard procedures. The 
CSP is publicly registered and the results are disclosed and/or published according to the 
AstraZeneca Global Policy on Bioethics and in compliance with prevailing laws and regulations. 
Protocol Number: D5161R00037 
Amendment Number: 1 
Study Intervention: No Drug 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 2 of 75 
Study Phase: Phase 4 
Short Title: Gene profile post Osimertinib 1L failure 
Acronym: GPS 
Medical Monitor Name and Contact Information will be provided separately 
Principal investigator: 
 
 
 
PPD

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 3 of 75 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
Document 
Date of Issue 
Original Protocol 
[25-Feb-2021] 
Protocol 2.0 
[20-Jan-2023] 
 
 
 
 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 4 of 75 
TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................ 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS ...................................................................................................... 4 
LIST OF FIGURES .............................................................................................................. 5 
LIST OF TABLES ................................................................................................................ 5 
1 
PROTOCOL SUMMARY .................................................................................. 7 
1.1 
Synopsis ............................................................................................................. 7 
1.2 
Schema ............................................................................................................. 13 
1.3 
Schedule of Activities ....................................................................................... 14 
2 
INTRODUCTION ............................................................................................ 17 
2.1 
Study Rationale ................................................................................................ 17 
2.2 
Background ...................................................................................................... 18 
2.3 
Benefit/Risk Assessment ................................................................................... 19 
2.3.1 
Risk Assessment ............................................................................................... 19 
2.3.2 
Benefit Assessment ........................................................................................... 20 
2.3.3 
Overall Benefit: Risk Conclusion ...................................................................... 20 
3 
OBJECTIVES AND ENDPOINTS ................................................................... 21 
4 
STUDY DESIGN ............................................................................................. 23 
4.1 
Overall Design .................................................................................................. 23 
4.2 
Scientific Rationale for Study Design ............................................................... 23 
4.2.1 
Rationale for primary and secondary endpoint .................................................. 23 
4.2.2 
Testing for common EGFR mutations ............................................................... 24 
4.3 
End of Study Definition .................................................................................... 24 
5 
STUDY POPULATION .................................................................................... 24 
5.1 
Inclusion Criteria .............................................................................................. 25 
5.2 
Exclusion Criteria ............................................................................................. 26 
5.3 
Lifestyle Considerations ................................................................................... 27 
5.4 
Screen Failures ................................................................................................. 27 
5.5 
Procedures for handling incorrectly enrolled patients ........................................ 27 
6 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .................................. 28 
6.1 
Participant Withdrawal from the Study.............................................................. 28 
6.2 
Lost to Follow-up ............................................................................................. 28 
7 
STUDY ASSESSMENTS AND PROCEDURES .............................................. 29 
7.1 
Enrolment/screening period .............................................................................. 29 
7.2 
General Assessments ......................................................................................... 30 
7.2.1 
Physical Examinations ...................................................................................... 30 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 5 of 75 
7.2.2 
WHO/ECOG Performance Status ..................................................................... 30 
7.3 
Biomarker research ........................................................................................... 30 
7.3.1 
Collection of Samples for Gene Profile Analysis ............................................... 31 
7.3.2 
Other Study Related Biomarker Assessments .................................................... 31 
7.3.3 
Storage and destruction of samples ................................................................... 32 
8 
STATISTICAL CONSIDERATIONS ................................................................ 32 
8.1 
Sample Size Determination ............................................................................... 32 
8.2 
Populations for Analyses ................................................................................... 33 
8.3 
Statistical Analyses ........................................................................................... 33 
8.3.1 
General Considerations ..................................................................................... 34 
8.3.2 
Genetic sample analysis .................................................................................... 34 
8.3.2.1 
Primary Endpoint .............................................................................................. 34 
8.3.2.2 
Secondary Endpoints ........................................................................................ 34 
8.4 
Data Analyses ................................................................................................... 36 
9 
DEFINITIONS AND REPORTING OF ADVERSE EVENTS .......................... 36 
9.1 
Definition of Adverse Event .............................................................................. 36 
9.2 
Definition of Serious Adverse Event ................................................................. 37 
9.3 
Definition of Adverse Drug Reaction (ADR) .................................................... 39 
9.4 
Reporting of Adverse Events ............................................................................. 39 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ........................................................................................ 39 
11 
REFERENCES ................................................................................................. 74 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................... 13 
LIST OF TABLES 
Table 1 
Schedule of Activities .............................................................................. 15 
Table 2 
Objectives and Endpoints......................................................................... 21 
Table 3 
Populations for Analysis .......................................................................... 33 
Table 4 
Summary of Imaging Modalities for Tumour Assessment ........................ 50 
Table 5 
RECIST 1.1 Evaluation of Target Lesions ............................................... 57 
Table 6 
RECIST 1.1 Evaluation of Non-Target Lesions ....................................... 58 
Table 7 
RECIST 1.1 Overall Visit Response ........................................................ 58 
Table 8 
Highly Effective Methods of Contraception (<1% Failure Rate) .............. 62 
Table 9                Validation information of tumor tissue sample detection .......................... 63 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 6 of 75 
Table 10              Validation information of plasma sample detection .................................. 64 
Table 11              Panel list of NGS ..................................................................................... 64 
Table 12             Validation information of tumor tissue sample detected by FISH…………69 
Table 13              Validation information of plasma sample detected by ddPCR…………….69 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ......................... 40 
Appendix B 
Handling of Human Biological Samples .................................................. 45 
Appendix C 
Genetic Sample ........................................................................................ 47 
Appendix D 
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumors) ...... 50 
Appendix E 
Contraception Requirements .................................................................... 60 
Appendix F 
NGS technology and sample requirements ............................................... 63 
Appendix G 
Abbreviations .......................................................................................... 71 
Appendix H 
Performance of droplet digital PCR (ddPCR) for MET amplification 
testing ...................................................................................................... 71 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 7 of 75 
1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: Gene profile in EGFRm locally advanced or metastatic NSCLC patients post 
Osimertinib 1L treatment failure: A real-world, multi-center study (GPS) 
Short Title: Gene profile post Osimertinib 1L failure 
Rationale: 
Osimertinib is a potent, oral, irreversible tyrosine kinase inhibitor (TKI) of EGFR mutation 
(EGFRm)-positive and T790M mutation-positive forms of EGFR with demonstrated clinical 
activity on central nervous system (CNS) metastases. Osimertinib is designed to have limited 
activity against wild-type (WT) EGFR. Osimertinib is approved globally, and marketed as 
Tagrisso®, for the first-line treatment of patients with locally advanced or metastatic NSCLC 
whose tumours have EGFR exon 19 deletions (ex19del) or exon 21 (L858R) substitution 
mutations and the treatment of patients with locally advanced or metastatic EGFR T790M 
mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy. It has 
been approved as first-line treatment for advanced EGFR mutated NSCLC in China, and has 
also been widely used in clinical practice no matter in the first-line or in the later-line.  
While similar to 1/2 G EGFR-TKI, acquired resistance to Osimertinib invariably often develops 
with a median PFS of 19 months[1]. The characterization of the landscape of resistance enables 
the development of subsequent therapies, but mechanisms of resistance to Osimertinib is 
primarily derived from patients who received Osimertinib after other EGFR-TKIs, such as 
EGFR C797, EGFR G724, EGFR L792, MET amplification, and so on[2-5]. Prior reports of 
acquired resistance mechanisms to Osimertinib primarily focus on patients who received 
Osimertinib as the second-line treatment. However, the mechanisms of resistance to Osimertinib 
in the first-line treatment are far from being clearly explored. As Osimertinib in the first-line 
treatment is applied more and more widely in advanced EGFRm+ NSCLC patients, we urgently 
need to know the resistance mechanisms to guide subsequent treatment strategy. Until now, the 
largest study to explore acquired resistance mechanism to 1L Osimertinib was FLAURA study, 
which detected 91 paired plasma samples by next generation sequencing (NGS) . The most 
common acquired resistance mechanisms were MET amplification (15%) and EGFR C797X 
mutation (7%)[6]. The result was quite different from the study conducted by Adam J. 
Schoenfeld et al using tissue (N=27), with squamous transformation accounting for 15% and 
MET amplification 7%[7]. The reason for different results maybe because these two studies 
used different samples to analyse resistance mechanisms, and the above two detection methods 
may have different sensitivity and specificity. In addition, Schoenfeld et al study was limited to 
patients at one site, Memorial Sloan Kettering Cancer Center in NY, USA. 
Although some small sample studies have reported the possible resistance mechanisms of 
Osimertinib in the first-line treatment, it is still an urgent need to explore the whole gene profile 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 11 of 75 
NSCLC, harboring common EGFRm of ex19del/L858R and having evidence of disease 
progression following 1L Osimertinib. 
Number of Participants: 
Approximately 200 participants in EGFRm locally advanced or metastatic NSCLC with the 
evidence of disease progression following 1L Osimertinib will be enrolled and 15 sites will be 
involved to elucidate the gene profile in paired tissue and plasma so that approximately 180 
participants whom would be get gene profile, assuming a 10% drop-out.  
Note: "Enrolled" means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but are 
not randomly assigned/assigned in the study, are considered “screen failures”, unless otherwise 
specified by the protocol.  
Human Biological Sample Analysis: 
Participants will be required to provide paired tissue and whole blood after disease progression 
following 1L Osimertinib. 200 tissue samples and 200 whole blood samples will be used to 
detect gene alteration by NGS, respectively. 200 tissue samples will be used to detect 
pathological transformation by IHC. Approximately 80-100 tissue samples will be used to test 
MET overexpression by MET IHC and MET amplification by FISH respectively. 
Approximately 80-100 whole blood samples will be used to test MET amplification by ddPCR.  
 
Statistical methods 
General Aspects 
A Statistical Analysis Plan (SAP) will be prepared and finalised prior to database lock. All 
statistical analyses will be completed using SAS version 9.4 or later. Descriptive statistics will 
be provided for all variables, as appropriate. Continuous variables will be summarized by the 
number of observations, mean, standard deviation, median, interquartile range (Q1, Q3), 
minimum, and maximum. Categorical variables will be summarized by frequency counts and 
percentages for each category. The 95% confidence interval (CI) will be calculated as 
appropriate.  
The primary, secondary 
 will be based on Full analysis set (FAS), 
which will include all patients who meet the required inclusion/exclusion criteria and have valid 
gene data from both plasma and tissue. FAS will be used for the analyses of all data collected. 
The Data Cut-off (DCO) date of the primary endpoint, gene profile in tissue, will be when all 
participants have completed their gene testing in tissue and whole blood and got their testing 
CCI

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 12 of 75 
results. The Data Cut-off (DCO) date is excepted to be approximately 12 weeks after LSI. The 
primary objective is to describe the gene profile in EGFRm advanced NSCLC patients after 
progression on 1L Osimertinib treatment. Gene profile in tissue will be analyzed by NGS 
method. All gene alterations in tissue(e.g., gene mutation, amplification, deletion, fusion, etc.) 
detected by NGS will be observed. Proportion of Gene X alteration(%) = (number of patients 
with Gene X, which is an example of a certain gene)/(total number of patients in the FAS)×100%. 
Some cases which patients have more than one gene alteration need to be considered.  
The secondary objective is to assess gene profile in plasma, concordance of plasma and tissue 
and the percentage of pathology transformation will be analysed by NGS method and IHC 
respectively. All gene alterations in plasma(e.g., gene mutation, amplification, deletion, fusion, 
etc.) detected will be observed. Proportion of Gene X alteration(%) = (number of patients with 
Gene X, which is an example of a certain gene)/(total number of patients in the FAS)×100%. 
Some cases which patients have more than one gene alteration need to be considered. Using 
selected representative genes (for example EGFR, MET, PIK3CA and etc.) to measure the 
concordance. Concordance of Gene X in plasma and tissue is defined as sensitivity, specificity, 
positive predictive value (PPV) and negative predictive value (NPV) between plasma and tissue 
results. Tissue sample is the reference standard. Sensitivity=(number of patients with positive 
result in both plasma and tissue)/(total number of patients with positive result in tissue 
samples)×100%; Specificity=(number of patients with negative result in both plasma and 
tissue)/(total number of patients with negative result in tissue samples)×100%. PPV 
(%)=(number of patients with positive result in both plasma and tissue)/(total number of patients 
with positive result in plasma samples)×100%; NPV (%)=(number of patients with negative 
result in both plasma and tissue)/(total number of patients with negative result in plasma 
samples)×100%. 
Pathology transformation defines as pathological type of lung cancer change, which will be 
confirmed by pathologists. Number and percentage of patients with pathology transformation 
will be summarized. Proportion of pathology transformation(%) = (number of patients with 
pathology transformation)/(total number of patients in the FAS)×100%. 
Two analyses are planned. The first interim analysis data cut-off (DCO) point will happen when 
100 patients have completed their gene testing in tissue and whole blood and got their testing 
results(50% maturity). The final analysis is planned for when the last patient has completed 
their gene testing in tissue and whole blood and got their testing results. 
 
 
 
 
 
CCI

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 13 of 75 
 
 
  
 
  
 
 
     
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
   
1.2 
Schema 
Figure 1 
Study Design 
 
CCI

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 15 of 75 
Table 1 
Schedule of Activities 
Procedure 
Screening 
and 
Data Collection 
 
Notes 
Details in CSP Section or Appendix 
Visit 
1 
 
 
 
Informed consent a 
X 
 
 
Sections 5.1 
Inclusion and exclusion criteria 
X 
 
 
Section 5.1 and 5.2 
Diagnostic clinical procedures 
Histology 
X 
 
 
 
Clinical stage with lymph node and distant 
metastasis at diagnosis and post 1L 
Osimertinib 
X 
 
 
 
Record documented 
common 
EGFR 
mutation 
results 
by 
an 
accredited 
laboratory through ARMS, Super-ARMS, 
and NGS testing b 
X 
 
 
 
Routine clinical procedures 
Demography and smoking history c 
X 
 
 
Section 7.2.1 
Physical examination and weight(Kgs) 
X 
 
 
Section 7.2.1 
Height(CMs) 
X 
 
 
Section 7.2.1 
Medical history and comorbid conditions d 
X 
 
 
Sections 5.1 and 5.2  
WHO/ECOG performance status post 
Osimertinib 1L treatment 
X 
 
 
Section 7.2.2 
Osimertinib Efficacy measurements 
Duration of 1L Osimertinib treatment e 
X 
 
 
 
Best response of 1L Osimertinib 
X 
 
 
 
Progression pattern post 1L Osimertinib 
X 
 
 
 
Genetic analysis 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 16 of 75 
Procedure 
Screening 
and 
Data Collection 
 
Notes 
Details in CSP Section or Appendix 
Mandatory screening tumour tissue sample 
(archived or newly acquired biopsy) for 
Central NGS testing and central MET 
FISH testing; local IHC testing (included 
MET overexpression by MET IHC and 
SCLC pathology transformation by IHC) 
X 
 
 
Section 7.3.1 
Mandatory screening blood sample (newly 
acquired; 2*10ml) for Central NGS testing 
and central ddPCR MET amplification 
testing 
X 
 
 
Section 7.3.1and Appendix C 
a 
Written informed consent and any locally required privacy act document authorisation must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations. 
b 
Participants are eligible to be considered for inclusion on the basis of local pre-existing EGFR tumour tissue or plasma testing results by molecular testing. 
c 
Include date of birth or age, gender, race, and ethnicity for all participants. 
d 
Include any treatment history before enrolling the study, complication and related history(chronic diseases which require treatment currently) 
e 
Include the start and end dates of 1L Osimertinib treatment; starting dose,  
Note: Data collection following study analysis until the end of the study is described in Section 7. 
Note: The screening visit will confirm that the patients will be receiving a biopsy (scheduled for after enrolment), but they will not actually receive a biopsy at the screening visit. 
CSP=Clinical Study Protocol; ECOG=Eastern Cooperative Oncology Group; ICF=informed consent form; WHO=World Health Organisation 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 17 of 75 
2 
INTRODUCTION 
According to the GLOBOCAN estimates of cancer incidence and mortality, lung cancer has 
become the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause 
of cancer death (18.4% of the total cancer deaths) worldwide[13]. Non-small cell lung cancer 
(NSCLC) represents approximately 80%-85% of all lung cancers. At the time of diagnosis, 
about 70% of NSCLC patients have locally advanced or metastatic disease who are not 
amenable to surgical resection. The 5-year overall survival rate for NSCLC patients with stage 
IV remains poor[14]. 
Fortunately, owing to the discovery of Epidermal Growth Factor Receptor (EGFR) pathway and 
the development of EGFR-targeted tyrosine kinase (TKI), the prognosis of advanced EGFR 
sensitive mutated (EGFRm+) NSCLC patients has improved significantly. The oncogenic 
EGFR mutation is present in 40-55% and 5-15% of lung adenocarcinoma cases in East Asia and 
in USA/European respectively[15]. The benefit of these EGFR-TKIs in EGFRm+ patients was 
initially demonstrated in the second-line and maintenance settings and subsequently confirmed 
in the first-line setting. As a result, the first- and second-generation EGFR-TKIs have been 
widely used in EGFRm+ NSCLC patients and brought improved ORR and PFS, but the benefit 
of overall survival is limited[16-18].  Based on the statistically significant improved PFS (18.9 
months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence 
interval [CI], 0.37 to 0.57; P<0.001) and OS (38.6 months vs. 31.8 months; hazard ratio for 
death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046) from FLAURA study, the third-generation 
EGFR-TKI Osimertinib has been become the new standard of care for advanced EGFR mutated 
NSCLC patients and has recommended as the preferred first-line treatment by NCCN 
guideline[1]. In China, Osimertinib has been approved as a first-line treatment for EGFR 
mutated advanced NSCLC in Aug 2019.  
2.1 
Study Rationale 
The third-generation EGFR-TKI Osimertinib has been approved as first-line treatment for 
advanced EGFR mutated NSCLC in China, and has also been widely used in clinical practice 
no matter in the first-line or in the later-line. Prior reports of acquired resistance mechanisms to 
Osimertinib primarily focus on patients who received Osimertinib as the second-line treatment. 
Although some small sample studies have reported the possible resistance mechanisms of 
Osimertinib in the first-line treatment, it is still an urgent need to explore the whole gene profile 
in EGFRm advanced NSCLC patients post Osimertinib 1L treatment failure by paired tissue 
and plasma after disease progression following 1L Osimertinib to guide subsequent treatment 
strategy[6, 7]. 
MET overexpression is key resistance mechanism after 1L Osimertinib failure[8]. 
SAVANNAH observed improved outcomes in post 1L Osimertinib resistant EGFRm NSCLC 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 18 of 75 
patients with MET IHC90+(≥90% tumour cells MET IHC3+) and/or FISH10+(MET copy 
number ≥10); the estimated prevalence of IHC90+ is 29% in SAVANNAH study published on 
2022 WCLC [9]. MET amplification is also a key resistance mechanism after 1L Osimertinib 
failure[8].FISH is golden standard testing method for MET amplification. The prevalence of 
FISH 5+(MET copy number ≥5 and/or MET/CEP7≥2) in INSIGHT 2 study [10] is 33%  and 
the prevalence of FISH10+ in SAVANNAH study is 20% [9]. The prevalence data of MET 
amplification by FISH testing and MET overexpression by IHC testing in Chinese advanced 
EGFRm NSCLC patients who had disease progression following 1L osimertinib are very 
limited and still need further explore. 
Tissue were unavailable for some patients post 1L Osimertinib and blood samples show high 
potential as an alternative sample [11]. ddPCR is as an alternative technique with high 
sensitivity and specificity for MET amplification testing and it has been explored in previous 
study[12]. Besides, ddPCR blood assay for MET amplification testing still need  be further 
validated through concordance of MET amplification between FISH testing in tissue and ddPCR 
testing in plasma.  
This real-world, multi-center study will elucidate the gene profile post Osimertinib 1L treatment 
in tissue and plasma and will also help to guide the following treatment. 
2.2 
Background 
While similar to 1/2 G EGFR-TKI, acquired resistance to Osimertinib invariably often develops 
with a median PFS of 19 months[1]. The characterization of the landscape of resistance enables 
the development of subsequent therapies, but mechanisms of resistance to Osimertinib is 
primarily derived from patients who received Osimertinib after other EGFR-TKIs, such as 
EGFR C797, EGFR G724, EGFR L792, MET amplification, and so on[2-5]. Besides, MET 
overexpression is also a key resistance mechanism after 1L Osimertinib failure[8]and the 
prevalence data of MET amplification by FISH testing (gold standard testing method for MET 
amplification) and MET overexpression by MET IHC testing in Chinese advanced EGFRm 
NSCLC patients who had disease progression following 1L osimertinib are very limited. The 
mechanisms of resistance to Osimertinib in the first-line treatment are far from being clearly 
explored. As Osimertinib in the first-line treatment is applied more and more widely in advanced 
EGFRm+ NSCLC patients, we urgently need to know the resistance mechanisms to guide 
subsequent treatment strategy. Until now, the largest study to explore acquired resistance 
mechanism to 1L Osimertinib was FLAURA study, which detected 91 paired plasma samples 
by next generation sequencing (NGS) . The most common acquired resistance mechanisms were 
MET amplification (15%) and EGFR C797X mutation (7%)[6]. The result was quite different 
from the study conducted by Adam J. Schoenfeld et al using tissue (N=27), with squamous 
transformation accounting for 15% and MET amplification 7%[7]. The reason for different 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 19 of 75 
results maybe because these two studies used different samples to analyse resistance 
mechanisms, and the above two detection methods may have different sensitivity and specificity. 
In addition, Schoenfeld et al study was limited to patients at one site, Memorial Sloan Kettering 
Cancer Center in NY, USA. 
Currently, analysis of circulating tumor DNA(ctDNA) has been the predominant method to 
investigate acquired resistance mechanisms, but non-genetic mechanisms of resistance, 
including histologic transformation and protein expression change cannot be captured by 
plasma NGS analysis. Compared to tissue analysis, sensitivity for copy number changes and 
chromosomal rearrangements using plasma samples is instable[3, 4, 19-23]. ddPCR is as 
technique with high sensitivity and specificity, which is widely used for the absolute 
quantification of nucleic acid through Poisson distribution [24] and also as  an alternative 
technique for MET amplification testing in plasma samples has been explored in some previous 
studies. Kitazono et al. have attempted to use ddPCR to detect MET amplification in three blood 
samples of NSCLC patients with EGFR-TKI resistance and proved its feasibility at the first 
time [25]. The recent study further explored the performance of MET amplification testing by 
ddPCR in tissues and paired peripheral blood samples from advanced NSCLC patients who had 
progressed on EGFR-TKI[26]. A total of tissues and the paired peripheral blood samples from 
103 advanced NSCLC patients who had progressed on EGFR-TKI were collected for MET 
amplification testing by using ddPCR. In parallel, MET amplification was verified by FISH in 
tissue samples. The concordance rate of MET amplification in tissue samples between ddPCR 
and FISH was 100% (102/102), and it was 94.17% (97/103) by ddPCR testing between tissue 
and paired and peripheral blood samples with performance of sensitivity 66.67% and specificity 
98.86%.  Therefore, ddPCR is an potentially alternative method for  MET amplification testing 
in both tissues and peripheral blood samples, which is worthy of exploring and validating in 
more studies (appendix H). 
 Thus, this study plans to use paired tumor tissue and whole blood to detect molecular and 
histologic mechanisms of resistance to 1L Osimertinib and to assess the concordance of plasma 
and tissue. And these paired tissue and blood samples are also used to assess the concordance 
of MET amplification between FISH and ddPCR testing as exploratory endpoints. Additional, 
the prevalence of MET amplification by FISH testing and MET overexpression by IHC testing, 
and the overlap ratio of prevalence between MET amplification and MET overexpression are 
also as exploratory endpoints in this study. 
2.3 
Benefit/Risk Assessment 
. 
2.3.1 
Risk Assessment 
This is a real-world study, which will not affect or interfere with patients’ routine medical 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 20 of 75 
diagnosis and treatment, so it will not increase other related risks. 
2.3.2 Benefit Assessment 
The results of the research may not be directly used for patients’ diagnosis and treatment, but the analysis 
of gene profile after Osimertinib 1L treatment will eventually help oncologists to make more effective 
treatment strategies in the future. 
2.3.3 Overall Benefit: Risk Conclusion 
Based on a review of the potential benefits and risks, it is considered to be reasonable and appropriate 
to investigate gene profile in EGFRm advanced NSCLC patients post Osimertinib 1L treatment failure 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 23 of 75 
4 
STUDY DESIGN 
4.1 
Overall Design 
This is a real-world, multi-center prospective study elucidating the gene profile in common 
EGFRm (ex19del and L858R) locally advanced or metastatic NSCLC patients post Osimertinib 
1L treatment. The main assumption is that gene profile in tissue and plasma could further guide 
the following treatment strategy. 
Approximately 200 participants in EGFRm locally advanced or metastatic NSCLC with the 
evidence of disease progression following 1L Osimertinib will be enrolled. 
Participants will be required to provide paired tissue and whole blood after disease progression 
following 1L Osimertinib. 200 tissue samples and 200 whole blood samples will be used to 
detect gene alteration by NGS, respectively. 200 tissue samples will be used to detect 
pathological transformation by IHC. The sample size of MET amplification testing by FISH 
and MET overexpression by MET IHC in tissue samples is approximately 80-100 respectively. 
The sample size for MET amplification testing by ddPCR in blood samples is the same.   
Baseline information consists of demography, smoking history, physical examination, medical 
history, ECOG/WHO performance status, EGFR mutation type, histology, clinical stage with 
lymph node and distant metastasis at diagnosis and post 1L Osimertinib, duration of 1L 
Osimertinib treatment, best response of 1L Osimertinib and progression pattern post 1L 
Osimertinib. 
4.2 
Scientific Rationale for Study Design 
4.2.1 
Rationale for primary, secondary and exploratory endpoint  
The primary objective is to describe the gene profile in tissue in EGFRm locally advanced or 
metastatic NSCLC patients post on 1L Osimertinib failure, which could help clinicians provide 
the following treatment strategy. 
The secondary objective is to describe the gene profile in plasma, to assess the concordance of 
plasma and tissue, and the percentage of pathology transformation. Gene profile in plasma and 
the percentage of pathology transformation will be detected and analysed by NGS and IHC, 
respectively. Concordance of plasma and tissue is to explore whether plasma can be substitute 
for tissue when patients cannot accept tissue biopsy, which is defined as sensitivity, specificity, 
PPV and NPV of representative genes. According to the assay performance, sensitivity 80% is 
acceptable. If the point estimate for sensitivity is ≥ 80%, plasma samples are supposed to be 
consistent with tissue sample for NGS testing. 
In the case of sufficient tissue samples, the exploratory endpoints is further to assess prevalence 
of MET amplification by FISH in tissue samples, the concordance of MET amplification 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 24 of 75 
between FISH testing in tissue samples and ddPCR testing in blood samples, the prevalence of 
MET overexpression by MET IHC testing and the overlap ratio of prevalence between MET 
amplification by FISH and MET overexpression by MET IHC. The prevalence data of MET 
overexpression by MET IHC and MET amplification by FISH in post 1L Osimertinib resistance 
patients in China are very limited.  
Tissue were unavailable for some patients post 1L Osimertinib and ddPCR testing will offer 
alternative method for MET amplification testing in blood samples. Concordance of MET 
amplification testing between ddPCR in plasma samples and FISH in tissue samples is to 
explore whether plasma can be substitute for tissue when patients cannot accept tissue biopsy, 
which is defined as sensitivity, specificity, PPV and NPV of representative genes.  
4.2.2 
Testing for common EGFR mutations 
Only participants with NSCLC with common EGFR mutations of ex19del and L858R will be 
eligible for inclusion in the study. A patient can be considered eligible for the study on the basis 
of documented EGFRm through any of ARMS, Super-ARMS, NGS analysis from accredited 
laboratories. 
For patients eligible for inclusion in the study based on the pre-existing common EGFRm 
plasma and/or tissue sample results, the local EGFR tissue testing laboratory methods will be 
recorded in the respective electronic case report forms (eCRF). 
4.3 
End of Study Definition 
The end of the study is defined as the date of the scheduled visit of the last participant in the 
study shown in the SoA in the study. 
The study is expected to start participant enrolment at in Q1 2022 and to end by Q1 2024. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. Depend on the determination of the study 
team. If the site is no patients enrol lasts for 3 months from the site initiation, it will be defined 
as slow recruitment. 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the scheduled procedure shown in the SoA. 
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings. 
5 
STUDY POPULATION 
The target population of interest in this study is participants with locally advanced or metastatic 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 25 of 75 
NSCLC, harbouring common EGFRm of ex19del/L858R and having evidence of disease 
progression following 1L Osimertinib. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Each subject should must meet all of the inclusion criteria and none of the exclusion criteria for 
this study. Under no circumstances can there be exceptions to this rule. Participants who do not 
meet the eligibility criteria requirements are screen failures; refer to Section 5.4. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Informed Consent 
1 
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
2 
Provision of signed and dated, written informed consent form prior to any mandatory study-
specific procedures, sampling, and analyses.  
The ICF process is described in Appendix A3., 
Sex and Age 
3 
Male or female, age at least 18 years. 
Type of Participant and Disease Characteristics 
4 
Pathologically confirmed non-small cell lung cancer (NSCLC) with documented EGFR 
sensitive mutation (EGFR 19del and L858R) positive before Osimertinib 1L. 
5 
Locally advanced (clinical stage IIIB, IIIC) or metastatic NSCLC(clinical stage IVA or 
IVB) or recurrent NSCLC (per Version 8 of the International Association for the Study of 
Lung Cancer [IASLC] Staging Manual in Thoracic Oncology), not amenable to curative or 
radiotherapy (e.g., this may occur as systemic recurrence after prior surgery for early stage 
disease or patients may be newly diagnosed with stage IIIB/IV disease, which is at the start 
of Osimertinib therapy). 
6 
Patients must have been treated with Osimertinib as first line therapy until disease 
progression. Evidence of disease progression following 1L Osimertinib can be confirmed 
by investigators with criteria in Response Evaluation Criteria in Solid Tumours (RECIST) 
Version 1.1. 
7 
Agree to provide adequate tissue and whole blood for testing after disease progression 
following 1L Osimertinib. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 26 of 75 
Reproduction 
8 
Female participants who are not abstinent (in line with the preferred and usual lifestyle 
choice of the participant) and intend to be sexually active with a male partner must be using 
highly effective contraceptive measures, must not be breast feeding, and must have a 
negative pregnancy test prior to the enrolment or must have evidence of non-child-bearing 
potential by fulfilling 1 of the following criteria at screening: 
- 
Post-menopausal, defined as more than 50 years of age and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments 
- 
Women under 50 years old would be considered as postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) 
levels in the post-menopausal range for the institution 
- 
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation. 
Further information is available in Appendix E (Definition of Women of Childbearing 
Potential and Acceptable Contraceptive Methods). 
9 
Male participants must be willing to use barrier contraception. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 
Any concurrent and/or other active malignancy that may affect tissue or whole blood testing 
results. 
2 
As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, 
which in the investigator’s opinion, makes it undesirable for the participant to participate 
in the study or that would jeopardise compliance with the protocol,.  Screening for chronic 
conditions is not required. 
Prior/Concomitant Therapy 
3 
Any concurrent anticancer treatment except local radiotherapy and radiotherapy for CNS 
metastasis. Concurrent use of hormonal therapy for non-cancer-related conditions 
(eg, hormone replacement therapy) is allowed. 
4 
 
Prior/Concurrent Clinical Study Experience 
5 
Judgment by the investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions and requirements. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 27 of 75 
Other Exclusions 
6 
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site). 
7 
In addition, the following are considered criteria for exclusion from the exploratory genetic 
research: 
• 
Prior allogeneic bone marrow transplant 
• 
Non-leukocyte depleted whole blood transfusion within 120 days of genetic 
sample collection. 
 
5.3 
Lifestyle Considerations 
1 
Female participants of child-bearing potential who are not abstinent (in line with the 
preferred and usual lifestyle choice of the participant) and intend to be sexually active with 
a male partner must use acceptable methods of contraception from screening until at least 
6 weeks after discontinuing study treatment.  
2 
Male participants must use barrier contraceptives (condoms) during sex with a female 
partner of child-bearing potential (including a pregnant partner) from the time of screening 
throughout the completion of the study. 
Participants must follow the contraception requirements outlined in Appendix E. 
 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria. 
5.5 
Procedures for handling incorrectly enrolled patients 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be enrolled. 
There can be no exceptions to this rule. Where a patient does not meet all the eligibility criteria 
but is enrolled in error, the Investigator should inform the AstraZeneca Study Physician 
immediately, and a discussion should occur between the AstraZeneca Study Physician and the 
Investigator regarding whether to continue or discontinue the patient from the study. The Study 
Physician should ensure all decisions are appropriately documented. The Investigator should 
make documentation in the medical record as appropriate. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 28 of 75 
6 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
6.1 
Participant Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for behavioural, compliance, or 
administrative reasons. This is expected to be uncommon. 
• 
At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted, as shown in the SoA. See SoA for data to be 
collected at the time of study withdrawal and for any further evaluations that need to be 
completed. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws from the study, it should be confirmed if he/she is still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study records 
and inform the Global Study Team. 
6.2 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and no contact has been established by the time the study is completed (see 
Section 4.3), such that there is insufficient information to determine the participant’s status at 
that time. 
Participants who decline to continue participation in the study should be documented as 
“withdrawal of consent” rather than “lost to follow-up.” Investigators should document attempts 
to re-establish contact with missing participants throughout the study period. If contact with a 
missing participant is re-established, the participant should not be considered lost to follow-up 
and evaluations should resume according to the protocol. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 29 of 75 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
7 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA. Data collection following study 
analysis until the end of the study is described below.  
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
7.1 
Enrolment/screening period 
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be enrolled into the study. 
The following will be performed at screening: 
Written informed consent 
Each potential patient will provide written informed consent prior to starting any study specific 
procedures. 
All patients will be required to consent for collection of a tumor sample and a plasma sample 
after disease progressed during 1L Osimertinib. This consent is included in the main patient 
informed consent form (ICF). 
Assignment of patient screening number 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 30 of 75 
As per standard, enrolment number(E-code) is assigned to the patient and Principle Investigator 
or delegate should perform enrolment/screening call. 
Collect clinical information 
Demographic data and other characteristics will be recorded and will include date of birth or 
age, gender, race and/or ethnicity, and smoking history, EGFR mutation type, histology, clinical 
stage with lymph node and distant metastasis at diagnosis and post 1L Osimertinib, 
ECOG/WHO performance status through electronic medical record or information follow-up. 
A standard medical and surgical history will be obtained. Duration of 1L Osimertinib treatment, 
best response of 1L Osimertinib and progression pattern post 1L Osimertinib, will be collected 
for analysing the correlation between gene profile post 1L Osimertinib and effect of Osimertinib 
1L treatment. 
7.2 
General Assessments 
7.2.1 
Physical Examinations 
Physical examination will be performed and include assessments 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. 
Physical examination, weight, height will be measured during screening only. 
7.2.2 
WHO/ECOG Performance Status 
WHO/ECOG performance status will be assessed at the times specified in the SoA based on the 
following: 
0 
Fully active; able to carry out all usual activities without restrictions. 
1 
Restricted in strenuous activity, but ambulatory and able to carry out light work or work of 
a sedentary nature (eg, light housework or office work). 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled; unable to carry out any self-care and totally confined to bed or chair. 
5 
Dead. 
7.3 
Biomarker research 
Instructions for the collection, handling, storage and shipping of biological samples will be 
provided in the study-specific laboratory manual, Appendix B and Appendix C. Samples should 
be stored in a secure storage space with adequate measures to protect confidentiality.  

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 31 of 75 
Samples will be destroyed at end of the study (as defined in the protocol) in line with consent 
and local requirements. 
• 
Samples collected in China will be stored and disposed of according to local laws and 
regulations during the study. 
• 
Remaining sample aliquots will be destroyed following completion of the study.  
 
For further details on Handling of Human Biological Samples, see Appendix B.  
7.3.1 
Collection of Samples for Gene Profile Analysis 
The subject’s consent to the use of donated biological samples for research is mandatory at 
disease progression following 1L Osimertinib in the SoA Samples will be collected from all 
participants and be used for detecting gene alteration and pathological transformation to explore 
the whole gene profile post Osimertinib 1L treatment for guiding subsequent treatment strategy.  
A unstained, archival tumor tissue sample from a fresh biopsy tissuein a quantity sufficient to 
allow for gene profile at the time of screening will be collected. Tissue samples will be used for 
the extraction and analysis of deoxyribonucleic acid (DNA). For the requirement of tissue 
sample and plasma sample, refer to appendix F. 
Whole blood samples (approx. 2*10 mL) will be taken at disease progression post Osimertinib 
1L treatment in the SoA (Table 1). Blood samples to generate plasma samples will be collected 
from all participants. These samples will be used for the extraction and analysis of circulating 
tumour deoxyribonucleic acid (ctDNA). 
Genetic profiles in tissue and plasma will be analyzed by the central lab NGS testingand then 
used to analysis positive percentage agreement, sensitivity/specificity of plasma to evaluate 
concordance between plasma and tissue for exploring whether plasma can be substitute for 
tissue when patients cannot accept tissue biopsy. The analytical method will be used is described 
in Section 8.3.2.  
7.3.2 
Other Study Related Biomarker Assessments 
Already collected tissue samples may be analysed on different biomarkers thought to play a role 
in protocol-specific rationale including, but not limited to, tissue biomarkers of SCLC by IHC 
to evaluate pathology transformation.Biomarkers of  SCLC include, but not limited to, CD56, 
Syn, CgA, TTF-1, CK, Ki-67 and CAM5.2, which is the routine testing in the clinical practice. 
The analytical method will be used is described in Section 8.3.2.  
In the case of sufficient tissue samples, these collected tissue samples may be analyzed on the 
prevalence of MET amplification and MET overexpression; the concordance of MET 
amplification between FSIH in tissue samples and ddPCR in blood samples; the overlap ratio 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 32 of 75 
of prevalence between MET amplification by FISH and MET overexpression by MET IHC. 
The MET amplification testing by FISH in  tissue samples and by ddPCR in blood samples 
(approx. 10 mL) will be tested in central lab.  
MET overexpression by MET IHC testing in tissue samples will be tested in the pathology 
department of local sites. 
The detailed analytical method will be used is described in Section 8.3.2.2.3. 
 
7.3.3 
Storage and destruction of samples 
The processes adopted for the coding and storage of samples for genetic analysis are important 
to maintain subject confidentiality. Sample storage and destruction will be performed according 
to the central labs’ policy and China HGR regulations. DNA is a finite resource that may be 
used up during experiments. The results of any further analyses will be reported either in the 
Clinical Study Report itself or as an addendum, or separately in a scientific report or publication. 
All genetic testing and analysis will be performed after China HGR approval. Mutation testing 
residual samples collected will be destroyed.  
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix B and the Laboratory Manual. 
8 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be performed by AstraZeneca or its representatives. A comprehensive 
SAP will be prepared with final amendments completed prior to database lock. 
There is a potential selection biases in this study. Selection bias: the patients who are eligible 
and consent to participate in the current study will be enrolled consecutively and without 
personal preference. 
8.1 
Sample Size Determination 
Approximately 200 participants will be enrolled to achieve NGS and IHC testing.  
Assuming some common gene alteration with an incidence of 20%, then with 200 subjects the 
95% CI will be around 14.7% - 26.2% based on an exact method (Clopper-Pearson).  
Table below summarizes the 95% CIs for the target incidences ranging from 10% to 50% with 
sample size of 200. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 33 of 75 
Assumed incidence of gene mutation  
95% CIs 
10% 
6.2%, 15.0% 
20% 
14.7%, 26.2% 
30% 
23.7%, 36.9% 
40% 
33.2%, 47.1% 
50% 
42.9%, 57.1% 
 
In addition, 200 subjects are enough to have 86% probability to observe at least one case if the 
incidence of an gene alteration is 1%. 
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but are 
not enrolled in the study, are considered” screen failures”, unless otherwise specified by the 
protocol.  
Assuming a potential dropout rate for loss to follow-up of 10%, the number to be accrued will 
be 180. 
 
8.2 
Populations for Analyses 
The following populations are defined: 
Table 3 
Populations for Analysis 
Population/Analysis Set 
Description 
Enrolled 
All participants who sign the ICF 
FAS 
All participants who meet the required inclusion/exclusion criteria and have valid 
Gene data from both plasma and tissue. The FAS will be used for the analyses of 
all data.  
 
8.3 
Statistical Analyses 
The SAP will be finalised prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 34 of 75 
secondary endpoints. 
8.3.1 
General Considerations 
Descriptive statistics will be provided for all variables, as appropriate. Continuous variables will 
be summarized by the number of observations, mean, standard deviation, median, interquartile 
range (Q1, Q3), minimum, and maximum. Categorical variables will be summarized by 
frequency counts and percentages for each category. The 95% confidence interval (CI) will be 
calculated as appropriate.  
8.3.2 
Biomarker  analysis 
8.3.2.1 
Primary Endpoint 
To evaluate the potential molecular resistance mechanism by tissue analysis at disease 
progression post 1L Osimertinib treatment, tissue samples will be collected at the disease 
progression. And then the gene profiling of molecular alterations including but not limited to 
mutations in, amplifications, deletion, fusion and expression of relevant pathway gene will be 
explored by NGS analysis. 
The primary objective is to describe the gene profile in EGFRm advanced NSCLC Patients after 
progression on 1L osimertinib treatment.  
Gene profile in tissue will be analysed by NGS method. All gene alterations(e.g., gene mutation, 
amplification, deletion, fusion, etc.) and histological transformation detected will be observed. 
Proportion of Gene X alteration(%) = (number of patients with Gene X, which is an example of 
a certain gene)/(total number of patients in the FAS)×100%. Some cases which patients have 
more than one gene alteration need to be considered.  
8.3.2.2 
Secondary Endpoints 
The secondary objective is to assess the concordance of plasma and tissue. Gene profile in 
plasma, concordance of plasma and tissue and the percentage of pathology transformation will 
be analysed by NGS method and IHC respectively.  
8.3.2.2.1 
Gene profile in plasma 
All gene alterations(e.g., gene mutation, amplification, deletion, fusion, etc.) and histological 
transformation detected will be observed. Proportion of Gene X alteration(%) = (number of 
patients with Gene X, which is an example of a certain gene)/(total number of patients in the 
FAS)×100%. Some cases which patients have more than one gene alteration need to be 
considered. The 95% confidence intervals using Pearson-Clopper method will be provided. 
8.3.2.2.2 
Concordance of plasma and tissue 
Using selected representative genes (for example EGFR, MET, PIK3CA and etc.) to measure 
the concordance. Concordance of Gene X in plasma and tissue is defined as sensitivity, 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 35 of 75 
specificity, positive predictive value (PPV)  and negative predictive value (NPV) between 
plasma and tissue results. Tissue sample is the reference standard. The 95% confidence intervals 
using Pearson-Clopper method will be provided. 
- 
sensitivity=(number of patients with positive result in both plasma and tissue)/(total 
number of patients with positive result in tissue samples)×100%;  
- 
specificity=(number of patients with negative result in both plasma and tissue)/(total 
number of patients with negative result in tissue samples)×100%. 
- 
PPV (%)=(number of patients with positive result in both plasma and tissue)/(total 
number of patients with positive result in plasma samples)×100%; 
- 
NPV (%)=(number of patients with negative result in both plasma and tissue)/(total 
number of patients with negative result in plasma samples)×100% 
8.3.2.2.3 
The percentage of pathology transformation 
Pathology transformation defines as pathological type of lung cancer change, which will be 
confirmed by pathologists. Number and percentage of patients with pathology transformation 
will be summarized. Proportion of pathology transformation(%) = (number of patients with 
pathology transformation)/(total number of patients in the FAS)×100%. The 95% confidence 
intervals using Pearson-Clopper method will be provided. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
CCI

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 36 of 75 
 
8.4 
Data Analyses  
The SAP will describe the planned interim analyses and final analyses in greater detail. 
Two analyses are planned. The first interim analysis data cut-off (DCO) point will happen when 
100 patients have completed their gene testing in tissue and whole blood and got their testing 
results. The final analysis is planned when the last patient has completed their gene testing in 
tissue and whole blood and got their testing results. 
9 
DEFINITIONS AND REPORTING OF ADVERSE EVENTS 
9.1 
Definition of Adverse Event 
An AE is the development of any untoward medical occurrence (other than progression of the 
malignancy under evaluation) in a participant or clinical study participant administered a 
study intervention and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally 
CCI

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 37 of 75 
associated with the use of a medicinal product, whether or not considered related to the study 
intervention.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
9.2 
Definition of Serious Adverse Event 
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires in-participant hospitalisation or prolongation of existing hospitalisation.  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital abnormality or birth defect. 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
AEs for malignant tumours reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the “Important Medical Event” criterion should be 
used. In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a 
Non-Serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as Non-Serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the study intervention under study and is not the development of new or 
progression of existing metastasis to the tumour under study). Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (e.g. Richter’s transformation of 
B cell chronic lymphocytic leukaemia into diffuse large B cell lymphoma) should not be 
considered a new malignant tumour. 
Life threatening 
“Life-threatening” means that the participant was at immediate risk of death from the AE as it 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 38 of 75 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. “Life-threatening” does not mean that had an AE occurred in a more 
severe form it might have caused death (e.g. hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study. 
Important medical event or medical treatment 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (e.g. neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 
Intensity rating scale: 
The grading scales found in the revised National Cancer Institute CTCAE latest version 5.0 
will be utilised for all events with an assigned CTCAE grading. For those events without 
assigned CTCAE grades, the recommendation in the CTCAE criteria that converts mild, 
moderate and severe events into CTCAE grades should be used. A copy of the CTCAE can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
The applicable version of CTCAE should be described clearly. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 9.2. An AE of severe 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 39 of 75 
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 in Section 9.2. 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 in Section 9.2. 
9.3 
Definition of Adverse Drug Reaction (ADR) 
An Adverse Drug Reaction (ADR) is an adverse event suspected to be causally related to the 
medicinal product. 
9.4 
Reporting of Adverse Events 
Since this study does not involve a specific AZ product, there is no requirement of proactive 
collection of AEs and other safety data for this study. However, we encourage investigators to 
report any ADRs related to AstraZeneca products to AstraZeneca spontaneously. 
Contact information of AstraZeneca PV China Team:  
Hotline: 4008208116 (Mobile & Landline Telephone) 
              8008208116 (Landline Telephone) 
              (Opening hours: 8:30-17:30 every working day) 
Online: https://aereporting.astrazeneca.com 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 40 of 75 
Appendix A Regulatory, 
Ethical, 
and 
Study 
Oversight 
Considerations 
A 1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC and applicable Regulatory Authority 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organisation but the accountability remains with AstraZeneca. 
A 2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
A 3 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorised representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary and they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the study. 
Participants or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 Code of Federal Regulations 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, 
where applicable, and the IRB/IEC or study centre. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 41 of 75 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorised 
representative. 
Participants who are rescreened are required to sign a new ICF.The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the samples 
and any potential future use. Participants will be told that they are free to refuse to participate 
in the future use and may withdraw their consent at any time and for any reason during the 
retention period. 
A 4 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the participant in the informed consent  
• 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Unless previously specified, the genetic data will have unknown clinical significance and 
AstraZeneca will not provide genetic results to participants, their family members, any 
insurance company, any employer, a clinical study investigator, a general physician, or any other 
third party, unless required to do so by law.  
The participant’s samples will not be used for any purpose other than those described in the 
study protocol. 
A 5 
Committees Structure 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators. 
A 6 
Dissemination of Clinical Study Data 
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 42 of 75 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted. 
A 7 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on the CRF unless transmitted to 
the sponsor or designee electronically (e.g. laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g. Contract 
Research Organisations). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years from the end of the study unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
A 8 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 43 of 75 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
A 9 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any Contract Research 
Organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study. 
A 10 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 44 of 75 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, 
which states: 
- 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of 
the version to be published and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 
1, 2, and 3 and 4. 
- 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript. These individuals 
should fully meet the criteria for authorship defined above. 
- 
Acquisition of funding, collection of data, or general supervision of the research 
group alone does not justify authorship. 
- 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
- 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
• 
All publications (e.g., manuscripts, abstracts, oral/slide presentations, book chapters) based 
on this study must be submitted to AstraZeneca for corporate review.  The vendor 
agreement will detail the procedures for, and timing of, AstraZeneca’s review 
of publications.  
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 45 of 75 
Appendix B Handling of Human Biological Samples 
B 1 
Chain of Custody 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle. If required, AstraZeneca will ensure that remaining 
biological samples are returned to the site according to local regulations or at the end of the 
retention period, whichever is the sooner. 
Withdrawal of Informed Consent for Donated Biological Samples AstraZeneca ensures that 
biological samples are returned to the source or destroyed at the end of the study as described 
in the informed consent. 
If a participant withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analysed, AstraZeneca is not obliged to destroy the results of this research. 
The participant will be presented with the option to opt out of the subsequent use of the donated 
samples during the withdrawal process. If the participant decides to opt out, then the donated 
samples will be disposed of. If the participant withdraws consent without opting out for the 
subsequent use of the donated samples, then the samples will be used as per protocol. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The investigator: 
• 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 46 of 75 
• 
Ensures that relevant human biological samples from that participant, if stored at the study 
site, are immediately identified, disposed of as appropriate, and the action documented. 
• 
Ensures that the participant and AstraZeneca are informed about the sample disposal. 
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified. 
B 2 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
IATA 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx 
) 
classifies 
infectious substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise 
healthy 
humans 
or 
animals. 
Category A pathogens are, for example, Ebola, Lassa fever virus. Infectious substances 
meeting these criteria which cause disease in humans or both in humans and animals must be 
assigned to UN 2814. Infectious substances which cause disease only in animals must be 
assigned to UN 2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 
650 
compliant 
packaging. 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry-ice require additional dangerous goods specification 
for the dry-ice content. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 47 of 75 
Appendix C Genetic Sample 
C 1 
Use/Analysis of DNA 
• 
The investigator at each centre intends to collect and store DNA for genetic research to 
explore how genetic variations may affect clinical parameters, risk and prognosis of 
diseases, and the response to medications. This genetic research may lead to better 
understanding of diseases, better diagnosis of diseases or other improvements in health care 
and to the discovery of new diagnostics, treatments or medications. Therefore, where local 
regulations and IRB/IEC allow, tissue and blood samples will be collected for DNA 
analysis from consenting participants. 
• 
This genetic research may consist of the analysis of the structure of the participant’s DNA, 
ie, the entire genome.  
• 
The results of genetic analyses may be reported in a separate study summary. 
• 
Each centre will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• 
Samples will be destroyed following completion of the study. 
 
C 2 
Genetic Research Plan and Procedures 
Selection of genetic research population 
• 
All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit.  
Inclusion criteria 
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and: Provide informed consent for the Genomics 
Initiative sampling and analyses. 
Exclusion criteria 
• 
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following: 
− 
Previous allogeneic bone marrow transplant. 
− 
Transfusion of non-leukocyte depleted blood or blood component within 120 days of 
genetic sample collection. 
− 
Healthy volunteers and paediatric participant samples will not be collected for the 
Genomics Initiative. 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 48 of 75 
Withdrawal of consent for genetic research 
Participants may withdraw from this genetic research at any time, independent of any decision 
concerning participation in the study. Procedures for withdrawal are outlined in Section 6.1 of 
the CSP. 
Collection of samples for genetic research 
The tissue and blood sample for this genetic research will be obtained from the participants at 
baseline(disease progression after 1L Osimertinib). Paired tissue and whole blood sample 
should be collected per participant for genetics during the study. 
Coding and storage of DNA samples 
• 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be destroyed following 
completion of the study. DNA is a finite resource that is used up during analyses. Samples 
will be stored and used until no further analyses are possible. 
• 
An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA). 
• 
The link between the participant enrolment/randomisation code and the second number will 
be maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent. 
Ethical and regulatory requirements 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A. 
Informed consent 
To participate in the genetic component of the study the participant must sign and date the 
consent form. Copies of signed and dated consent forms must be given to the participant and 
the original filed at the study centre. The principal investigator(s) is responsible for ensuring 
that consent is given freely and that the participant understands that they may freely withdrawal 
from the study at any time. 
Participant data protection 
• 
AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 49 of 75 
• 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the participant. In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a participant. For example, 
in the case of a medical emergency, an AstraZeneca physician or an investigator might 
know a participant’s identity and also have access to his or her genetic data. Regulatory 
authorities may require access to the relevant files, though the participant’s medical 
information and the genetic files would remain physically separate. 
Data management 
• 
Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples. 
• 
AstraZeneca and its designated organisations may share summary results from this genetic 
research with other researchers, such as hospitals, academic organisations or health 
insurance companies. This can be done by placing the results in scientific databases, where 
they can be combined with the results of similar studies to learn even more about health 
and disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers.  
• 
Some or all of the clinical datasets from the study may be merged with the genetic data in 
a suitable secure environment separate from the clinical database. 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 50 of 75 
Appendix D Guidelines for Evaluation of Objective Tumour 
Response Using RECIST 1.1 Criteria (Response 
Evaluation Criteria in Solid Tumors) 
Introduction 
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009). 
Investigator assessments will use the RECIST 1.1 guidelines described in this appendix. 
Imaging modalities and acquisition specifications for RECIST 1.1 
A summary of the imaging modalities that can be used for tumour assessment of TLs, NTLs 
and NLs is provided in Table . 
Table 4 
Summary of Imaging Modalities for Tumour Assessment 
Target Lesions  
Non-Target Lesions 
New Lesions 
CT 
MRI 
CT 
MRI 
Plain X-ray 
Chest X-ray 
CT 
MRI 
Plain X-ray 
Chest X-ray 
Bone scan (Scintigraphy) 
18F-fluoro-deoxyglucose-PET/CT 
CT=computed tomography; PET/CT=positron emission tomography/CT; MRI=magnetic resonance imaging. 
 
Computed Tomography and Magnetic Resonance Imaging  
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for tumour 
assessments (ie, for measurement of TLs, assessment of NTLs, and identification of NLs). It is 
essential that the same correct imaging modality, image acquisition parameters (e.g. anatomic 
coverage, imaging sequences, etc), imaging facility, tumour assessor (e.g. radiologist), and 
method of tumour assessment (e.g. RECIST 1.1) are used consistently for each participant 
throughout the study. The use of the same scanner for serial scans is recommended, if possible. 
It is important to follow the image collection/tumour assessment schedule as closely as possible 
(refer to the SoA), and this on-study imaging schedule MUST be followed regardless of any 
delays in dosing or missed imaging visits. If an unscheduled assessment is performed (eg, to 
investigate clinical signs/symptoms of progression) and the participant has not progressed, 
every attempt should be made to perform the subsequent scan acquisitions at the next scheduled 
imaging visit. 
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (e.g. heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 51 of 75 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse sequence. 
In general, local oncology diagnostic imaging parameters are applied for scan acquisition. It is 
beyond the scope of this appendix to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. 
The most critical CT and MRI image acquisition parameters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval. 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may be 
involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing PD, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumour 
measurements but also identification of new disease. 
Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these time points are specified 
in the SoA. Examples include the following: 
• 
IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis). 
• 
Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver and 
both adrenal glands) (-pelvis). 
• 
IV contrast-enhanced CT or MRI of the head and neck. 
• 
IV contrast-enhanced MRI (preferred) or CT of the brain. 
 
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order of 
preference, with additional options (2 to 4) for consideration when participants have sensitivity 
to IV contrast or have compromised renal function: 
1 
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred). 
2 
Chest CT without IV-contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study. 
3 
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 52 of 75 
4 
Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any time 
during the study. 
 
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumour 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given participant. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen and pelvis. 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5 mm thickness throughout the entire 
anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses >5 mm. If this occurs, 
the minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans. 
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study. 
Chest X-ray 
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that a 
higher resolution modality, such as CT, be used to confirm the presence of NLs. 
Plain X-ray  
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the presence 
of new bone lesions. 
Isotopic bone scan  
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray). 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed equivocal 
hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, or X-ray) of 
the same anatomical region shall not be the only trigger for a PD assessment at that time point. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 53 of 75 
18F-Fluoro-deoxyglucose-PET/CT 
18F-fluoro-deoxyglucose positron emission tomography(PET)/CT scans may be used as a 
method for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake1 not present on baseline or prior 18F-fluoro-deoxyglucose-PET 
scan or in a location corresponding to a NL on a companion CT/MRI collected close in time to 
the 18F-fluoro-deoxyglucose-PET scan. The PET portion of the PET/CT introduces additional 
data that may bias an investigator if it is not routinely or serially performed. Therefore, if there 
is no baseline or prior 18F-fluoro-deoxyglucose-PET scan available for comparison, and no 
evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI assessments should 
continue as per the regular imaging schedule to verify the unequivocal presence of NLs. 
At 
present, 
low-dose 
or 
attenuation 
correction 
CT 
portions 
of 
a 
combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated diagnostic 
contrast-enhanced CT scans for tumour measurements by RECIST 1.1. In exceptional situations, 
if a site can document that the CT performed, as part of a PET/CT examination, is of identical 
diagnostic quality (with IV contrast) to a dedicated diagnostic CT scan, then the CT portion of 
the PET/CT can be used for RECIST 1.1 tumour assessments. Caution that this is not 
recommended because the PET portion of the CT introduces additional (PET) data that may 
bias an investigator if it is not routinely or serially performed. 
Ultrasound  
Ultrasound examination will not be used for RECIST 1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumour size. Tumours identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan. 
Other tumour assessments 
Clinical examination  
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will not 
be used for RECIST 1.1 assessments. Tumours identified by clinical examination will need to 
be assessed by correlative CT or MRI anatomical scans. 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment. 
 
1 
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake 
value) greater than twice that of the surrounding tissue or liver is observed. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 54 of 75 
Histology and cytology 
Histology or tumour markers on tumour biopsy samples will not be used as part of the tumour 
response assessment as per RECIST 1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment as per RECIST 1.1. 
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) would 
be changed to PR if an effusion remains present radiologically. 
Measurability of tumour lesions at baseline 
RECIST 1.1 measurable lesions at baseline 
A tumour lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please 
see additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatis lymph nodes. 
Non-measurable lesions at baseline 
• 
Truly non-measurable lesions include the following: 
− 
Bone lesions (see exception below for soft tissue component). 
− 
Leptomeningeal disease. 
− 
Ascites, pleural effusion, or pericardial effusion. 
− 
Inflammatory breast disease. 
− 
Lymphangitic involvement of skin or lung. 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥10 mm to <15 mm short axis diameter at baseline).3 
• 
Previously irradiated lesions.4 
• 
Brain metastasis. 
Special considerations regarding lesion measurability at baseline 
• 
Bone lesions: 
 
2 
The short axis is defined as the longest in-plane axis perpendicular to the long axis. 
3 
Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or followed 
as NTLs. 
4 
Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or followed 
as NTLs. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 55 of 75 
− 
Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques 
to measure bone lesions; however, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
− 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. 
− 
Blastic lesions are considered non-measurable. 
• 
Cystic lesions thought to represent cystic metastases can be considered measurable lesions 
if they meet the criteria for measurability from a radiological point of view, but if non-
cystic lesions are present in the same participant, these should be selected over cystic 
lesions as TLs. 
 
RECIST 1.1 TL selection at baseline 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should 
be identified as TLs at baseline. TLs should be selected on the basis of their size (longest 
diameter for non-nodal lesions or short axis diameter for nodal lesions), but in addition should 
be those that lend themselves to reproducible repeated measurements. It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be selected. 
Lymph nodes, in any location (local/regional and distant), are collectively considered as a single 
organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (e.g. adrenal glands), a 
segmented organ (e.g. liver), or a multilobed organ (e.g. lung) is each considered as a single 
organ. 
The site and location of each TL should be documented, as well as the longest axis diameter for 
non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimetres. At baseline, the sum of the diameters for all TLs will be calculated and 
reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all TLs 
will be calculated and reported as the follow-up sum of diameters. 
Special cases for TL assessment at baseline 
• 
For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter. 
• 
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for the 
maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce should 
similarly be assessed by the longest axis diameter. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 56 of 75 
• 
Tumour lesions selected for newly acquired screening biopsy should not be selected as TLs, 
unless imaging occurred at least approximately 2 weeks after biopsy, allowing time for 
healing. 
• 
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan. 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a lesion 
appears in the same location on a subsequent scan, it will be recorded as a NL. 
 
RECIST 1.1 NTL selection at baseline 
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up. 
Evaluation of tumour response and progression 
RECIST 1.1 TL assessment at follow-up 
This section defines the criteria used to determine objective tumour visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter for 
non-nodal lesions or short axis diameter for lymph node lesions. All measurements should be 
recorded in millimetres. The sum of the diameters for all TLs at each follow-up visit will be 
compared with the baseline sum of diameters (for response or SD) or to the smallest prior (nadir) 
sum of diameters (for progression). 
Special cases for TL assessment at follow-up: 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a lesion 
appears in the same location on a subsequent scan, it will be recorded as an NL. 
• 
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be recorded. 
• 
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate mass, 
the vector of the longest diameter of the coalesced mass should be used to determine the 
perpendicular vector for the maximal short axis diameter. 
• 
If a TL is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned. If an accurate measure can be given, this should be recorded, 
even if it is below 5 mm. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 57 of 75 
• 
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. The choice of “Too large to measure” in the CRF will trigger an overall 
visit response of PD. 
• 
When a TL has had any intervention (e.g. definitive radiotherapy, embolization, surgery, 
transarterial chemoembolization, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 CRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm. 
 
Table 5 
RECIST 1.1 Evaluation of Target Lesions 
CR 
Disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must 
have a reduction in short axis diameter to <10 mm. 
PR 
At least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline 
sum of diameters. 
SD 
Neither sufficient decrease in the sum of diameters to qualify for PR nor sufficient increase to 
qualify for PD. 
PD 
At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest 
previous sum of diameters (nadir). This includes the baseline sum if that is the smallest on 
study. In addition to the relative increase of 20%, the sum must demonstrate an absolute 
increase of at least 5 mm from nadir. 
NE 
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, missing anatomy) 
or had a lesion intervention at this visit. Note: If the sum of diameters meets the PD criteria, 
PD overrides NE as a TL response. 
Not applicable 
Only relevant if no TLs present at baseline. 
CR=complete response; NE=not evaluable; PD=progression of disease; PR=partial response; SD=stable disease; TL=target 
lesion. 
RECIST 1.1 NTL assessment at follow-up 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit, an overall assessment of the NTL response should be recorded 
by the investigator. 
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, the 
overall tumour burden has increased sufficiently to merit unequivocal progression by NTLs. A 
modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PD of target disease will therefore be extremely 
rare. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 58 of 75 
Table 6 
RECIST 1.1 Evaluation of Non-Target Lesions 
CR 
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
Non CR/non PD 
Persistence of 1 or more NTLs. 
PD 
Unequivocal progression of existing NTLs. Unequivocal progression may be due 
to an important progression in 1 lesion only or in several lesions. In all cases, the 
progression MUST be clinically significant for the physician to consider changing 
(or stopping) therapy. 
NE 
Only relevant when 1 or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit. 
Note: For participants without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met. 
Not applicable 
Only relevant if no NTLs present at baseline. 
CR=complete response; NE=not evaluable; NTL=non-target lesion; PD=progression of disease; TL=target lesion. 
 
RECIST 1.1 NL identification at follow-up 
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the CRF. The presence of 1 or more NLs is assessed as progression. The finding 
of a NL should be unequivocal, ie, not attributable to differences in scanning technique, change 
in imaging modality, or findings thought to represent something other than tumour. If a NL is 
equivocal, for example because of its small size, the treatment and tumour assessments should 
be continued until the previously (pre-existing) NL has been assessed as unequivocal at a 
follow-up visit, and then the progression date should be declared using the date of the initial 
scan when the NL first appeared. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate PD. 
RECIST 1.1 evaluation of overall visit response at follow-up 
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table . 
Table 7 
RECIST 1.1 Overall Visit Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Visit Response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD  
No 
PR 
CR 
NE 
No  
PR 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 59 of 75 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Visit Response 
PR 
Non PD or NE or NA 
No 
PR 
SD  
Non PD or NE or NA 
No 
SD 
NA 
Non-CR/Non-PD 
No 
SD (non-CR/non-PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
NA 
NA 
No 
NED 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Non-CR/Non-PD for overall response if only NTL (no TLs) are present at baseline. 
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if ascites remains 
present radiologically. 
CR=complete response; NA=not applicable (only relevant if there were no TLs at baseline or NTLs at baseline), NE=not 
evaluable; NED=no evidence of diseases (only relevant if there were neither target lesions nor non-target lesions at baseline); 
NTL=non-target lesion; PD=progression of disease; PR=partial response; SD=stable disease; TL=target lesion. 
 
The following overall visit responses are possible depending on the extent of tumour disease at 
baseline: 
• 
For participants with TLs (at baseline): CR, PR, SD, PD, or NE. 
• 
For participants with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE. 
• 
For participants with no disease at baseline: no evidence of disease (available as an option 
in the eCRF), PD, or NE. 
References 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 60 of 75 
Appendix E Contraception Requirements 
Contraception requirements for this study are as follows. 
E 1 
Female Participants 
Women of Childbearing Potential (WoCBP) are defined as women between menarche and 
menopause who have not been permanently or surgically sterilized and are capable of 
procreation. 
Women not of childbearing potential are defined as those who are surgically sterile (ie, bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who are post-menopausal. 
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in the 
post-menopausal range for the institution. 
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago. 
 
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a nonsterilised male partner must use at least 1 highly 
effective method of contraception (Table ). They should have been stable on their chosen 
method of birth control for a minimum of 3 months before entering the study and continue to 
use it throughout the study.  
Non-sterilised male partners of a woman of childbearing potential must use a male condom plus 
spermicide (condom alone in countries where spermicides are not approved) throughout this 
period. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Total sexual abstinence is an acceptable method provided it is the 
usual lifestyle of the participant. Female participants should refrain from breastfeeding 
throughout this period. 
E 2 
Male Participants with a Female Partner of Childbearing Potential 
Non-sterilised male participants (including males sterilised by a method other than bilateral 
orchidectomy, e.g. vasectomy) who intend to be sexually active with a female partner of 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 61 of 75 
childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) from 
the time of screening throughout the completion of the study to prevent pregnancy in a partner.  
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods 
of contraception. Male participants should refrain from sperm donation or banking throughout 
this period. 
Vasectomised (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study. 
Even if the female partner is pregnant, male participants should still use a condom plus 
spermicide, as indicated above during the clinical study, if there is a concern about damaging 
the developing foetus from drug in ejaculate. 
Female partners (of childbearing potential) of male participants must also use a highly effective 
method of contraception throughout this period (Table ). 
E 3 
Highly Effective Methods of Contraception 
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table . Note 
that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 62 of 75 
Table 8 
Highly Effective Methods of Contraception (<1% Failure Rate) 
Non-Hormonal Methods 
Hormonal Methods 
• 
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant) 
• 
Vasectomised sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia) 
• 
Tubal occlusion 
• 
Intrauterine 
device 
(provided 
coils 
are 
copper-banded) 
• 
Injection: 
Medroxyprogesterone 
injection 
(e.g. Depo-Provera®)a 
• 
Levonorgestrel-releasing 
intrauterine 
system 
(e.g. Mirena®)a 
• 
Implants: 
Etonogestrel-releasing 
implants 
(e.g. Implanon® or Norplant®) 
• 
Intravaginal 
devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (e.g. NuvaRing®)  
• 
Combined pill: Normal and low dose combined 
oral contraceptive pill 
• 
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (e.g. Ortho Evra®) 
• 
Mini pill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill 
a 
Hormonal methods not prone to drug-drug interactions. 
 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 63 of 75 
Appendix F NGS technology, FISH technology, ddPCR technology 
and sample requirements 
 
NGS Company: Geneplus-Beijing Clinical Laboratory Co.,Ltd 
Tissue Sample requirements 
FFPE: 10 slides, 5mm length * 5mm width * 5um thickness; 
Tumor content: ≥20% 
De-duplicate sequencing depth: ≥500x 
Table 9      Validation information of tumor tissue sample detection 
Sample type 
Tissue 
De-duplicate 
sequencing depth 
≥500x 
Accuracy 
PPA>95%; PPV >95%；NPA>95% 
Sensitivity 
Mutation type 
Lod of Hot spot 
（Limit of 
Detection） 
Lod of Non hot spot 
（Limit of Detection） 
SNV 
≥2.0% 
≥5.0% 
InDel 
≥2.0% 
≥5.0% 
SV(Fusion) 
≥2.0% 
≥5.0% 
CNV 
≥3.8 copies 
Specificity 
>95% 
Repeatability 
100% 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 64 of 75 
Plasma Sample requirements 
Whole blood: 10ml 
De-duplicate sequencing depth: ≥1000x 
Table 10     Validation information of plasma sample detection 
Sample type 
Plasma 
De-duplicate 
sequencing depth 
≥1000x 
Accuracy 
PPA>95%; PPV >95%；NPA>95% 
Sensitivity 
Mutation type 
Lod of Hot spot 
(Limit of Detection) 
Lod of Non hot spot 
(Limit of Detection) 
SNV 
≥0.5% 
≥1.0% 
InDel 
≥0.5% 
≥1.0% 
SV(Fusion) 
≥0.5% 
≥1.0% 
CNV 
≥3.2 copies 
Specificity 
>95% 
Repeatability 
100% 
 
Table 11       Panel list of NGS 
ABL1 
FANCC 
NFKBIA 
TP53 
CBR1 
EIF4A2 
HIST1H2AC 
MCC 
PLCG2 
SMC1B 
XPC 
ACVR1B 
FANCD2 NKX2-1 
TSC1 
CBR3 
EIF4G3 
HIST1H2AG MCM3 
PLK1 
SNCAIP 
XRCC1 
AKT1 
FANCE 
NOTCH1 
TSC2 
CCDC168 ELAC2 
HIST1H2AL 
MDC1 
PLXNA1 
SNTG1 
XRCC3 
AKT2 
FANCF 
NOTCH2 
TSHR 
CCNA1 
ELF1 
HIST1H2AM MECOM 
PLXNB2 
SNX29 
YAP1 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 65 of 75 
AKT3 
FANCG 
NOTCH3 
U2AF1 
CCNB3 
ELF3 
HIST1H2BC 
MEF2C 
PNRC1 
SOD2 
YY1AP1 
ALK 
FANCL 
NPM1 
VEGFA 
CCT3 
ELMO1 
HIST1H2BD 
MGA 
POLQ 
SOS1 
ZBTB16 
APC 
FANCM 
NRAS 
VHL 
CCT5 
ELN 
HIST1H2BJ 
MIB1 
POM121 
SOX10 
ZC3H11A 
AR 
FAS 
NSD1 
WRN 
CCT6B 
EME2 
HIST1H2BK 
MIOS 
POM121L12 SOX17 
ZFHX3 
ARAF 
FAT1 
NTHL1 
WT1 
CD22 
EMID2 
HIST1H2BO 
MKL1 
POU2AF1 
SPEN 
ZFP36L1 
ARID1A 
FAT2 
NTRK1 
XPO1 
CD33 
EML4 
HIST1H3B 
MLL4 
PPM1D 
SPRR3 
ZFP36L2 
ARID1B 
FBXW7 
NTRK2 
XRCC2 
CD5L 
EPC1 
HIST1H3C 
MLLT3 
PPP1R17 
SPSB4 
ZFPM2 
ARID2 
FGF19 
NTRK3 
ZMAT3 
CD74 
EPHA1 
HIST1H3D 
MMP11 
PPP6C 
SPTA1 
ZIC3 
ASXL1 
FGF3 
PALB2 
ABCA13 
CDA 
EPHA4 
HIST1H3F 
MMP2 
PRDM16 
SRD5A2 
ZNF217 
ATM 
FGF4 
PARK2 
ABCB1 
CDH11 
EPHA7 
HIST1H3G 
MN1 
PREX2 
SRGAP1 
ZNF384 
ATR 
FGFR1 
PARP1 
ABCC1 
CDH18 
EPHB2 
HIST1H3H 
MNDA 
PRF1 
SRGAP3 
ZNF521 
ATRX 
FGFR2 
PAX5 
ABCC11 
CDH23 
EPHB4 
HIST1H3I 
MNX1 
PRKAA1 
SRSF2 
ZNF638 
AURKA 
FGFR3 
PBRM1 
ABCC2 
CDK13 
EPOR 
HIST1H4I 
MSH4 
PRKCB 
SRSF7 
ZNF750 
AURKB 
FGFR4 
PCK1 
ABCG2 
CHD1 
EPPK1 
HIST3H3 
MSN 
PRKCI 
STAG1 
ZNF804B 
AXIN1 
FH 
PDCD1 
ABL2 
CHD1L 
EPS15 
HLF 
MSR1 
PRKDC 
STAT1 
HLA-A 
AXIN2 
FLCN 
PDCD1LG2 ACACA 
CHD4 
ERBB2IP 
HMCN1 
MTHFR 
PRRX1 
SUCLG1 
HLA-B 
AXL 
FLT1 
PDGFRA 
ACIN1 
CHD6 
ERCC2 
HNF1B 
MTRR 
PRX 
SUCLG2 
HLA-C 
B2M 
FLT3 
PDGFRB 
ACTB 
CHD8 
ESR2 
HNRPDL 
MUC5B 
PSG2 
SULT1A1 
 
BAP1 
FLT4 
PDK1 
ACTG1 
CHD9 
ETS1 
HOXA11 
MYH11 
PSIP1 
SUZ12 
 
BARD1 
FOXA1 
PIK3CA 
ACTG2 
CHFR 
ETV1 
HOXA13 
MYH14 
PSMB1 
SVEP1 
 
BCL2 
FOXL2 
PIK3CB 
ACVR2A 
CHI3L1 
ETV5 
HOXA3 
MYH9 
PSMB5 
SYNCRIP 
 
BCL2L1 
FOXP1 
PIK3CG 
ACVRL1 
CHN1 
ETV6 
HOXA9 
MYO3A 
PTGS1 
SYNE1 
 
BCOR 
FUBP1 
PIK3R1 
ADAM29 
CIITA 
EWSR1 
HOXC13 
MYOD1 
PTGS2 
TAF1 
 
BLM 
GALNT12 PIK3R2 
ADAMTS5 CLDN18 
EZR 
HOXD11 
NAP1L1 
PTPN13 
TAF15 
 
BMPR1A 
GATA3 
PMS1 
ADCY1 
CLP1 
F8 
HOXD13 
NAV3 
PTPN2 
TAF1L 
 
BRAF 
GNA11 
PMS2 
AFF1 
CLSPN 
FAM131B HSD3B1 
NCAM2 
PTPRB 
TAL1 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 66 of 75 
BRCA1 
GNAQ 
POLD1 
AFF2 
CLTC 
FAM135B HSP90AA1 
NCF2 
PTPRK 
TBL1XR1 
 
BRCA2 
GNAS 
POLE 
AFF3 
CNOT3 
FAM157B HSP90AB1 
NCF4 
PTPRO 
TBX15 
 
BRD4 
GRIN2A 
POT1 
AHNAK 
CNOT4 
FAM46C 
HSPA8 
NCK1 
PTPRS 
TBX22 
 
BRIP1 
GRM3 
PPP2R1A 
AKAP9 
CNTN1 
FAM5C 
HSPD1 
NCOA3 
PTPRT 
TCEB1 
 
BTK 
HDAC1 
PRDM1 
ALB 
CNTN5 
FAP 
HSPH1 
NCOA4 
PTPRU 
TCF12 
 
CARD11 
HGF 
PRKAR1A AMOT 
CNTNAP1 FASLG 
ICK 
NCOR2 
RAB35 
TCF3 
 
CASP8 
HNF1A 
PTCH1 
ANGPT1 
CNTNAP5 FAT3 
ICOSLG 
NCSTN 
RAC2 
TCF4 
 
CBFB 
HOXB13 
PTCH2 
ANK3 
COL1A1 
FAT4 
ID3 
NDUFA13 RAD21 
TCL1A 
 
CBL 
HRAS 
PTEN 
ANKRD11 COL2A1 
FCGR1A 
IFITM3 
NFATC4 
RAD54B 
TEC 
 
CCND1 
IDH1 
PTPN11 
ANKRD30A COL5A1 
FCGR2A 
IGF1 
NFE2L3 
RANBP2 
TENM3 
 
CCND2 
IDH2 
PTPRD 
ANKRD30B COL5A2 
FCGR2B 
IGF2 
NKX3-1 
RASA1 
TERT 
 
CCND3 
IFNG 
RAC1 
APEX1 
COL5A3 
FCGR3A 
IGF2R 
NLRC3 
RASGRP1 
TET1 
 
CCNE1 
IFNGR1 
RAD50 
APOBEC3B COPS2 
FCRL4 
IGLL5 
NOD1 
RBL1 
TFDP1 
 
CD274 
IGF1R 
RAD51 
ARAP3 
CPS1 
FGF10 
IKZF2 
NOS3 
REL 
TFDP2 
 
CDC73 
IKBKE 
RAD51B 
ARFGEF1 
CRIPAK 
FGF12 
IKZF3 
NOTCH4 RELN 
TFE3 
 
CDH1 
IKZF1 
RAD51C 
ARFGEF2 
CRLF2 
FGF14 
IL10 
NQO1 
RFC1 
TGFBR1 
 
CDK12 
IL7R 
RAD51D 
ARHGAP29 CRNKL1 
FGF23 
IL1RAPL1 
NR1I2 
RGS3 
THBS2 
 
CDK4 
INPP4B 
RAD52 
ARHGAP35 CRTC1 
FGF6 
IL21R 
NR2F2 
RHEB 
TJP1 
 
CDK6 
IRF2 
RAD54L 
ARID4B 
CSF1 
FLG 
IL6 
NR4A2 
RHOH 
TLE1 
 
CDK8 
IRS2 
RAF1 
ARID5B 
CSF3R 
FLI1 
IL6ST 
NRG1 
RHOT1 
TLL2 
 
CDKN1A 
JAK1 
RARA 
ARNT 
CSMD1 
FLNC 
IMPG1 
NRP2 
RIT1 
TLR4 
 
CDKN1B 
JAK2 
RB1 
ASCL4 
CSMD3 
FMN2 
ING1 
NRXN1 
RNASEL 
TLX3 
 
CDKN2A 
JAK3 
RBM10 
ASH1L 
CSNK1A1 FN1 
INHBA 
NTM 
ROBO1 
TMEM132D  
CDKN2B 
JUN 
RECQL 
ASMTL 
CSNK1G3 FNDC4 
INPP4A 
NUMA1 
ROBO2 
TNFSF11 
 
CDKN2C 
KDM5A 
RECQL4 
ASPM 
CTLA4 
FOXA2 
INPPL1 
NUP107 
ROBO3 
TNN 
 
CEBPA 
KDM5C 
RET 
ASTN1 
CTNNA2 
FOXO1 
INSR 
NUP210 
ROCK1 
TP53BP1 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 67 of 75 
CHEK1 
KDM6A 
RHOA 
ASXL2 
CTNND1 
FOXO3 
IRF4 
NUP93 
RPGR 
TP63 
 
CHEK2 
KDR 
RICTOR 
ATIC 
CUX1 
FOXQ1 
IRF6 
NUP98 
RPS6KB1 
TP73 
 
CIC 
KEAP1 
RINT1 
ATP11B 
CXCR4 
FRMPD4 
IRS1 
OBSCN 
RPS6KB2 
TPM3 
 
CREBBP 
KIT 
RNF43 
ATP12A 
CYBA 
FUS 
ITGB3 
OGDH 
RSPO2 
TPR 
 
CRKL 
KRAS 
ROS1 
ATP1A1 
CYP19A1 FXR1 
ITK 
OMD 
RSPO3 
TRAF2 
 
CSF1R 
LRP1B 
RPTOR 
ATP2B3 
CYP1A1 
FYN 
ITSN1 
OPCML 
RUNX1T1 
TRAF7 
 
CTCF 
MAF 
RUNX1 
BAZ2B 
CYP1B1 
FZD1 
JARID2 
OR11G2 
RUNX2 
TRIM24 
 
CTNNA1 
MAP2K1 SDHA 
BBC3 
CYP2A13 G3BP1 
KALRN 
OR2T4 
RXRA 
TRIM58 
 
CTNNB1 
MAP2K2 SDHAF2 
BBS9 
CYP2C8 
G3BP2 
KAT6A 
OR4A15 
RYR1 
TRIO 
 
CUL3 
MAP2K4 SDHB 
BCAS1 
CYP2D6 
GAB2 
KAT6B 
OR4C6 
RYR2 
TRPC5 
 
CYLD 
MAP3K1 SDHC 
BCL10 
CYP3A4 
GABRA6 
KCNJ5 
OR5L2 
SBDS 
TRRAP 
 
DAXX 
MAPK1 
SDHD 
BCL11A 
CYP3A5 
GATA1 
KCNQ2 
OR6F1 
SCUBE2 
TSHZ2 
 
DDR1 
MAX 
SERPINB3 BCL11B 
DCC 
GATA2 
KDM2B 
P2RY8 
SDC4 
TSHZ3 
 
DDR2 
MCL1 
SERPINB4 BCL2A1 
DDX3X 
GFRAL 
KEL 
P4HB 
SEC31A 
TTF1 
 
DICER1 
MDM2 
SETD2 
BCL2L11 
DDX5 
GIGYF1 
KIF5B 
PABPC1 
SEMA3A 
TUBA3C 
 
DNMT3A 
MDM4 
SF3B1 
BCL3 
DEK 
GKN2 
KLF4 
PABPC3 
SEMA3E 
TUBB3 
 
DOT1L 
MED12 
SLX4 
BCL6 
DHX35 
GLB1L3 
KLHL6 
PAG1 
SEMA6A 
TUSC3 
 
EGFR 
MEF2B 
SMAD2 
BCL9 
DHX9 
GLI1 
KLK1 
PAK1 
SERPINA7 
TXNIP 
 
EIF1AX 
MEN1 
SMAD3 
BCORL1 
DIAPH1 
GLI2 
KRTAP5-5 
PAK3 
SETBP1 
TYMS 
 
C11orf30 
MET 
SMAD4 
BCR 
DIS3L2 
GLI3 
L3MBTL1 
PASK 
SETDB1 
TYR 
 
EP300 
MITF 
SMARCA4 BIRC3 
DLC1 
GMPS 
LAMA2 
PAX3 
SF1 
UBE2D2 
 
EPAS1 
MLH1 
SMARCB1 BMPR2 
DMD 
GNA13 
LATS1 
PAX7 
SF3A1 
UBR5 
 
EPCAM 
MLH3 
SMO 
BNC2 
DNAH6 
GNG2 
LATS2 
PC 
SFPQ 
UGT1A1 
 
EPHA2 
MLL 
SOCS1 
BPTF 
DNAJB1 
GPC3 
LCP1 
PCDH18 
SGCZ 
UMPS 
 
EPHA3 
MLL2 
SOX2 
BRD2 
DNM2 
GPR124 
LEF1 
PCSK6 
SGK1 
UPF3B 
 
EPHA5 
MLL3 
SOX9 
BRD3 
DNMT1 
GPS2 
LGALS8 
PCSK7 
SH2B3 
USH2A 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 68 of 75 
EPHB1 
MPL 
SPOP 
BRSK1 
DNMT3B GPX1 
LIFR 
PDCD11 
SH2D1A 
USP6 
 
EPHB6 
MRE11A SRC 
BRWD1 
DOCK2 
GRB7 
LPHN2 
PDE4DIP SH3PXD2A USP8 
 
ERBB2 
MS4A1 
STAG2 
BTLA 
DOCK7 
GSK3B 
LPP 
PDGFB 
SHH 
VEZF1 
 
ERBB3 
MSH2 
STAT3 
BUB1 
DPYD 
GSTM5 
LRP2 
PDILT 
SI 
VIM 
 
ERBB4 
MSH3 
STK11 
C15orf23 
DRGX 
GSTP1 
LRP4 
PER1 
SIN3A 
VTCN1 
 
ERCC1 
MSH6 
SUFU 
C15orf55 
DTX1 
GUSB 
LRP5 
PGR 
SLC16A1 
WASF3 
 
ERCC3 
MST1R 
SYK 
C1QA 
DUSP22 
H3F3A 
LRP6 
PHF1 
SLC1A2 
WDR90 
 
ERCC4 
MTOR 
TBX3 
C1S 
DYSF 
H3F3B 
LRRC7 
PHF6 
SLC22A16 
WDTC1 
 
ERCC5 
MUTYH 
TCF7L2 
C3orf70 
E2F3 
H3F3C 
LRRK2 
PIK3C2A SLC22A18 
WHSC1 
 
ERG 
MYC 
TERC 
C7orf53 
EBF1 
HCLS1 
LYN 
PIK3C2B SLC22A2 
WHSC1L1  
ERRFI1 
MYCL1 
TET2 
C8orf34 
ECT2L 
HCN1 
LZTS1 
PIK3C2G SLC22A3 
WIPF1 
 
ESR1 
MYCN 
TGFBR2 
CACNA1E EED 
HDAC4 
MACF1 
PIK3C3 
SLC34A2 
WNK1 
 
EXT1 
MYD88 
TMEM127 CADM2 
EEF1A1 
HDAC9 
MAD1L1 
PIM1 
SLCO1B3 
WNT5A 
 
EXT2 
NBN 
TMPRSS2 
CALR 
EGFL7 
HECW1 
MAGI2 
PKD1L2 
SLIT1 
WSCD2 
 
EZH2 
NCOR1 
TNFAIP3 
CAMTA1 
EGR3 
HEY1 
MAML2 
PKHD1 
SLIT2 
WWOX 
 
FAM123B 
NF1 
TNFRSF14 CASP1 
EIF2AK3 
HIST1H1C MAML3 
PLAG1 
SMARCD1 
WWP1 
 
FAM175A 
NF2 
TOP1 
CASQ2 
EIF2C3 
HIST1H1D MAP3K13 
PLCB1 
SMARCE1 
WWP2 
 
FANCA 
NFE2L2 
TOP2A 
CBLB 
EIF3A 
HIST1H1E MAPK3 
PLCG1 
SMC1A 
XIAP 
 
 
NGS raw data Process: 
1. Filter out low quality reads from raw data by NCfilter. 
2. The clean reads were aligned to the human genome build hs37d5 using sentieon bwa software. 
Subsequent BAM files were further processed for deduplication, base quality recalibration, and 
indel realignment using sentieon software. 
3. Data quality control was performed using NCbamInfo from the final BAM files. 
4. Somatic single nucleotide variants (SNVs) and somatic small insertions and deletions (Indels) 
were called using realDcaller and sentieon TNScope, respectively. The candidate somatic SNVs 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 69 of 75 
and indels were annoted，and reviewed by BedAnno and HChot software. A series of designed 
filter rules were subsequently applied to filter out false positive sites. 
5. Somatic structural variants (SV) were identified, annoted and filtered by by NCsv, annosv, 
and filtersv software, respectively.  
6. Gene-level copy number variations (CNVs) were calculated by using CNVKit. Annocnv and 
filtercnv software were used for subsequent annotation and filterition. 
All final candidate variants were manually verified with the integrative genomics viewer 
browser. 
The central lab of FISH testing (tissue samples) and ddPCR testing (plasma samples): 
Righton Clinical Laboratory Co.,Ltd 
Tissue Sample requirements 
FFPE: 2 slides, 5mm length * 5mm width * 5um thickness; 
Tumor content: ≥20% 
Table 12      Validation information of tumor tissue sample detected by FISH 
Assay  
Vysis MET SpectrumRed FISH Probe kit (Abbott) 
Sample type 
Tissue 
Tumor cells 
20-30 cells 
Cut off  
GCN ≥ 10  
 
Plasma Sample requirements 
Peripheral whole blood sample: 10ml 
Table 13     Validation information of plasma sample detected by ddPCR 
Sample type 
Plasma 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 70 of 75 
Sample requirement 
1. non- hemolysis 
2. extraction DNA ≥ 0.5 ng/ul 
3. total DNA content ≥ 25 ng 
Assay 
MET gene amplification testing assay -ddPCR 
Cut off  
MET/CEP7 ≥ 2 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 71 of 75 
Appendix G Abbreviations 
Abbreviation or Special 
Term 
Explanation 
CD 
cluster of differentiation 
CI 
confidence interval 
CR 
complete response 
CRF 
Case report form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
computed tomography 
ctDNA 
circulating tumour DNA 
DCO 
data cut-off 
DNA 
deoxyribonucleic acid  
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EGFR 
epidermal growth factor receptor 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed and paraffin embedded 
FISH 
fluorescent in situ hybridization 
GCP 
Good Clinical Practice 
HR 
hazard ratio 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
MRI 
magnetic resonance imaging 
NE 
not evaluable 
NL 
new lesion 
NSCLC 
non-small cell lung cancer 
NTL 
non-target lesion 
ORR 
objective response rate 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 72 of 75 
Abbreviation or Special 
Term 
Explanation 
OS 
overall survival 
PD 
progression of disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PR 
partial response 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SoA 
Schedule of Activities 
TKI 
tyrosine kinase inhibitor 
TL 
target lesion 
TOC 
Table of Contents  
TTD 
time to treatment discontinuation or death 
VAF 
variant allele frequency 
WHO 
World Health Organisation 
ddPCR 
droplet digital PCR 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 73 of 75 
Appendix H Performance of droplet digital PCR (ddPCR) for 
MET amplification testing 
Table A: The consistency of ddPCR and FISH in detecting MET amplification in tissue 
samples 
 
Table B: The concordance of MET amplification between tissue and matched peripheral blood 
samples detected by ddPCR 
 
Table A: In tissue samples from 102 advanced NSCLC patients who had progressed on EGFR-TKI, the consistency 
of MET amplification between ddPCR testing and FISH testing. (1 case failed for FISH detection owing to the 
lack of sufficient tumor cells, remaining 102 cases had both FISH and ddPCR results) [26] 
Table B: In tissue and the matched peripheral blood samples from 103 advanced NSCLC patients who had 
progressed on EGFR-TKI, the concordance of MET amplification detected by ddPCR between tissue and matched 
peripheral blood samples (In total, all 103 patients were involved in this analysis) [26]. 
 

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 74 of 75 
11 
REFERENCES 
FDA Guidance for Industry (issued July 2009)  ‘Drug-induced liver injury: Premarketing 
clinical 
evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf 
[1]S S Ramalingam, J Vansteenkiste, D Planchard, et al. Overall Survival with Osimertinib in 
Untreated, EGFR-Mutated Advanced NSCLC[J]. N Engl J Med, 2020, 1: 41-50.  
[2]D Rangachari, C To, J E Shpilsky, et al. EGFR-Mutated Lung Cancers Resistant to 
Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors 
but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples[J]. J 
Thorac Oncol, 2019, 11: 1995-2002.  
[3]Z Piotrowska, H Isozaki, J K Lennerz, et al. Landscape of Acquired Resistance to 
Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET 
Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion[J]. Cancer Discov, 2018, 
12: 1529-1539.  
[4]X Le, S Puri, M V Negrao, et al. Landscape of EGFR-Dependent and -Independent 
Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in 
EGFR-Mutant NSCLC[J]. Clin Cancer Res, 2018, 24: 6195-6203.  
[5]C Mehlman, J Cadranel, G Rousseau-Bussac, et al. Resistance mechanisms to Osimertinib 
in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French 
study[J]. Lung Cancer, 2019, 149-156.  
[6]S S Ramalingam, Y Cheng, et al. Mechanisms of acquired resistance to first-line Osimertinib: 
preliminary data from the phase III FLAURA study. 2018ESMO LBA8. 
[7]A J Schoenfeld, J M Chan, D Kubota, et al. Tumor Analyses Reveal Squamous 
Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line 
Osimertinib in EGFR-Mutant Lung Cancer[J]. Clin Cancer Res, 2020, 11: 2654-2663. 
[8]Schmid S, Li JJN, Leighl NB. Lung Cancer. 2020 Sep;147:123-129. 
[9]Poster presented at 2022 World Conference on Lung Cancer, August 6–9, Vienna, Austria, 
by Myung-Ju Ahn 
[10]Poster presented at 2022 ESMO 
[11]Cescon DW, Bratman SV, Chan SM, Siu LL (2020) Circulating tumor DNA and liquid 
biopsy in oncology. Nature Cancer 1:276–290 
[12]Olmedillas-Lopez S, Garcia-Arranz M, Garcia-Olmo D (2017) Current and emerging 
applications of droplet digital PCR in oncology. Mol Diagn Ther 21:493–510 
[13]F Bray, J Ferlay, I Soerjomataram, et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer 
J Clin, 2018, 6: 394-424.  
[14]W D Travis, H Asamura, A A Bankier, et al. The IASLC Lung Cancer Staging Project: 
Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-

Clinical Study Protocol - 2.0 
AstraZeneca 
<<D5161R00037>> 
CONFIDENTIAL AND PROPRIETARY 
 75 of 75 
Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer[J]. 
J Thorac Oncol, 2016, 8: 1204-1223.  
[15]T Kohno, T Nakaoku, K Tsuta, et al. Beyond ALK-RET, ROS1 and other oncogene fusions 
in lung cancer[J]. Transl Lung Cancer Res, 2015, 2: 156-64.  
[16]Maemondo M, Inoue A, Kobayashi K, et al; North-East Japan Study Group. Gefitinib or 
chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 
2010;362(25):2380-2388.   
[17]Rosell R, Carcereny E, Gervais R, et al; Spanish Lung Cancer Group in collaboration with 
Groupe Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line 
treatment for European patients with advanced EGFR mutation–positive non-small-cell lung 
cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 
2012;13(3):239-246.  
[18]Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus 
pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin 
Oncol. 2013;31(27):3327-3334.   
[19]N Guibert, Y Hu, N Feeney, et al. Amplicon-based next-generation sequencing of plasma 
cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung 
cancer[J]. Ann Oncol, 2018, 4: 1049-1055.  
[20]J J Chabon, A D Simmons, A F Lovejoy, et al. Circulating tumour DNA profiling reveals 
heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients[J]. Nat 
Commun, 2016, 11815.  
[21]C M Blakely, T B K Watkins, W Wu, et al. Evolution and clinical impact of co-occurring 
genetic alterations in advanced-stage EGFR-mutant lung cancers[J]. Nat Genet, 2017, 12: 1693-
1704.  
[22]J K Sabari, M Offin, D Stephens, et al. A Prospective Study of Circulating Tumor DNA to 
Guide Matched Targeted Therapy in Lung Cancers[J]. J Natl Cancer Inst, 2019, 6: 575-583.  
[23]J G Supplee, M S D Milan, L P Lim, et al. Sensitivity of next-generation sequencing assays 
detecting oncogenic fusions in plasma cell-free DNA[J]. Lung Cancer, 2019, 96-99.  
[24] Olmedillas-Lopez S, Garcia-Arranz M, Garcia-Olmo D (2017) Current and emerging 
applications of droplet digital PCR in oncology. Mol Diagn Ther 21:493–510. https:// doi. org/ 
10. 1007/s40291- 017- 0278-8[25] Kitazono S, Sakai K, Yanagitani N, Ariyasu R, Yoshizawa 
T, Dotsu Y, Koyama J, Saiki M, Sonoda T, Nishikawa S et al (2019) Barcode sequencing 
identifies resistant mechanisms to epidermal growth factor receptor inhibitors in circulating 
tumor DNA of lung cancer patients. Cancer Sci 110:3350–3357. https:// doi. org/ 10. 1111/ 
cas.14153. 
[26] Ying Fan, Rui Sun, Zhizhong Wang, et al. Detection of MET amplification by droplet 
digital PCR in peripheral blood samples of non‑small cell lung cancer. Journal of Cancer 
Research and Clinical Oncology, 2022, https://doi.org/10.1007/s00432-022-04048-4.