A Phase II Study Assessing the Efficacy of Osimertinib in Combination With Savolitinib in Patients With EGFRm+ and MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib.
Phase: PHASE2
Conditions: Carcinoma
Sponsor: AstraZeneca

Clinical Study Protocol – 8.0
AstraZeneca
Osimertinib + savolitinib - D5084C00007
CONFIDENTIAL AND PROPRIETARY
1 of 207
Clinical Study Protocol 
Drug Substance
Osimertinib + savolitinib
Study Code
D5084C00007
Version
8.0
Date
24 May 2024
A Phase II Study Assessing the Efficacy of Osimertinib in Combination 
with Savolitinib in Patients with EGFRm+ and MET+, Locally Advanced 
or Metastatic Non-Small Cell Lung Cancer who have Progressed Following 
Treatment with Osimertinib (The SAVANNAH Study)
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifying Number(s):
EudraCT number: 2018-003012-51
EU CT number: 2024-512564-58-00
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Disclosure

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Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 3 of 207 
 
randomised patients (Sections 1.2, 4.1.1, and 9.5). The provision that additional OS follow 
up analyses may be performed was removed (Section 9.5). 
Updates made throughout the protocol for MET amplified/overexpressed (FISH10 + and/or 
IHC90+) patients who will be randomised under CSP version 7.0, including removal of 
single arm from study title, numbers of patients planned and enrolled (Sections 1.2 and 
4.1.1), schedules (including schedule added in Table 2) for patients who cross over), study 
schema (Section 1.3), additional primary and secondary objectives/endpoints for MET 
amplified/overexpressed (FISH10+ and/or IHC90+) populations (Sections 1.2 and  3), 
study design including rationale (Section 4), Inclusion Criterion (Section 5.1; no. 6), 
placebo/ unblinding added to study interventions (Section 6), discontinuation of study 
intervention (Section 7.1), addition of brain imaging at screening and further clarification 
on BICR (Sections 8.1.1 and 9.4.3), and statistical considerations including sample size, 
futility analysis, study populations, stratification factor, and study analyses (Section 8.7). 
An additional primary objective/ endpoint was added to determine the ORR (by 
investigator assessment per RECIST 1.1) of savolitinib 300 mg bid in combination with 
osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or 
IHC90+) who have progressed following treatment with 1L osimertinib. In addition, the 
following secondary investigator-assessed objectives were added: 1) To determine the 
efficacy (DoR, PFS, OS) of savolitinib (300 mg bid) in combination with osimertinib in 
MET amplified/overexpressed (FISH10 + and/or IHC90+) patients who have progressed 
following treatment with 1L osimertinib 2) To describe the difference in the efficacy of 
savolitinib (300 mg bid) in combination with osimertinib and savolitinib (300 mg bid) in 
combination with placebo in MET amplified/overexpressed patients (FISH10 + and/or 
IHC90+) who have progressed following treatment with1L osimertinib therapy under CSP 
version 7.0, and 3) To evaluate the safety of savolitinib + placebo. The remaining 
secondary objectives were modified as follows (1) To determine the efficacy of savolitinib 
(300 mg od and 600 mg od) in combination with osimertinib in MET-
amplified/overexpressed (FISH10+ and/or IHC90+) patients following treatment with 1L 
osimertinib (2) To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 
600 mg od) in combination with osimertinib in patients with MET amplified/overexpressed 
(FISH10+ and/or IHC90+) patients who have progressed following treatment of ≥ 2L 
osimertinib (3) To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 
600 mg od) in combination with osimertinib in MET amplified/overexpressed (FISH5+ 
and/or IHC50+) patients who have progressed following osimertinib. A secondary 
objective was added to determine the efficacy in all patient populations by BICR. 
Biomarker cut-offs in objectives were clarified, and DoR, PFS, and OS were added as 
endpoints (Section 1.2 and Section 3). Exploratory objectives were added to assess the 
efficacy of savolitinib plus osimertinib and savolitinib plus placebo, respectively, on 
1) CNS metastases in patients with CNS metastases at baseline and 2) the prevention of 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 4 of 207 
 
CNS metastases in patients without CNS metastases at baseline (Section 3). Statistical 
considerations in Section 9 including hypotheses, sample size, populations, and efficacy 
endpoint analyses updated accordingly. 
As the dosing regimen of 300 mg bid for savolitinib has been selected for further 
evaluation, the previously planned IA3 was removed. A futility analysis for the savolitinib 
300 mg bid + placebo arm was added (Sections 1.2, 4.1.1 and 9.5). 
Program-wide measures to mitigate and manage the risk of drug-induced liver injury were 
added based on FDA feedback and hepatic safety knowledge group review including the 
introduction of an Independent Hepatic Assessment Committee (Sections 1.2, 9.6 and 
Appendix A 5), exclusion of patients with serious/chronic liver disease (exclusion criterion 
12), updates to drug-related hepatotoxicity management guidelines (Appendix I 3.3.1), and 
guidance on patients with HBV infection updated (Exclusion Criterion 7 clarified and 
Appendix I 2 [new]). 
Clarified the use of direct oral anticoagulants and warfarin as treatment for cancer-related 
thromboembolism (Inclusion criterion 14 and Section 6.5). 
Safety data for osimertinib updated (Section 2.3.1) and guidelines added for the 
management of aplastic anaemia, a newly classified adverse drug reaction, osimertinib-
related QTc prolongation, and dose adjustments for adverse reactions based on a review of 
all available safety data and subsequent investigator’s brochure update (Appendix I 1). 
List of restricted medications updated based on latest in vitro and in vivo data on drug-drug 
interactions (Section 6.5). 
Dose modifications for savolitinib updated based on latest safety data (Appendix I 3) and 
guidance regarding potential interactions of savolitinib with concomitant medications 
updated based on latest drug-drug interaction data (Appendix J), including new appendix 
(Appendix J 4 [new]) on medicines whose exposures may be affected by savolitinib that 
AstraZeneca strongly recommend are not combined with savolitinib and guideline added 
for the management of overlapping toxicities between osimertinib and savolitinib 
(Appendix I 3.5 [new]). 
New sections added for further clarity including benefit of treatment (Section 2.3.2), rescue 
medicine (6.5.1), follow-up post treatment discontinuation (Section 7.1.3) follow up for 
survival (Section 7.1.4), and ECOG performance status (Section 8.2.7). 
Added a column to SoAs to clarify that blood sample for biomarker analyses and optional 
tumour biopsy are to be taken at disease progression (Section 1.1). PK sampling for 

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Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
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enrolment of patients with a pre-existing MET amplification result by NGS testing has been 
added to the Study Design in section 4.1. 
References to “local” NGS testing are changed to “pre-existing” NGS testing in order to 
make clear that this result must have been obtained prior to obtaining consent for pre-
screening and screening for the SAVANNAH study. Also to make clear that the NGS 
testing laboratory approved by AstraZeneca as being suitable to assess eligibility for the 
SAVANNAH study, may be local to the participating investigational site or may be external 
to the site. This change is made to Inclusion criterion 6 in Section 5.1 and throughout. 
Simplification of the reference to acceptance criteria in section 4.1 to allow flexibility in 
these requirements which are assessed by the Sponsor. N.B. This testing is not an 
alternative to the central MET testing by FISH and IHC required for all patients and is not 
performed as part of the SAVANNAH study. It is in addition to the central testing and is 
intended to allow a patient already known to be MET+ by NGS to start treatment without 
delay in the best interests of the patient. 
The study rationale in Section 2.1 is corrected to refer to overexpression in addition to 
amplification of the MET receptor tyrosine kinase as a mechanism for resistance to 
EGFR-TKIs. Clarification made that this study will explore overcoming MET-mediated 
osimertinib resistance. 
Tumour imaging to assess efficacy is required every 6 weeks (±7 days). Clarification added 
to the Schedule of Assessments in section 1.1 Table 1, that this timing is relative to the first 
dose of treatment and not relative to the previous tumour imaging, also Section H 3.1.  
Further guidance on performance of ePRO assessments is added to Table 1 Schedule of 
activities to footnote o and to section 8.1.2.5. The Screening timepoint is optional and offers 
the site and the patient an opportunity to prepare for the mandatory baseline ePROs before 
dosing on Cycle 1 Day 1 when the patient will take the device home. The Screening 
timepoint also serves as a back-up to ensure a baseline is recorded. 
The ctDNA clearance secondary objective is corrected to determining the prevalence rather 
than rate of ctDNA clearance after osimertinib and savolitinib treatment in Section 1.2, 
Section 3 and Section 9.4.6 to more accurately reflect the endpoint of total clearance in 
EGFR mutations at 6-weeks after therapy initiation. 
Patients should come to the clinic fasted and be given a moderate breakfast at the clinic. 
Clarification added to Section 5.3.1 and 8.5.1 that the pre-dose PK sample may be drawn 
before dosing, either before or after this moderate breakfast. Also clarified that fasted means 
the patient should not eat but may drink beforehand, Section 5.3.1. 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
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Information to be collected for screen failure patients will include MET status information, 
added to list of minimal information in Section 5.4. 
Acknowledgement that SAEs will be reported according to local regulations added to 
Section 8.3.2. 
Guidance introduced to Appendix I Dose modification for the management of AEs for 
osimertinib management for erythema multiforme and Stevens-Johnson syndrome Section 
I 1.4.  
Clarification to dose modification due to drug-related hepatotoxicity to withhold dosing if 
ALT or AST 3 x ULN and concurrent total bilirubin should be above 1.5 x ULN rather than 
1.5 x ULN, Section I 3.3.1. 
Guidance on concomitant therapy in Section 6.5 Table 4 Prohibited Medications relating to 
savolitinib is removed and introduced into Appendix J (J 6) to provide consolidated 
guidance for the combination treatment of osimertinib and savolitinib in the same part of 
the protocol (updates to J 1 and Table 26 in relation to osimertinib or savolitinib treatment 
and Table 27 and J 5 in relation to savolitinib treatment). Additions to J 3 ‘Medicines whose 
exposures may be affected by osimertinib’ that AstraZeneca considers may be allowed with 
caution of P-gp substrate, fexofenadine, aliskerin, dabigatran etixelate and digoxin. 
 
Version 3.0, 31 May 2019 
All patients will be assigned to 300 mg od savolitinib flat dosing (see Figure 1) replacing 
the previous weight-based dosing regimen where patients were assigned to either 300mg od 
or 600 mg od savolitinib dependent upon their weight at Screening. Rationale for this 
change is described in sections 1.2, 2, 0, 4.3 and in a revised study design schema in section 
1.3 Figure 1, and revised layout of Table 9 showing savolitinib dose reductions. Preliminary 
review of emerging clinical data from the Phase I TATTON study carried out by the 
Sponsor indicated that there was an improvement in overall safety profile with no apparent 
reduction in objective response rate between weight-based savolitinib dosing (TATTON 
Part B) and 300 mg dose (TATTON Part D) in combination with osimertinib 80mg QD. 
Patients who commenced study treatment at 600 mg savolitinib can choose to either 
continue at this dose or change to 300 mg (no subsequent re-escalation will be permitted 
after changing to 300 mg dose).  
The primary and secondary variables will be summarised only on patients treated at 300 mg 
od savolitinib and not on patients treated at 600 mg od savolitinib. The interim, primary and 
final analyses triggers will be based on the number of patients treated at 300 mg savolitinib 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
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section 9.5, 1.2, 3. The approximate study population of 172 patients refers only to patients 
treated at 300 mg savolitinib (see section 1.2, 9.2), patients treated at 600 mg savolitinib 
will be in addition. Statistical analyses will be presented by the assigned starting dose (see 
Section 9.4).  
The proportion of patients treated on this study in the second line setting will be increased 
from a third to a half (see section 1.2).  
Patients may be repeatedly pre-screened. If the patient has received EGFR-TKI therapy in 
the interval since initial pre-screening, then a new blood sample for ctDNA analysis for 
diagnostic development is requested, see section 1.1 Table 1 footnote b. 
The minimum requirement for tumour tissue for central MET testing has been reduced from 
12 to 10 slides. This is documented in the Central Laboratory Manual in detail. Reference to 
the approximate number of slides required is revised from 12-22 to 10-20 slides in 
footnote c of Table 1 Schedule of Activities. 
Introduction of sequence of ECGs and extension to existing PK sampling timepoints on 
Cycle 3 Day 1 to evaluate QTc interval around the time for savolitinib and osimertinib 
maximum concentration. Triplicate ECGs and blood samples for PK assessment of 
osimertinib and savolitinib will be required Pre-dose (a blood sample for PK assessment is 
already required Pre-dose), and at the following new sample timepoints at 1 hour (h), 3 h, 
4h, and 6 h post-dose shown in Table 1 footnote p, Table 13 and section 9.4.5.  
Statement added to section 8.5.1 that actual date, time and amount of the last doses of IP 
prior to each PK sample will be recorded. 
Simplification of description of planned evaluation of PK of both IPs (section 9.4.5 and 
section 8.6, and removal of section 9.4.3.1 which gave details of population analysis of PK/ 
pharmacodynamic variables) because these analyses will be reported separately from the 
main CSR in Bioanalytical reports and do not require this level of detail in the CSP. 
Window for electronic clinical outcome assessments (eCOA) questionnaires reduced from 
±5 days to ±2 days relative to the first dose of treatment in Cycles 1 and 2 (28 day cycle). 
The increase to a ±5 day window for these assessments was an error in the previous CSP 
version 2.0; see Table 1. 
Inclusion criterion 4 amended to allow rare EGFR mutations known to be associated with 
EGFR-TKI sensitivity if permitted in the osimertinib national label in section 5.1. 
Statements added clarify that viral screening is not required to diagnose hepatitis B or 
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immunodeficiency virus, for the assessment of eligibility for the study, section 5.2 
Exclusion criteria 7 and 8. Criteria to allow inclusion of patients with a past or resolved 
HBV or HCV infection are already provided.  
Clarification added to section 5.4 Screen failures to define Pre-screen failures.  
Dose modification to osimertinib for cardiac adverse reactions are removed from Table 9. 
More detailed guidance provided in Table 1 for management of missed/late doses of 
osimertinib and savolitinib. If a daily dose of either IP is more than 12 hours late this is 
considered a missed dose and should not be taken. If a patient vomits after taking a dose a 
repeat dose should not be taken. 
Correction of the requirement for reporting AEs and SAEs during Pre-screening, prior to 
provision of a patient’s consent to the main study in section 8.3.2. Only procedure-related 
AEs and SAEs for those patients who provide a new tumour biopsy occurring within 
21 days after the procedure require reporting. This was the intended meaning of the 
previous version of the CSP and so the revised wording is to clarify the reporting 
requirements. 
Usage guidance for drugs that prolong QT interval has been consolidated into one entry in 
Table 7 Restricted medications as an administrative change. 
Guidance for the management of QTc prolongation for osimertinib and savolitinib are 
shown side by side in a revised Table 12 
Dose modifications for QTc prolongation in 
section 8.4.5.2 Management of savolitinib-related toxicities. Assessment of causality is not 
required in order to implement these dose modifications. Details of management of these 
adverse reactions has been removed from Table 11 and direction to Table 12 added to 
section 8.4.5.1.  
 
Version 2.0, 20 February 2019 
Correction to the note to Inclusion criterion 6 that local NGS testing requirements are not 
provided in the Central Laboratory Manual (these requirements are added to the CSP in this 
revision to Inclusion criterion 7). Statement added to the inclusion criterion that if 
performed this local NGS testing must be pre-approved by the Sponsor. 
Inclusion criterion 7 in section 5.1 requires patients to have available tissue from a biopsy 
for MET analysis or willingness to collect additional tissue for central testing obtained 
following progression on therapy. In this revision, the requirements for this available tissue 
are added to this inclusion criterion to reflect the importance of provision of this tumour 

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tissue and to ensure compliance with requirements already described in current Central 
Laboratory Manual and guidance in this CSP as follows: Tissue must be collected following 
progression on osimertinib therapy; obtained within 2 years of submission for MET 
analysis; and sufficient to meet the minimum tissue requirement defined in the current 
Central Laboratory Manual. The exact number of slides of tissue is not described in the CSP 
as this is subject to change. The Sponsor will continue to seek to minimise the amount of 
tissue requested during the study and this requirement will be documented in the Central 
Laboratory Manual and supporting instructions provided to sites. 
Introduction of ±7 day window for collection of blood samples for plasma for ctDNA 
analyses scheduled to be collected on the day of every RECIST 1.1 scan to offer flexibility 
for site staff and patients in Table 1, and footnote h. Addition of the purpose of ctDNA 
sampling (in Table 1 and footnotes b and h) to differentiate between use of ctDNA to 
support potential development of MET clinical diagnostic collected at Pre-screening and 
Screening for all patients and ctDNA sampling to measure clearance of EGFR mutation 
alleles and for exploratory analysis collected for eligible patients at baseline, weekly during 
Cycle 1 of treatment, Cycle 2 Day 1, at every RECIST 1.1 scan and treatment 
discontinuation to explore response to study treatment. In section 8.6, clarification that 
blood rather than plasma samples are requested for circulating DNA/RNA for consistency 
with Table 1, and clarification that the baseline sample will be collected prior to the first 
dose.  
Demography and Medical/Surgical history are requested at Pre-screening in order to allow 
collection of relevant information to support development of clinical diagnostic of either 
FISH and/or IHC MET testing, see Table 1. Demography is removed from the Screening 
assessments as this information will not change. Medical/surgical history should be 
reviewed again at Screening to assess the patient’s eligibility for the trial. 
Clarification of the two types of tumour biopsy tissue collected in footnote j of Table 1. 
Tumour biopsy tissue is required for all patients for submission to the central MET testing 
laboratory collected after progression on previous osimertinib therapy. Collection of a new 
tumour biopsy is requested following disease progression on study treatment to look at 
possible resistance mechanisms for savolitinib; collection and provision of this biopsy is 
optional. 
Addition of collection of blood samples for PK analyses on Cycle 1 Day 1 and Cycle 2 
Day 1 to Table 1 to match existing description of PK sampling schedule in section 8.5.1 and 
Table 13. 
Introduction of acceptable time windows around the preferred timing of collection of blood 
samples for PK analyses to inform clinical staff scheduling and collecting these samples; 

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Pre-dose, up to 2 hours pre-dose; 1 hour post-dose, ±5 minutes; 3 hours post-dose, ±10 
minutes to Table 1. 
Window for electronic clinical outcome assessments (eCOA) questionnaires increased from 
±2 or ±3 days to ±5 days relative to the first dose of treatment in Cycles 1 and 2 (28 day 
cycle) for ease of scheduling for the patient; see Table 1 footnote c) and section 4.1 Overall 
design: clarification of the timing of when to provide tumour tissue for central MET testing 
for those minority of patients enrolled with MET+ tumour tested by local NGS as being as 
soon as possible during Pre-screening, Screening or early during study treatment. 
Addition of serum samples to types of biological samples to be collected and stored for 
companion diagnostic development and exploratory analyses in the Exploratory objective, 
section 1.2. Addition of circulating tumour protein in addition to DNA or RNA in the 
corresponding exploratory study endpoint/variable. 
Introductory paragraph to Section 3 Objectives and Endpoints wording adjusted to make 
clear that patients included in the “All patients” population includes all patients, including 
those centrally confirmed as MET+ by either FISH and/or IHC. 
Section 4.1 Criteria for local NGS MET test to be used for assessment of patient eligibility 
require completion of the local NGS testing laboratory questionnaire to obtain Sponsor 
approval with reference to the Sponsor acceptance criteria. These criteria are not described 
in the Central Laboratory Manual and so this reference has been removed. Clarification that 
a pre-existing local NGS test result is for assessment of MET testing of tumour for the 
purpose of assessment of eligibility. Guidance that sites must provide the minimum required 
tumour tissue samples for central confirmation of MET status by central FISH and IHC 
testing as defined in the Central Laboratory Manual as soon as possible during Pre-
screening, Screening or early during study treatment. This central testing is required to 
allow determination of the study populations for each patient according to MET status by 
central FISH, central IHC and/or all patients. 
Section 7.3 Guidance on withdrawal of a patient from the study has been corrected by 
removal of the following statement "Personal information and samples that have already 
been collected prior to withdrawal will still be used as intended in the CSP.” in order to 
align with the options for withdrawal of consent available to a patient. The guidance 
included earlier in this section covers the intent of this statement “the sponsor may retain 
and continue to use any data collected before the consent is withdrawn”. The patient may 
explicitly choose to withdraw his/her consent for future use or genetic testing of samples 
already provided. The patient may choose to withdraw consent for the use of their personal 
data. 

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combination with osimertinib to the listing of standard safety parameters under rationale for 
study endpoints. 
Appendix I 3.4 recommendations for clinical management of hypersensitivity revised 
following review by the Sponsor of reported safety information for patients treated with the 
combination of savolitinib with osimertinib on the Phase I TATTON study. Investigators 
are recommended to continue treatment with savolitinib through initial mild symptoms of 
potential hypersensitivity with optimal supportive care rather than mandating immediate 
dose interruption and subsequent rechallenge. The rationale for this change in management 
is the Sponsor’s observation that the majority of severe acute hypersensitivity reactions, 
including in some cases anaphylaxis, occurred following dose interruption and rechallenge.  
If savolitinib dosing is interrupted, intense medical monitoring for restart at the institution is 
required with medical equipment readily available for resuscitation and management of 
anaphylaxis, vital status recording before and for at least 4 hours after dosing, 24 hour 
observation in the clinic prior to discharge. Should symptoms of potential hypersensitivity 
recur, or an acute anaphylactic reaction occur, immediate intervention must be instituted for 
appropriate management of the event and savolitinib must be permanently discontinued. 
These recommendations are guidelines only and final decisions concerning management of 
individual patients reside with the investigator or the treating physician. Clarification in the 
Benefit/risk assessment in Section 2.3 that these toxicity management guidelines apply to 
patients who experience hypersensitivity or pyrexia. 
Clarification that Appendix I 3.2 Dose modification guidelines due to savolitinib-related 
toxicity apply to general toxicities. Restart of savolitinib dosing following dosing hold due 
to NCI CTCAE Grade 3 or recurrence of Grade 3 toxicity must follow the specific restart 
guidelines if the event includes symptoms of pyrexia, skin reactions, myalgia, arthralgia, or 
hypersensitivity, as per section I 3.4, added as footnote b to Table 23 for NCI CTCAEs of 
Grade 3 or recurrence of Grade 3 toxicities. 
Criteria to discontinue savolitinib dosing due to drug-related hepatotoxicity have been 
revised in Appendix I 3.3.1 to clarify elevated ALT or AST >8 x ULN with total bilirubin 
elevation above baseline or ULN; or ALT or AST >5 x ULN for >2 weeks with total 
bilirubin elevation above baseline or ULN. Dosing should be withheld if ALT or AST >5 x 
ULN for >2 weeks or 8 x ULN without total bilirubin elevation above baseline or ULN. 
Dosing should be withheld if ALT or AST >3 x ULN and concurrent total bilirubin 1.5 x 
ULN. Dosing should be discontinued for recurrent ALT or AST >3 x ULN rather than >3 to 
5 x ULN; for total bilirubin >1.5 x ULN rather than >1.5 to 2 x ULN; withheld for recurrent 
ALT or AST >3 rather than >3 to 5 x ULN without total bilirubin elevation above baseline 
or ULN. 

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Appendix I 1 provides osimertinib dose modification and guidance:  
- 
An opening statement has been introduced that clinical management should be in 
accordance with the local label in the first instance which takes precedence over the 
management guidance provided in this CSP and the osimertinib investigator’s brochure.  
- 
Dose adjustment information for cardiac adverse reactions to osimertinib in Table 11 
are revised for QTcF interval greater than 500msec on at least 2 separate ECGs. 
Osimertinib should be withheld until QTcF interval is <481msec or recovery to baseline 
if baseline QTCF is >481 msec within 3 weeks of onset. Dosing can be restarted at a 
reduced dose (40mg) or at the same dose (80mg) at the discretion of the Investigator 
(also included in section I 1.2.) 
- 
The footnote to Table 11 has been updated to refer to NCI CTCAE version 5.0 in line 
with the rest of the CSP. 
- 
Addition of guidance for investigators to correct clinically significant electrolyte 
abnormalities to within normal ranges prior to first dose and during study treatment (see 
section I 1.2 QTcF prolongation). 
Aclarubicin added to list of Drugs inducing Torsades de Pointes in J 5.1 Table 29. 
Version 1.0, 20 August 2018 
Initial creation 
 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol 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. 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ............................................................................................................... 2 
TABLE OF CONTENTS ........................................................................................................ 20 
LIST OF TABLES .................................................................................................................. 23 
LIST OF FIGURES ................................................................................................................. 24 
LIST OF APPENDICES ......................................................................................................... 24 
1 
PROTOCOL SUMMARY.................................................................................... 25 
1.1 
Schedule of activities (SoA) ................................................................................. 25 
Schedule of activities (SoA) for allocated / randomised treatment ...................... 26 
Schedule of activities (SoA) for patients who cross over ..................................... 35 
1.2 
Synopsis ................................................................................................................ 40 
1.3 
Schema .................................................................................................................. 47 
2 
INTRODUCTION ................................................................................................ 48 
2.1 
Study rationale ...................................................................................................... 55 
2.2 
Background ........................................................................................................... 56 
2.3 
Benefit/risk assessment ......................................................................................... 56 
2.3.1 
Risk assessment .................................................................................................... 56 
2.3.2 
Benefit assessment ................................................................................................ 59 
2.3.3 
Overall benefit: risk conclusion ............................................................................ 60 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 60 
4 
STUDY DESIGN ................................................................................................. 63 
4.1 
Overall design ....................................................................................................... 63 
4.1.1 
Treatment allocation /randomisation study design ............................................... 63 
4.1.2 
Crossover .............................................................................................................. 66 
4.2 
Scientific rationale for study design ..................................................................... 67 
4.2.1 
Rationale for study design .................................................................................... 67 
4.2.2 
Rationale for endpoints ......................................................................................... 69 
4.3 
Justification for dose ............................................................................................. 70 
4.4 
End of study definition ......................................................................................... 72 
5 
STUDY POPULATION ....................................................................................... 73 
5.1 
Inclusion criteria ................................................................................................... 73 
5.2 
Exclusion criteria .................................................................................................. 75 
5.3 
Lifestyle restrictions ............................................................................................. 79 
5.3.1 
Meals and dietary restrictions ............................................................................... 79 
5.3.2 
Pregnancy and contraception ................................................................................ 79 
5.3.3 
Other lifestyle restrictions..................................................................................... 79 
5.4 
Screen failures ...................................................................................................... 80 

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6 
STUDY INTERVENTION .................................................................................. 80 
6.1 
Study Intervention(s) administered....................................................................... 80 
6.1.1 
Investigational products ........................................................................................ 80 
6.2 
Preparation/handling/storage/accountability of interventions .............................. 82 
6.3 
Measures to minimise bias: randomisation and blinding ..................................... 82 
6.4 
Study intervention compliance ............................................................................. 84 
6.5 
Concomitant therapy ............................................................................................. 85 
6.5.1 
Rescue Medicine ................................................................................................... 87 
6.6 
Dose modification ................................................................................................. 88 
6.6.1 
Meals and dietary restrictions ............................................................................... 88 
6.7 
Intervention after the end of the study .................................................................. 88 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ............................................................ 89 
7.1 
Discontinuation of study intervention .................................................................. 89 
7.1.1 
Rechallenge........................................................................................................... 90 
7.1.2 
Procedures for discontinuation of study treatment ............................................... 90 
7.1.3 
Follow-up of patients post discontinuation of study intervention ........................ 91 
7.1.4 
Follow-up for survival .......................................................................................... 91 
7.2 
Lost to follow-up .................................................................................................. 91 
7.3 
Withdrawal from the study ................................................................................... 92 
8 
STUDY ASSESSMENTS AND PROCEDURES................................................ 92 
8.1 
Efficacy assessments ............................................................................................ 93 
8.1.1 
CT and MRI scans tumour assessments (RECIST 1.1) ........................................ 93 
8.1.2 
Clinical outcome assessments............................................................................... 95 
8.1.2.1 
EORTC-QLQ-C30 and QLQ LC13...................................................................... 95 
8.1.2.2 
PGIS ...................................................................................................................... 96 
8.1.2.3 
PRO-CTCAE ........................................................................................................ 96 
8.1.2.4 
EQ-5D-5L ............................................................................................................. 96 
8.1.2.5 
Administration of ePRO questionnaires ............................................................... 96 
8.1.3 
Survival Follow-up ............................................................................................... 98 
8.2 
Safety assessments ................................................................................................ 98 
8.2.1 
Clinical safety laboratory assessments ................................................................. 98 
8.2.2 
Physical examinations .......................................................................................... 99 
8.2.3 
Vital signs ........................................................................................................... 100 
8.2.4 
Electrocardiograms ............................................................................................. 100 
8.2.5 
Multi-gated acquisition (MUGA)/echocardiogram (ECHO).............................. 101 
8.2.6 
Pregnancy assessments ....................................................................................... 101 
8.2.7 
ECOG Performance Status ................................................................................. 101 
8.3 
Collection of adverse events ............................................................................... 102 
8.3.1 
Method of detecting AEs and SAEs ................................................................... 102 
8.3.2 
Time period and frequency for collecting AE and SAE information ................. 102 
8.3.3 
Follow-up of AEs and SAEs............................................................................... 103 
8.3.4 
Adverse event data collection ............................................................................. 103 

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8.3.5 
Causality collection ............................................................................................ 103 
8.3.6 
Adverse events based on signs and symptoms ................................................... 104 
8.3.7 
Adverse events based on examinations and tests ............................................... 104 
8.3.8 
Hy’s law .............................................................................................................. 104 
8.3.9 
Disease-under study ............................................................................................ 105 
8.3.10 
Disease progression ............................................................................................ 105 
8.3.11 
New cancers ........................................................................................................ 105 
8.3.12 
Handling of deaths .............................................................................................. 105 
8.3.13 
Adverse events of special interest....................................................................... 106 
8.4 
Safety reporting and medical management......................................................... 106 
8.4.1 
Reporting of serious adverse events ................................................................... 106 
8.4.2 
Pregnancy ........................................................................................................... 107 
8.4.2.1 
Maternal exposure .............................................................................................. 107 
8.4.2.2 
Paternal exposure ................................................................................................ 108 
8.4.3 
Reporting of overdose......................................................................................... 108 
8.4.4 
Medication Error, Drug Abuse, and Drug Misuse .............................................. 109 
8.4.4.1 
Timelines ............................................................................................................ 109 
8.4.4.2 
Medication Error ................................................................................................. 109 
8.4.4.3 
Drug Abuse ......................................................................................................... 109 
8.4.4.4 
Drug Misuse........................................................................................................ 109 
8.4.5 
Management of IP-related toxicities ................................................................... 109 
8.4.5.1 
Management of osimertinib-related toxicities .................................................... 109 
8.4.5.2 
Management of savolitinib-related toxicities ..................................................... 110 
8.5 
Human biological samples .................................................................................. 111 
8.5.1 
Pharmacokinetics ................................................................................................ 112 
8.5.1.1 
Determination of drug concentration .................................................................. 113 
8.5.2 
Immunogenicity Assessments ............................................................................ 113 
8.5.3 
Pharmacodynamics ............................................................................................. 113 
8.6 
Human biological sample biomarkers ................................................................ 113 
8.6.1 
Collection of mandatory samples for biomarker analysis .................................. 113 
8.6.2 
Storage, re-use and destruction of biomarker samples ....................................... 115 
8.6.3 
Collection of optional biomarker samples .......................................................... 115 
8.6.4 
Other study related biomarker research .............................................................. 115 
8.7 
Optional genomics initiative sample .................................................................. 115 
9 
STATISTICAL CONSIDERATIONS ............................................................... 116 
9.1 
Statistical hypotheses .......................................................................................... 116 
9.2 
Sample size determination .................................................................................. 116 
9.3 
Populations for analyses ..................................................................................... 120 
9.4 
Statistical analyses .............................................................................................. 121 
9.4.1 
General considerations........................................................................................ 121 
9.4.2 
Stratification factor(s) ......................................................................................... 121 
9.4.3 
Efficacy analyses ................................................................................................ 122 
9.4.3.1 
Analysis of the primary endpoints ...................................................................... 122 
9.4.3.2 
Analysis of the secondary endpoints .................................................................. 123 

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9.4.3.3 
EORTC QLQ-C30 and QLQ-LC13 ................................................................... 125 
9.4.4 
Safety analyses.................................................................................................... 127 
9.4.5 
Pharmacokinetic analyses ................................................................................... 128 
9.4.6 
Other analyses ..................................................................................................... 129 
9.5 
Interim, futility, primary, and final analyses ...................................................... 130 
9.6 
Data Monitoring Committees ............................................................................. 132 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .......................................................................................... 133 
11 
REFERENCES ................................................................................................... 201 
 
LIST OF TABLES  
Table 1 
Schedule of Activities for allocated / randomised treatment ...................... 26 
Table 2 
Schedule of activities for patients who cross over to savolitinib plus 
osimertinib from savolitinib plus placebo ................................................... 35 
Table 3 
Risk Assessment .......................................................................................... 57 
Table 4 
Study objectives .......................................................................................... 60 
Table 5 
Patient Enrolment onto SAVANNAH Dosing Regimens ........................... 64 
Table 6 
Study treatments .......................................................................................... 81 
Table 7 
Restricted medications ................................................................................ 85 
Table 8 
Dose reduction for osimertinib (or placebo to osimertinib) to manage 
adverse events ............................................................................................. 88 
Table 9 
Dose reduction for savolitinib to manage adverse events ........................... 88 
Table 10 
Laboratory safety variables ......................................................................... 99 
Table 11 
Osimertinib dose adjustment information for adverse reactions ............... 110 
Table 12 
Dose modifications for QTc prolongation ................................................ 111 
Table 13 
Pharmacokinetic sampling schedule ......................................................... 112 
Table 14 
Visit Response for HRQoL and disease-related symptoms ...................... 127 
Table 15 
Summary of methods of assessment (RECIST) ........................................ 164 
Table 16 
Overall visit response for target lesions .................................................... 168 
Table 17 
Evaluation of non-target lesions ................................................................ 169 
Table 18 
Overall visit response ................................................................................ 170 
Table 19 
Dose reduction for osimertinib to manage adverse events ........................ 174 
Table 20 
Osimertinib Dose Adjustment Information for Adverse Reactions .......... 175 
Table 21 
Dose Modifications for Osimertinib-Related QTc Prolongation .............. 176 
Table 22 
Dose reduction for savolitinib to manage adverse events ......................... 178 

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Table 23 
Dose modifications for savolitinib-related toxicities ................................ 178 
Table 24 
Dose modifications for savolitinib-related QTc prolongation .................. 181 
Table 25 
Management of QTc prolongation ............................................................ 182 
Table 26 
Drugs inducing CYP3A4 .......................................................................... 184 
Table 27 
Drugs inhibiting CYP1A2 ......................................................................... 185 
Table 28 
Exposure, pharmacological action and toxicity may be increased or 
decreased by osimertinib ........................................................................... 185 
Table 29 
Drugs with a known risk of Torsades de Pointes (TdP) ............................ 187 
Table 30 
Drugs that may prolong QT interval ......................................................... 188 
 
LIST OF FIGURES  
Figure 1 
Study design ................................................................................................ 47 
 
LIST OF APPENDICES  
Appendix A 
Regulatory, ethical and study oversight considerations ............................ 133 
Appendix B 
Adverse event definitions and additional safety information ................... 142 
Appendix C 
Handling of human biological samples ..................................................... 147 
Appendix D 
Genetics optional genomics initiative sample ........................................... 150 
Appendix E 
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law ............................................................................. 154 
Appendix F 
New York Heart Association classification of heart disease .................... 160 
Appendix G 
Definition of women of childbearing potential and acceptable 
contraceptive methods ............................................................................... 161 
Appendix H 
Guidelines for evaluation of objective tumour response using 
RECIST 1.1 ............................................................................................... 163 
Appendix I 
Dose modifications for the management of adverse events ...................... 174 
Appendix J 
Guidance regarding potential interactions with concomitant medications 184 
Appendix K 
Patient reported outcome assessments ...................................................... 189 
Appendix L 
Abbreviations ............................................................................................ 197 
 

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1 
PROTOCOL SUMMARY  
1.1 
Schedule of activities (SoA)  
The schedule of activities (SoA) at screening, treatment period, discontinuation, follow-up 
period and progression is shown in Table 1. The SoA for patients who cross over to 
savolitinib 300 mg bid plus osimertinib from the savolitinib 300 mg bid plus placebo arm is 
shown in Table 2. 
 

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Schedule of activities (SoA) for allocated / randomised treatment  
Table 1 
Schedule of Activities for allocated / randomised treatment  
Visit 
Pre-
screening Screening 
Treatment Period 
Follow-upa 
Details 
in CSP 
section 
Cycle 1 
(28-day cycle) 
Cycles 2 to 
6 
(28-day 
cycle) 
Cycle 7 
onwards 
(28-day 
cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
Visitb 
Progre-
ssion 
Follow-
upc 
Surviv-
al 
Follow 
up 
Week (Day 1 of) 
NA 
-4 to 0 
1 to 4 
5 to 24 
25 onwards 
Study Day 
 
-28 to -1 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
NA 
 
1 
8 
15 
22 
1 
1 
Visit window  
 
 
±1 day 
±3 days 
±3 days 
Within 7 days of 
the final dose of 
the last IP 
±7 days 
±7 days 
± 7 days 
 
Informed consent for MET 
status testing 
X 
 
 
 
 
 
 
 
 
 
 
 
5.1 
Retrieve or collect tumour 
tissue for MET status 
testing 
Xe 
 
 
 
 
 
 
 
 
 
 
 
5.1 and 
8.6 
Blood sample for ctDNA 
for diagnostic 
development)d 
X 
X 
 
 
 
 
 
 
 
 
  
 
8.6 
Confirm tumour harbours 
EGFRm (exon 19 deletion 
and/or L858R) 
Xf 
 
 
 
 
 
 
 
 
 
 
 
5.1 
Informed consent for main 
study 
 
X 
 
 
 
 
 
 
 
 
 
 
5.1 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
5.1 and 
5.2 

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Visit 
Pre-
screening Screening 
Treatment Period 
Follow-upa 
Details 
in CSP 
section 
Cycle 1 
(28-day cycle) 
Cycles 2 to 
6 
(28-day 
cycle) 
Cycle 7 
onwards 
(28-day 
cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
Visitb 
Progre-
ssion 
Follow-
upc 
Surviv-
al 
Follow 
up 
Week (Day 1 of) 
NA 
-4 to 0 
1 to 4 
5 to 24 
25 onwards 
Study Day 
 
-28 to -1 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
NA 
 
1 
8 
15 
22 
1 
1 
Visit window  
 
 
±1 day 
±3 days 
±3 days 
Within 7 days of 
the final dose of 
the last IP 
±7 days 
±7 days 
± 7 days 
 
Routine clinical procedures 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
5.1 
Physical examination  
 
X 
X 
X 
X 
X 
Every visit 
X 
 
 
 
8.2.2 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
8.2.3 
Weight 
 
Xg 
X 
 
 
 
Day 1 of 
every cycle 
Every 
8 weeks 
X 
 
 
 
8.2.3 
Medical/surgical history 
and comorbid conditions 
X 
X 
 
 
 
 
 
 
 
 
 
 
5.1 
ECOG/WHO performance 
score 
 
X 
X 
X 
X 
X 
Day 1 of every cycle 
X 
X 
 
 
5.1 
Vital signs 
 
X 
X 
X 
X 
X 
Day 1 of every cycle 
X 
X 
 
 
8.2.3 
Triplicate ECG  
 
X 
X 
X 
X 
X 
Day 1 of every cycle 
Cycle 3 Day 1t 
X 
Xh 
 
 
8.2.4 
MUGA/ECHO  
 
X 
Q12W (±2 weeks) relative to randomisation (patients 
recruited under CSP v7.0) or first dose of study drug 
(patients recruited prior to CSP v7.0) 
X 
Xh 
 
 
8.2.5 
Concomitant medication 
and procedures 
 
X 
At every visit and may be conducted by phone if not tied 
to a clinic visit 
X 
X 
 
 
6.5 

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Visit 
Pre-
screening Screening 
Treatment Period 
Follow-upa 
Details 
in CSP 
section 
Cycle 1 
(28-day cycle) 
Cycles 2 to 
6 
(28-day 
cycle) 
Cycle 7 
onwards 
(28-day 
cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
Visitb 
Progre-
ssion 
Follow-
upc 
Surviv-
al 
Follow 
up 
Week (Day 1 of) 
NA 
-4 to 0 
1 to 4 
5 to 24 
25 onwards 
Study Day 
 
-28 to -1 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
NA 
 
1 
8 
15 
22 
1 
1 
Visit window  
 
 
±1 day 
±3 days 
±3 days 
Within 7 days of 
the final dose of 
the last IP 
±7 days 
±7 days 
± 7 days 
 
Routine safety measurements 
Adverse events 
 
X 
At every visit and may be conducted by phone if not tied 
to a clinic visit 
X 
X 
 
 
8.3 
Pregnancy test (serum or 
urine, WOCBP only) 
 
X 
Day 1 of every cycle 
X 
 
 
 
8.2.6 
Safety laboratory 
assessments (clinical 
chemistry, haematology 
and urinalysis) 
 
X 
X 
X 
X 
X 
Every visit 
X 
 
 
 
8.2.1 
Coagulation 
 
X 
 
 
 
 
 
5.1 and 
8.2.1 
Liver function testsi 
 
X 
Weekly for the first 10 weeks, then Day 1 of every 
subsequent cycle 
X 
 
 
 
8.2.1 
Biomarker analyses 
Blood sample for ctDNA 
for EGFR mutation alleles 
and exploratory analysisj 
 
 
Pre-dose on Day 1 and at 
every subsequent visit in 
Cycle 1 
Day 1 of Cycle 2 and then 
on occurrence of every 
RECIST 1.1 scanj  
 
 
X 
(taken at 
progre-
ssion) 
 
8.6 

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CCI

Clinical Study Protocol – 8.0 
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CONFIDENTIAL AND PROPRIETARY 
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Visit 
Pre-
screening Screening 
Treatment Period 
Follow-upa 
Details 
in CSP 
section 
Cycle 1 
(28-day cycle) 
Cycles 2 to 
6 
(28-day 
cycle) 
Cycle 7 
onwards 
(28-day 
cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
Visitb 
Progre-
ssion 
Follow-
upc 
Surviv-
al 
Follow 
up 
Week (Day 1 of) 
NA 
-4 to 0 
1 to 4 
5 to 24 
25 onwards 
Study Day 
 
-28 to -1 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
NA 
 
1 
8 
15 
22 
1 
1 
Visit window  
 
 
±1 day 
±3 days 
±3 days 
Within 7 days of 
the final dose of 
the last IP 
±7 days 
±7 days 
± 7 days 
 
Efficacy measurements 
Tumour imaging (RECIST 
Version 1.1)p 
 
Xq 
Q6W (±7 days) up to 24 weeks, then every Q8W (±7 days) until objective disease progression relative to 
randomisation (patients recruited under CSP v7.0) or the first dose of treatment (patients recruited prior to CSP 
v7.0) 
8.1 
EORTC QLQ-C30 
 
X 
Q4W (±2 days) relative to randomisation (patients 
recruited under CSP v7.0) or the first dose of treatment 
(patients recruited prior to CSP v7.0)r 
Xs 
 
 
 
8.1.2.1 
QLQ-LC13 
 
X 
Weekly (±2 days) in Cycles 1 and 2 and then Q4W 
(±2 days) relative to randomisation (patients recruited 
under CSP v7.0) or the first dose of treatment from 
Cycle 3 onwards (patients recruited prior to CSP v7.0)r 
Xs 
 
 
 
8.1.2.1 
PGIS 
 
X 
Q8W (±2 days) relative to randomisation (patients 
recruited under CSP v7.0) or the first dose of treatment 
(patients recruited prior to CSP v7.0)r 
Xs 
 
 
 
8.1.2.2 
PRO-CTCAE 
 
X 
Weekly (±2 days) in Cycles 1 and 2 and then Q4W 
(±2 days) relative to randomisation (patients recruited 
under CSP v7.0) or the first dose of treatment (patients 
recruited prior to CSP v7.0) from Cycle 3 onwardsr 
Xs 
 
 
 
8.1.2.3 

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Visit 
Pre-
screening Screening 
Treatment Period 
Follow-upa 
Details 
in CSP 
section 
Cycle 1 
(28-day cycle) 
Cycles 2 to 
6 
(28-day 
cycle) 
Cycle 7 
onwards 
(28-day 
cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
Visitb 
Progre-
ssion 
Follow-
upc 
Surviv-
al 
Follow 
up 
Week (Day 1 of) 
NA 
-4 to 0 
1 to 4 
5 to 24 
25 onwards 
Study Day 
 
-28 to -1 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
NA 
 
1 
8 
15 
22 
1 
1 
Visit window  
 
 
±1 day 
±3 days 
±3 days 
Within 7 days of 
the final dose of 
the last IP 
±7 days 
±7 days 
± 7 days 
 
EQ-5D-5L 
 
X 
Q4W (±2 days) relative to randomisation (patients 
recruited under CSP v7.0) or the first dose of treatment 
(patients recruited prior to CSP v7.0)r 
Xs 
 
 
 
8.1.2.4 
Study treatment administration 
Dose with osimertinib or 
placebo to osimertinib 
 
 
X (daily dosing) 
 
 
 
 
6 
Dose with savolitinib 
 
 
X (daily dosing) 
 
 
 
 
6 
Survival follow up 
Survival statusu 
 
 
 
 
 
 
 
 
 
 
 
Q12W 
8.1.3 
Subsequent anti-cancer 
treatment  
 
 
 
 
 
 
 
 
 
 
 
Q12W 
8.1.3 
 
a 
The follow up period is only applicable for those who discontinue allocated/ randomised treatment and do not cross over to treatment with savolitinib plus 
osimertinib. Patients who cross over are to carry on assessments as per the SoA in Table 2. 
b 
As a minimum, telephone contact should be made with the patient 28 days following the discontinuation of both IPs to collect new AEs and follow up on 
any ongoing AEs and concomitant medications (including any subsequent cancer therapy, if appropriate). 

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Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 33 of 207 
 
o 
Plasma concentrations of osimertinib, savolitinib and their metabolites. Collected on: Cycle 1, Day 1: predose, 1 and 3 hours postdose; Cycle 2, Day 1; 
predose, 1 and 3 hours post-dose; Cycle 3 Day 1: pre-dose, 1, 3, 4 and 6 hours post-dose; Cycles 6 and 11, Day 1: predose only. PK sample collection 
windows are: Pre-dose, up to 2 hours pre-dose; 1 hour post-dose, ±5 minutes; 3, 4, and 6 hours post-dose, ±10 minutes. For patients receiving twice daily 
dosing (savolitinib 300 mg bid), PK samples will be collected following the first dose of the day. 
p 
Patients who discontinue study drug for reasons other than investigator-confirmed disease progression will continue RECIST 1.1 tumour assessments every 
6 weeks (±7 days) until Cycle 7 (ie, 24 weeks) and then every 8 weeks (±7 days) (relative to randomisation [patients recruited under CSP v7.0] or the first 
dose of treatment [patients recruited prior to CSP v7.0]) until objective disease progression per RECIST 1.1 as assessed by the investigator, unless they 
withdraw consent to the entire study. At the same time points, vital signs, ECGs, and plasma samples for ctDNA will be collected. SAEs considered related 
to study treatment and/or study procedures will be collected throughout progression follow-up. 
q 
At screening the MRI/CT scans will include brain imaging (MRI preferred) for all patients randomised under CSP version 7.0. Those determined to have 
brain metastases at baseline or those who had a history of brain metastases will have their brain rescanned (using the same modality as at baseline) at all 
subsequent tumour assessments until RECIST 1.1-defined PD (including PD). In patients without brain metastases at baseline and without a history of brain 
metastases, brain scans will be performed only when there is a suspected CNS progression and at the RECIST 1.1-defined extracranial progression. The 
brain scan is required for all patients at PD by investigator assessment per RECIST 1.1 and should be performed within 4 weeks, but preferably as soon as 
possible, to allow the assessment of new lesions in the brain. 
r 
ePRO (Electronic devices; LogPads) must be assigned to patients confirmed as eligible for the study, following registration in IWRS after which the device 
may be taken home by the patient: baseline ePROs must be completed by patients prior to dosing on Cycle 1 Day 1. Screening ePRO assessments offer the 
opportunity for site staff to set up the device, add the patient, and for the patient to practice reporting ePROs for the first time and make themselves familiar 
with the device before the baseline assessment at Cycle 1 Day 1. PRO-CTCAE will be administered only in the languages where a linguistically validated 
version exists. LogPads used for ePRO collection should be returned to site at the nearest visit as soon as the last assessment is completed by patient. 
s 
For patients on the savolitinib 300 mg bid + placebo arm who are eligible for cross over to the savolitinib 300 mg + osimertinib combination arm, the ePRO 
must be completed after progressive disease is assessed and confirmed by the Investigator, and before crossing over to the combination arm (within 7 days 
of the final dose of savolitinib + placebo). 
t 
Triplicate ECGs will be required on Cycle 3 Day 1 collected to coincide with collection of blood samples for assessment of PK of osimertinib and 
savolitinib at this visit. 
u 
Patients will be contacted for survival follow-up every 12 weeks until death, withdrawal of consent or the end of the study ie, at the time of final analysis. 
Patients should be contacted in the week following the data cut-offs to provide complete survival data. SAEs considered related to study treatment will be 
collected throughout survival follow-up. 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 34 of 207 
 
AE  Adverse event; bid  twice daily; CSP  Clinical Study Protocol; ctDNA  Circulating tumour deoxyribonucleic acid; CNS  Central nervous system; CT  
Computed tomography; CTSQ-16  Cancer Therapy Satisfaction Questionnaire-16; DNA  Deoxyribonucleic acid; ECG  Electrocardiogram; 
ECHO  Echocardiogram; ECOG  Eastern Cooperative Oncology Group; EGFR  Epidermal growth factor receptor; EORTC-QLQ-C30  European Organisation 
for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; ePRO  electronic patient reported outcomes; EQ-5D-5L  EuroQol 5 dimensions, 
5 levels; FACT-L  Functional Assessment of Cancer Therapy – Lung Cancer; HLA  human leukocyte antigen; IHC  Immunohistochemistry; IP  Investigational 
product; IWRS  Interactive Web Response System; MET  Mesenchymal epithelial transition factor; MRI  Magnetic resonance imaging; MUGA  Multi-gated 
acquisition; NA  Not applicable; NGS  Next generation sequencing; PD  Progressive disease; PK  Pharmacokinetics; PRO-CTCAE  Patient reported outcomes 
version of the Common Terminology Criteria for Adverse Events; Q4W  Every 4 weeks; Q6W  Every 6 weeks; Q8W  Every 8 weeks; Q12W  Every 12 weeks;  
QLQ-LC13  Quality of Life Questionnaire-Lung Cancer 13; RECIST 1.1  Response Evaluation Criteria in Solid Tumours version 1.1; TKI  Tyrosine kinase 
inhibitor; WHO  World Health Organization; WOCBP  Women of child-bearing potential. 
 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 35 of 207 
 
Schedule of activities (SoA) for patients who cross over  
Table 2 
Schedule of activities for patients who cross over to savolitinib plus osimertinib from savolitinib plus placebo  
Crossover Visit 
Prior to 
crossover 
Crossover Period  
Follow-up 
Details 
in CSP 
Section  
Cycle 1  
(28-day cycle) 
Cycles 2 to 6  
(28-day cycle) 
Cycle 7 
onwards  
(28-day cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
visita 
Progre-
ssion 
Follow-
upb 
Survival 
Follow-up  
Week (Day 1 of) 
1 to 4 
5 to 24 
25 onwards 
Study day of crossover 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
1 
8 
15 
22 
1 
1 
Visit window 
NA 
± 1 day 
± 3 days 
± 3 days 
Within 7 days of 
the final dose of 
the last IP 
± 7 days 
± 7 days 
± 7 days 
 
Informed consent for 
crossover 
X 
 
 
 
 
 
 
 
5.1 
Routine clinical procedures 
Physical examination  
 
X 
 
 
 
Every visit 
X 
 
 
 
8.2.2 
Weight 
 
X 
 
 
 
Day 1 of every 
cycle 
Q8W 
X 
 
 
 
8.2.3 
ECOG/WHO performance 
score 
 
X 
 
 
 
Day 1 of every cycle 
X 
X 
 
 
5.1 
Vital signs 
 
X 
 
 
 
Day 1 of every cycle 
X 
X 
 
 
8.2.3 
Triplicate ECG 
 
X 
 
 
 
Day 1 of every cycle 
X 
Xc 
 
 
8.2.4 
MUGA/ECHO 
 
Q12W (±2 weeks) relative to crossover C1D1 
X 
Xc 
 
 
8.2.5 
Concomitant medication 
and procedures 
 
At every visit, and may be conducted by phone if not tied 
to a clinical visit 
X 
X 
 
 
6.5 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 36 of 207 
 
Crossover Visit 
Prior to 
crossover 
Crossover Period  
Follow-up 
Details 
in CSP 
Section  
Cycle 1  
(28-day cycle) 
Cycles 2 to 6  
(28-day cycle) 
Cycle 7 
onwards  
(28-day cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
visita 
Progre-
ssion 
Follow-
upb 
Survival 
Follow-up  
Week (Day 1 of) 
1 to 4 
5 to 24 
25 onwards 
Study day of crossover 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
1 
8 
15 
22 
1 
1 
Visit window 
NA 
± 1 day 
± 3 days 
± 3 days 
Within 7 days of 
the final dose of 
the last IP 
± 7 days 
± 7 days 
± 7 days 
 
Routine safety measurements 
Adverse events 
 
At every visit, and may be conducted by phone if not tied 
to a clinical visit 
X 
X 
 
 
8.3 
Pregnancy test (serum or 
urine, WOCBP only) 
 
Day 1 of every cycle 
X 
 
 
 
8.2.6 
Safety laboratory 
assessments (clinical 
chemistry, haematology 
and urinalysis)d 
 
Xd 
 
 
 
Every visit 
X 
 
 
 
8.2.1 
Liver function testse 
 
Weekly for the first 10 weeks of the study as per 
Table 1e, then Day 1 of every subsequent cycle 
X 
 
 
 
8.2.1 

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Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 38 of 207 
 
Crossover Visit 
Prior to 
crossover 
Crossover Period  
Follow-up 
Details 
in CSP 
Section  
Cycle 1  
(28-day cycle) 
Cycles 2 to 6  
(28-day cycle) 
Cycle 7 
onwards  
(28-day cycle) 
Treatment 
Discontinuation 
Visit 
28-day 
Follow-up 
visita 
Progre-
ssion 
Follow-
upb 
Survival 
Follow-up  
Week (Day 1 of) 
1 to 4 
5 to 24 
25 onwards 
Study day of crossover 
1 to 28 
29 to 168 
169 onwards 
Day of cycle 
1 
8 
15 
22 
1 
1 
Visit window 
NA 
± 1 day 
± 3 days 
± 3 days 
Within 7 days of 
the final dose of 
the last IP 
± 7 days 
± 7 days 
± 7 days 
 
Study treatment administration 
Dose with osimertinib 
 
X (daily dosing) 
 
 
 
 
6 
Dose with savolitinibi 
 
X (daily dosing) 
 
 
 
 
6 
Survival follow-up 
Survival statusj 
 
 
 
 
 
 
 
 
 
 
Q12W 
8.1.3 
Subsequent anti-cancer 
treatment 
 
 
 
 
 
 
 
 
 
 
Q12W 
8.1.3 
a 
As a minimum, telephone contact should be made with the patient 28 days following the discontinuation of both IPs to collect new AEs and follow up on 
any ongoing AEs and concomitant medications (including any subsequent cancer therapy, if appropriate). 
b 
At the investigator’s discretion, study treatment may continue after progression if a patient continues to derive clinical benefit per guidelines. Patients who 
continue on treatment following progression should maintain the schedule of assessments at each cycle (28 days): Routine safety measurements (AEs, 
safety laboratory assessments [clinical chemistry, haematology and urinalysis], and creatinine clearance calculation) and Routine clinical procedures 
(physical exam, WHO PS, vital signs, Echo/multi-gated acquisition (MUGA), and concomitant medications). In addition, patients will continue to be 
followed up for survival status every 12 weeks until death, or withdrawal of consent. 
c 
A 28-day follow-up assessment will be required if an on-treatment assessment was abnormal at the time of discontinuation of study therapy to confirm 
reversibility of the abnormality. 
d 
The frequency of safety laboratory assessments will depend on the timepoint at which the patient crosses over. Safety laboratory assessments should be 
performed weekly on Days 1, 8, 15, and 22 during the first 4 weeks of the study (ie, for patients who cross over prior to completing the first 4 weeks of the 
study) then every subsequent cycle visit in the crossover period. 

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PPD

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 41 of 207 
 
This Phase II study (SAVANNAH) will investigate the efficacy and safety of osimertinib 
(80 mg od) in combination with savolitinib (300 mg od, 300 mg bid or 600 mg od) in patients 
with EGFRm+ and MET-amplified/overexpressed (patients with FISH10+ and/or IHC90+ 
status across all clinical study protocol (CSP) versions and patients with FISH5+ and/or 
IHC50+ status prior to CSP version 7.0), locally advanced or metastatic NSCLC who have 
progressed following treatment with osimertinib. The study will also investigate the difference 
in efficacy of savolitinib in combination with osimertinib and savolitinib monotherapy in the 
population enrolled under CSP version 7.0 with MET-amplified/overexpressed (FISH10+ 
and/or IHC90+) status who have progressed following treatment with 1L osimertinib therapy. 
Objectives and Endpoints 
Primary Objective: 
Endpoint: 
• 
To determine the efficacy of savolitinib (300 mg 
bid) in combination with osimertinib in patients 
with EGFRm+ and MET amplified/overexpressed 
(FISH10+ and/or IHC90+)a, locally advanced or 
metastatic NSCLC who have progressed 
following treatment with 1L osimertinib 
• 
To determine the efficacy of savolitinib (300 mg 
od) in combination with osimertinib in patients 
with EGFRm+, MET amplified/overexpressed 
(FISH5+ and/or IHC50+)b, locally advanced or 
metastatic NSCLC who have progressed 
following osimertinib. 
• 
ORR by investigator assessment in accordance 
with RECIST 1.1. 
Secondary Objectives: 
Endpoints: 
To determine the efficacy of savolitinib (300 mg bid) 
in combination with osimertinib in patients with 
EGFRm+ and MET amplified/overexpressed 
(FISH10+ and/or IHC90+)a, locally advanced or 
metastatic NSCLC who have progressed following 
treatment with 1L osimertinib. 
• 
DoR and PFS by investigator assessment in 
accordance with RECIST 1.1 
• 
OS 
To describe the difference in the efficacy of savolitinib 
(300 mg bid) in combination with osimertinib and 
savolitinib (300 mg bid) in combination with placebo 
in patients with EGFRm+, MET 
amplified/overexpressed (FISH10+ and/or IHC90+)a, 
locally advanced or metastatic NSCLC who have 
progressed following treatment with 1L osimertinib 
therapy under CSP version 7.0. 
 
• 
ORR by investigator assessment in accordance 
with RECIST 1.1 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 42 of 207 
 
To determine the efficacy of savolitinib (300 mg od 
and 600 mg od, respectively) in combination with 
osimertinib in patients with EGFRm+, 
MET-amplified/overexpressed (FISH10+ and/or 
IHC90+)a, locally advanced or metastatic NSCLC who 
have progressed following treatment with 1L 
osimertinib. 
• 
ORR, DoR, and PFS, by investigator 
assessment in accordance with RECIST 1.1. 
• 
OS 
To determine the efficacy of savolitinib (300 mg od, 
300 mg bid, and 600 mg od, respectively) in 
combination with osimertinib in patients with 
EGFRm+, MET-amplified/overexpressed (FISH10+ 
and/or IHC90+)a, locally advanced or metastatic 
NSCLC who have progressed following treatment of 
≥ 2L osimertinib. 
• 
ORR, DoR, and PFS, by investigator 
assessment in accordance with RECIST 1.1. 
• 
OS 
To determine the efficacy of savolitinib (300 mg od, 
300 mg bid, and 600 mg od, respectively) in 
combination with osimertinib in patients with 
EGFRm+, MET-amplified/overexpressed (FISH5+ 
and/or IHC50+)b, locally advanced or metastatic 
NSCLC who have progressed following osimertinib. 
• 
ORR (except 300 mg od), DoR, and PFS by 
investigator assessment in accordance with 
RECIST 1.1. 
• 
OS 
To determine the efficacy of (1) 300 mg od, 300 mg 
bid and 600 mg od of savolitinib in combination with 
osimertinib in patients with EGFRm+ MET amplified/ 
overexpressed (FISH 10+ and/or IHC90+)a,b; 
(2) 300 mg od, 300 mg bid and 600 mg od of 
savolitinib in combination with osimertinib in patients 
with EGFRm+ MET amplified/overexpressed 
(FISH5+ and/or IHC50+)b (3) savolitinib 300 mg bid 
in combination with osimertinib and savolitinib 
300 mg bid in combination with placebo, respectively, 
in patients with EGFRm+ MET amplified/ 
overexpressed (FISH10+ and/or IHC90+)a following 
treatment with 1L osimertinib. 
• 
ORR, DoR, and PFS assessed by BICR in 
accordance with RECIST 1.1 
To assess the impact of savolitinib and osimertinib on 
disease-related symptoms and HRQoL in this patient 
population. 
• 
Mean change from baseline in EORTC QLQ-
C30 and QLQ-LC13. 
To evaluate the pharmacokinetics of osimertinib and 
savolitinib in this patient population. 
• 
Plasma concentrations of osimertinib, 
savolitinib and their metabolites. 
To determine the prevalence of ctDNA clearance after 
osimertinib and savolitinib treatment in this patient 
population. 
• 
Total clearance in EGFR mutations at 6-weeks 
after therapy initiation (percentage and absolute 
change from baseline in EGFR mutation allele 
frequencies). 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 43 of 207 
 
Safety Objectives: 
Endpoints: 
To evaluate the safety and tolerability of savolitinib in 
combination with osimertinib and savolitinib in 
combination with placebo. 
• 
AEs, SAEs and discontinuation rate due to AEs. 
• 
Clinical chemistry/haematology including 
LFTs. 
• 
ECHOs, ECGs and vital signs including blood 
pressure and heart rate. 
a 
Patients with MET-amplified/overexpressed NSCLC with FISH10+ (≥10 MET gene copies according to 
central MET FISH test) and/or IHC90+ (≥90% of tumour cells staining at strong 3+ intensity according to 
central MET IHC test). 
b 
Patients with MET-amplified/overexpressed NSCLC with FISH5+ (≥5 MET gene copies or MET:CEP7 
ratio ≥2) and/or IHC50+ (≥50% of tumour cells staining at strong 3+ intensity). 
Osimertinib 80 mg od is administered in the combination dosing regimens. 
1L  First line;  2L  Second line;  AE  Adverse event; bid  twice daily; BICR  Blinded independent central review; 
CTCAE  Common Terminology Criteria for Adverse Events; DoR  Duration of response; ECG  
Electrocardiogram; ECHO  Echocardiogram; EGFR  Epidermal growth factor receptor; EGFRm+  Epidermal 
growth factor receptor mutation positive; EQ-5D-5L  EuroQol 5 dimensions, 5 levels; FACT-L  Functional 
Assessment of Cancer Therapy - Lung Cancer; FISH  Fluorescence in situ hybridisation; HRQoL  Health-related 
quality of life; IHC  Immunohistochemistry; LFT  liver function test; MET  Mesenchymal epithelial transition 
factor; MET/CEP7  Mean MET per cell and chromosome 7 centromere ratio; NGS  Next generation sequencing; 
NSCLC  Non-Small Cell Lung Cancer; od  once daily; ORR  Objective response rate; OS  Overall survival; 
PFS  Progression-free survival; PRO  Patient reported outcomes; QLQ-LC13  Quality of Life Questionnaire-
Lung Cancer 13; RNA  Ribonucleic acid; SAE  Serious adverse events. 
 
Overall design: 
This is a Phase II study to investigate the efficacy of osimertinib administered orally with 
savolitinib in patients with EGFRm+ and MET-amplified/overexpressed, locally advanced or 
metastatic NSCLC who have progressed following treatment with osimertinib. 
Under CSP version 7.0, the SAVANNAH study will be expanded to further investigate the 
efficacy of savolitinib 300 mg bid + osimertinib in MET-amplified/overexpressed (FISH10+ 
and/or IHC90+) patients who have progressed following 1L osimertinib treatment. Per CSP 
version 7.0, the study will also describe the difference in the efficacy of osimertinib in 
combination with savolitinib 300 mg bid and savolitinib monotherapy in the treatment of 
EGFRm+ NSCLC patients with MET FISH10+ and/or IHC90+ status whose tumour has 
progressed following 1L osimertinib treatment. 
The study design for patients who were enrolled under CSP versions 1.0 to 6.0, and for 
patients who will be enrolled under CSP version 7.0 is summarised in Figure 1. 
Study Period: 
• 
Estimated date of first patient enrolled: Q4 2018 
• 
Estimated date of last patient completed (final data cut-off): Q1 2025 

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1.3
Schema
Figure 1
Study design
a
IHC50+: ≥50% of tumour cells staining at strong 3+ intensity; FISH5: ≥5 MET gene copies or MET:CEP7 ratio ≥2 as determined by central testing. Under 
CSP versions 1-5, MET amplification as determined by pre-existing local NGS were also allowed. Under CSP version 6, only MET FISH5+ status as 
determined by central testing was allowed for eligibility.
b
IHC90+: >=90% of tumour cells staining at strong 3+ intensity; FISH10: ≥10 MET gene copies; as determined by central testing.
c
A futility analysis for the savolitinib + placebo arm is planned after 
 patients have been randomised under CSP version 7.0 and have had an opportunity to 
have 2 post-baseline scans. If the decision is made that treatment with savolitinib + placebo is futile, further enrolment into the savolitinib + placebo arm 
will be stopped.
1L  First-line; bid; Twice daily; CSP  Clinical Study Protocol; ECOG  Eastern Cooperative Oncology Group; EGFRm+  Epidermal growth factor receptor 
mutation positive; EGFR-TKI  EGFR-tyrosine kinase inhibitor; FISH  Fluorescence in situ hybridisation; IHC  Immunohistochemistry; MET  Mesenchymal 
epithelial transition factor; MET/CEP7  Mean MET per cell and chromosome 7 centromere ratio; NSCLC  Non-small cell lung cancer; od  once daily; PD  
Progressive disease; RECIST  Response Evaluation Criteria in Solid Tumours.
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Osimertinib + savolitinib - D5084C00007 
 
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2 
INTRODUCTION  
Lung cancer has been the most common cancer in the world for several decades, and by 2012, 
there were an estimated 1.8 million new cases, representing 12.9% of all new cancers. It was 
also the most common cause of death from cancer, with 1.59 million deaths (19.4% of the 
total) (GLOBOCAN 2012). Non-small cell lung cancer (NSCLC) represents approximately 
80% to 85% of all lung cancers. Unfortunately, at the time of diagnosis approximately 70% of 
NSCLC patients already have advanced or metastatic disease not amenable to surgical 
resection. Furthermore, a significant percentage of early-stage NSCLC patients who have 
undergone surgery subsequently develop distant recurrence and die as a result of their lung 
cancer (Pisters and Le Chevalier 2005). Patients presenting with unselected advanced NSCLC 
have a median overall survival (OS) of 10 to 12 months (Bonomi 2010). 
In current clinical practice, therapeutic decisions for patients with advanced NSCLC are 
informed by the molecular subtypes of the tumour (Keedy et al 2011; Leigh et al 2014; 
National Comprehensive Cancer Network [NCCN 2018]; Reck et al 2014; Soria et al 2015; 
Travis et al 2011). Epidermal growth factor receptor (EGFR) mutation and anaplastic 
lymphoma kinase rearrangement are the most well-known genetic alterations in NSCLC. 
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the established first-line therapy in patients 
with NSCLC possessing activating mutations in EGFR (EGFRm+) (Masters et al 2015; 
National Comprehensive Cancer Network [NCCN 2018]; Reck et al 2014). The presence of 
EGFRm in patients with NSCLC tumours confers sensitivity to the EGFR-TKI class of drugs 
in a high percentage of patients, however, the response to this class of agents is eventually lost 
due to development of a variety of resistance mechanisms, with the EGFR T790M mutation 
being a major route of development of resistance to this class of therapy. In addition to the 
development of T790M mutations, other routes of acquired resistance to EGFR-TKI therapy 
include activation of a bypass signalling pathway (such as hepatocyte growth factor [HGF] 
receptor, mesenchymal epithelial transition factor [MET] amplification, human epidermal 
growth factor receptor-2 upregulation or reticular activating system mutations), histological 
transformation to small cell lung cancer and epithelial mesenchymal transition (Camidge et al 
2014; Chong and Jänne 2013; Ohashi et al 2012).  
Treatment following progression on EGFR-TKI therapy will be guided by patient 
performance status, symptoms, molecular aberration and extent of disease. In patients able to 
tolerate doublet chemotherapy and who are T790M-negative, or if osimertinib is unavailable, 
platinum-based chemotherapy would most often be the preferred second-line treatment 
(NCCN 2018). There is no global standard of care for later lines of therapy; following 
progression on an EGFR-TKI or doublet chemotherapy, the only remaining options are 
rechallenge with EGFR-TKI or salvage single-agent chemotherapy or clinical trials (Langer et 
al 2013). Platinum-based chemotherapy post EGFR-TKI for EGFRm+ NSCLC generally 
provides response rates in the range of 20% to 30% (Gridelli et al 2012; Soria et al 2015), and 

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the progression free survival (PFS) is relatively short (median PFS approximately 3 to 
6 months). These data together with the toxicity burden associated with doublet chemotherapy 
(including nausea, vomiting, bone marrow suppression resulting in risk of infection and 
bleeding, alopecia, fatigue and peripheral neuropathy) supports an unmet medical need in this 
patient population. 
Osimertinib (TAGRISSO™, AZD9291) is a potent and specific irreversible dual inhibitor of 
both the sensitising EGFR mutations and the T790M resistance mutation with margin against 
EGFR wild type (Ballard et al 2016; Cross et al 2014). EGFR tyrosine kinase inhibitors 
(TKIs) are now the established 1L therapy in patients with NSCLC known to have activating 
mutations in EGFR (EGFRm+) (Masters et al 2015, NCCN 2018, Reck et al 2014). Based on 
recent data (Becker et al 2011; Mok et al 2016; Langer et al 2013) and Food and Drug 
Administration approval, the NCCN recommend osimertinib as a 1L treatment in patients with 
metastatic EGFR positive NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations 
in tumour specimens and as subsequent therapy for patients with metastatic EGFR T790M 
mutation positive NSCLC who have progressed on EGFR-TKI therapy (NCCN 2018). 
Evidence from the AURA Phase I/II study (NCT01802632) of osimertinib in advanced 
NSCLC patients with disease progression following prior EGFR-TKI therapy, suggest that 
patients with T790M-negative tumour status may also derive benefit from osimertinib 
(Jänne et al 2015). In this study, 69 pre-treated patients with T790M-negative status by central 
testing, received osimertinib with an objective response rate (ORR) of 25% (95% CI: 15, 37) 
and disease control rate of 64% (95% confidence interval [CI]: 51, 75). Subsequently, the 
Phase III trial FLAURA, conducted in untreated EGFRm+ advanced NSCLC patients, has 
demonstrated a significantly longer PFS with osimertinib versus standard EGFR-TKIs 
(gefitinib or erlotinib) (18.9 months versus 10.2 months; hazard ratio [HR] 0.46; 95% CI 0.37 
to 0.57; P<0.001; Soria et al 2015). 
Up to 22% of patients with NSCLC who progress on first-line EGFR-TKIs have MET 
amplification or other MET-based mechanisms of resistance (Bean et al 2007; 
Engelman et al 2007; Sequist et al 2011). Using tissue biopsy, MET-amplification is 
commonly found after acquired resistance to osimertinib (Piotrowska et al 2017). Moreover, 
in a subgroup of the AURA patients who were treatment-naïve and provided post-progression 
plasma samples (n=38), no evidence of acquired EGFR T790M mutation was found. 
Nine of 19 patients had putative resistance mechanisms, including amplification of MET in 
1 patient (Ramalingam et al 2018). 
The MET pathway is one of the most frequently dysregulated pathways in human cancer. 
Receptor activation leads to the recruitment and activation of specific downstream signalling 
partners that participate in the regulation of diverse processes such as tumour cell growth, 
migration, scattering and metastasis. In endothelial cells and stroma cells around tumour 
tissue, HGF/MET works as a proangiogenesis factor to stimulate endothelial cell proliferation, 

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migration and survival, which can cause angiogenesis and support tumour expansion and 
progression. HGF and MET expression have been observed in tumour biopsies of most solid 
tumours, and MET signalling has been documented in a wide range of human malignancies, 
including bladder, breast, cervical, colorectal, gastric, head and neck, liver, lung, ovarian, 
pancreatic, prostrate, renal and thyroid cancers, as well as in various sarcomas, haematopoietic 
malignancies and melanoma. Activating mutations in the tyrosine kinase domain of MET have 
been positively identified in patients with a hereditary form of papillary renal cancer, directly 
implicating MET in human tumourigenesis (Eder et al 2009). In several clinical studies, 
aberrant MET overexpression has been correlated with poor clinical outcome, with rapid 
disease progression and short survival (Park et al 2012). Overexpression of MET and HGF are 
also thought to result in resistance of tumour cells to chemotherapy and radiotherapy, 
correlating with development of distant metastases and shorter metastasis-free survival 
(Schmidt et al 1997). 
There is a considerable unmet clinical need in patients with epidermal growth factor receptor 
mutation positive (EGFRm+) advanced non small cell lung cancer (NSCLC) following 
progression on epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) 
therapy. Resistance to first/second line use of third generation EGFR-TKIs such as osimertinib 
is an emerging clinical problem. One of the mechanisms for resistance is amplification of the 
HGF receptor MET tyrosine kinase, which activates downstream intracellular signalling 
independent of EGFR. The combination of osimertinib with savolitinib is exploring how to 
overcome resistance driven by MET amplification. 
Savolitinib (international non-proprietary name) (AZD6094, HMPL-504, volitinib) is a potent 
and highly selective MET kinase inhibitor (Jia et al 2014) which has demonstrated 
anti-tumour activity in MET driven papillary renal cell carcinoma (Choueiri et al 2017a). A 
Phase III trial has been initiated in this indication (Choueiri et al 2017b). 
The combination of osimertinib plus savolitinib in the Phase I TATTON study 
(NCT02143466) explored how to overcome MET-amplification against tumours that have 
developed resistance to EGFR-TKI agents in NSCLC or delay the development of subsequent 
resistance via these alternative routes. In the TATTON Part A dose escalation cohort, 
savolitinib plus osimertinib had an acceptable safety profile and demonstrated evidence of 
anti-tumour activity in patients with EGFRm+ NSCLC (Oxnard et al 2015). A summary of 
preclinical combination data is provided in the savolitinib Investigator’s Brochure. 
Data from the TATTON Part B dose expansion were presented at the World Conference on 
Lung Cancer 2017 (Ahn et al 2017) and published by Sequist et al 2020 (28 February 2018 
data cut-off date). Patients were treated with osimertinib 80 mg in combination with 
savolitinib 600 mg (both given orally once daily [od]). Encouraging anti-tumour activity was 
seen in patients with centrally confirmed MET-amplified status in the prior 3rd generation 

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Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 56 of 207 
 
The SAVANNAH study will investigate the overall efficacy of osimertinib in combination 
with savolitinib in patients with EGFRm+ and MET-amplified/overexpressed, locally 
advanced or metastatic NSCLC who have progressed following treatment with osimertinib. 
Based on emerging pre-clinical and clinical data (see Section 2), the SAVANNAH Study 
(CSP version 7.0) will be expanded to further investigate the efficacy of savolitinib 300 mg 
bid + osimertinib in MET-amplified/overexpressed (FISH10+ and/or IHC90+) patients who 
have progressed following 1L osimertinib treatment. Per CSP version 7.0, the study will also 
describe the difference in the efficacy of osimertinib in combination with savolitinib 300 mg 
bid and savolitinib monotherapy in the treatment of EGFRm+ NSCLC patients with MET 
FISH10+ and/or IHC90+ status whose tumour has progressed following 1L osimertinib 
therapy under CSP version 7.0. 
The rationale for the design of the study is presented in Section 4.2. 
2.2 
Background  
Refer to Section 2. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of osimertinib and 
savolitinib is provided in their respective Investigator’s Brochures. 
2.3 
Benefit/risk assessment  
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of osimertinib and savolitinib may be found in their respective Investigator’s 
Brochures. 
2.3.1 
Risk assessment  
Investigators for a study using savolitinib monotherapy in patients with EGFRm+ NSCLC 
will be cognisant of the potential risk of rapid disease progression via EGFRm tumour driver 
reactivation. The NCCN Guidelines for NSCLC (NCCN 2020) include a warning about the 
risk of flare phenomenon occurring in patients who discontinue EGFR-TKI. Tumour flare 
after discontinuation of EGFR-TKI has been a recognised phenomenon for many years (Chaft 
et al 2011; Chen et al 2013) and indicates that the EGFRm sensitising mutation is not 
eliminated from the tumour following treatment with an EGFR-TKI in most patients. In some 
patients, this may cause a rapid clinical deterioration after discontinuing EGFR-TKI prior to 
entering the study (see Section 4.2.1). To minimise this risk, patients will be closely 
monitored over the first month of participation in the study to look for evidence of tumour 
flare. At investigator-assessed progressive disease (PD) per RECIST 1.1, treatment allocation 
will be unblinded and those patients randomised to the savolitinib plus placebo arm will have 
the opportunity to cross over to the savolitinib plus osimertinib regimen. Patients will be 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 57 of 207 
 
informed of the possibility of cross over to savolitinib plus osimertinib during the informed 
consent process and at the time of progression on randomised treatment. 
A summary of the safety profile of osimertinib based on the program of AstraZeneca-
sponsored Phase I to III studies of patients with EGFR TKI-naïve first-line EGFRm disease 
and in patients with ≥ second line T790M-mutated NSCLC is provided in Section 5 of the 
osimertinib Investigator’s brochure. Overall, osimertinib has been generally well-tolerated in 
these trials. Based on safety data from the osimertinib clinical development program 
conducted to date, the risks associated with osimertinib, as applicable to the current study, are 
presented in Table 3. 
Table 3 
Risk Assessment  
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
ILD 
ILD is an important identified risk and 
AESI for osimertinib. Adverse events of 
ILD have been reported in 3.7% 
(55/1479) of patients in the osimertinib 
pivotal clinical studies dataset, with 0.8% 
(12/1479) of these being severe (CTCAE 
Grade 3 or 4) and 0.3% (5/1479) 
resulting in a fatal outcome 
Patients with a past medical history or 
concurrent clinically active ILD are 
excluded from the current study (see 
Section 5.2). Furthermore, dose 
modification guidelines for 
ILD/pneumonitis (which include dose 
interruption, rechallenge, and permanent 
discontinuation criteria) are in place to 
protect study participants (see Appendix I 
for further details). 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 58 of 207 
 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Cardiac failure 
Cardiac failure is an important potential 
risk and AESI for osimertinib. A 
numerical imbalance in the number of 
patients with an AE from the Cardiac 
Failure SMQ or Cardiomyopathy SMQ 
and in LVEF decreases between the 
2 treatment arms was noted in the Phase 
III D5160C00003 study (AURA3; 
NCT02151981). A similar numerical 
imbalance was also noted between 
treatment arms (osimertinib versus SoC 
therapy [erlotinib or gefitinib]) in 
Phase III Study D5160C00007 
(FLAURA; NCT02296125). However, 
results from the more recent 
placebo-controlled ADAURA study 
demonstrated there is no clinical 
difference from placebo in decrease 
LVEF. Based on the complete body of 
evidence available, the overall 
interpretation does not support a causal 
relationship between osimertinib and 
changes in cardiac contractility 
manifesting as either LVEF decreases or 
heart failure. 
In patients with cardiac risk factors and 
those with conditions that can affect 
LVEF, cardiac monitoring, including an 
assessment of LVEF at baseline and 
during study intervention, should be 
considered. Consequently, routine 
cardiac assessment (by ECHO / MUGA) 
is mandated at baseline and should be 
considered throughout the study 
intervention period if clinically indicated. 
Furthermore, dose modification 
management guidelines for changes in 
cardiac contractility (which include dose 
interruption, rechallenge, and permanent 
discontinuation criteria) are in place to 
protect study participants (see Appendix I 
for further details). 
AESI  Adverse event of special interest;  CTCAE  Common Terminology Criteria for Adverse Events;  ECHO  
echocardiogram; ILD  Interstitial lung disease; LVEF  Left ventricular ejection fraction; MUGA  multigated 
acquisition;  SMQ Standardised MedDRA query; SOC  standard of care. 
The important identified risks for savolitinib are hepatotoxicity and hypersensitivity reactions 
(including anaphylaxis and Stevens-Johnson syndrome [SJS]). Specific monitoring and 
guidelines for toxicity management are in place to mitigate/manage these risks (see 
Appendix I).  
Hepatotoxicity has been identified as a risk for patients receiving savolitinib and requires 
specific monitoring. Frequent monitoring of liver function tests will take place as outlined in 
the study plan. The hepatotoxicity management algorithm included in the protocol clearly 
defines and limits the patients who can be re-challenged to those with lower grade 
abnormalities with rapid resolution (see Appendix I). As stated in the eligibility criteria and 
risk mitigation sections, patients with abnormal baseline liver function tests will be excluded 
from the study and patients will be required to discontinue treatment with statins or reduce it 
to the lowest dose, prior to study entry. 

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CCI

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 60 of 207 
 
2.3.3 
Overall benefit: risk conclusion  
Overall the benefit/risk assessment supports the further investigation of savolitinib and 
osimertinib and savolitinib monotherapy in patients with advanced NSCLC with high MET 
amplification/overexpression based upon: the emerging non-clinical and clinical safety 
profile, the risk minimisation and enhanced AE management guidelines, the study design, the 
limited life expectancy due to malignant disease, the lack of effective alternative treatments, 
the strength of the scientific hypothesis under evaluation and the emerging clinical efficacy 
data to date. 
3 
OBJECTIVES AND ENDPOINTS  
Table 4 
Study objectives  
Primary Objective: 
Endpoint: 
• 
To determine the efficacy of savolitinib (300 mg 
bid) in combination with osimertinib in patients 
with EGFRm+ and MET amplified/overexpressed 
(FISH10+ and/or IHC90+)a, locally advanced or 
metastatic NSCLC who have progressed 
following treatment with 1L osimertinib 
• 
To determine the efficacy of savolitinib (300 mg 
od) in combination with osimertinib in patients 
with EGFRm+, MET amplified/overexpressed 
(FISH5+ and/or IHC50+)b, locally advanced or 
metastatic NSCLC who have progressed 
following osimertinib. 
• 
ORR by investigator assessment in accordance 
with RECIST 1.1. 
Secondary Objectives: 
Endpoints: 
To determine the efficacy of savolitinib (300 mg bid) 
in combination with osimertinib in patients with 
EGFRm+ and MET amplified/overexpressed 
(FISH10+ and/or IHC90+)a, locally advanced or 
metastatic NSCLC who have progressed following 
treatment with 1L osimertinib. 
• 
DoR and PFS by investigator assessment in 
accordance with RECIST 1.1 
• 
OS 
To describe the difference in the efficacy of savolitinib 
(300 mg bid) in combination with osimertinib and 
savolitinib (300 mg bid) in combination with placebo 
in patients with EGFRm+, MET 
amplified/overexpressed (FISH10+ and/or IHC90+)a, 
locally advanced or metastatic NSCLC who have 
progressed following treatment with 1L osimertinib 
therapy under CSP version 7.0. 
• 
ORR by investigator assessment in accordance 
with RECIST 1.1 
To determine the efficacy of savolitinib (300 mg od 
and 600 mg od, respectively) in combination with 
• 
ORR, DoR, and PFS, by investigator 
assessment in accordance with RECIST 1.1. 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 61 of 207 
 
osimertinib in patients with EGFRm+, 
MET-amplified/overexpressed (FISH10+ and/or 
IHC90+)a, locally advanced or metastatic NSCLC who 
have progressed following treatment with 1L 
osimertinib. 
• 
OS 
To determine the efficacy of savolitinib (300 mg od, 
300 mg bid, and 600 mg od, respectively) in 
combination with osimertinib in patients with 
EGFRm+, MET-amplified/overexpressed (FISH10+ 
and/or IHC90+)a, locally advanced or metastatic 
NSCLC who have progressed following treatment of 
≥ 2L osimertinib. 
• 
ORR, DoR, and PFS, by investigator 
assessment in accordance with RECIST 1.1. 
• 
OS 
To determine the efficacy of savolitinib (300 mg od, 
300 mg bid, and 600 mg od, respectively) in 
combination with osimertinib in patients with 
EGFRm+, MET-amplified/overexpressed (FISH5+ 
and/or IHC50+)b, locally advanced or metastatic 
NSCLC who have progressed following osimertinib. 
• 
ORR (except 300 mg od), DoR, and PFS by 
investigator assessment in accordance with 
RECIST 1.1. 
• 
OS 
To determine the efficacy of (1) 300 mg od, 300 mg 
bid and 600 mg od of savolitinib in combination with 
osimertinib in patients with EGFRm+ MET amplified/ 
overexpressed (FISH 10+ and/or IHC90+)a,b; 
(2) 300 mg od, 300 mg bid and 600 mg od of 
savolitinib in combination with osimertinib in patients 
with EGFRm+ MET amplified/overexpressed 
(FISH5+ and/or IHC50+)b (3) savolitinib 300 mg bid 
in combination with osimertinib and savolitinib 
300 mg bid in combination with placebo, respectively, 
in patients with EGFRm+ MET amplified/ 
overexpressed (FISH10+ and/or IHC90+)a following 
treatment with 1L osimertinib. 
• 
ORR, DoR, and PFS assessed by BICR in 
accordance with RECIST 1.1 
To assess the impact of savolitinib and osimertinib on 
disease-related symptoms and HRQoL in this patient 
population. 
• 
Mean change from baseline in EORTC QLQ-
C30 and QLQ-LC13. 
To evaluate the pharmacokinetics of osimertinib and 
savolitinib in this patient population. 
• 
Plasma concentrations of osimertinib, 
savolitinib and their metabolites. 
To determine the prevalence of ctDNA clearance after 
osimertinib and savolitinib treatment in this patient 
population. 
• 
Total clearance in EGFR mutations at 6-weeks 
after therapy initiation (percentage and absolute 
change from baseline in EGFR mutation allele 
frequencies). 

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 62 of 207 
 
Safety Objectives: 
Endpoints: 
To evaluate the safety and tolerability of savolitinib in 
combination with osimertinib and savolitinib in 
combination with placebo. 
• 
AEs, SAEs and discontinuation rate due to AEs. 
• 
Clinical chemistry/haematology including 
LFTs. 
• 
ECHOs, ECGs and vital signs including blood 
pressure and heart rate. 
Exploratory Objectives: 
 
To assess the efficacy of savolitinib plus osimertinib 
and savolitinib plus placebo, respectively, on CNS 
metastases in patients with CNS metastases at baseline 
• 
CNS PFS by BICR assessments in accordance 
with RECIST 1.1  
To assess the efficacy of savolitinib plus osimertinib 
and savolitinib plus placebo, respectively, on the 
prevention of CNS metastases in patients without CNS 
metastases at baseline.  
• 
The presence/absence of CNS lesions at 
progression by BICR assessments in accordance 
with RECIST 1.1 
To assess the impact of savolitinib in combination 
with osimertinib on patient reported treatment-related 
symptoms. 
• 
PRO CTCAE symptoms. 
To assess patients’ overall impression of severity of 
cancer symptoms. 
• 
Patient’s Global Impression of Severity (PGIS). 
To explore the impact of treatment and disease on 
health state utility 
• 
EQ-5D-5L 
To explore the factors of resistance and sensitivity to 
treatment. 
• 
Protein, RNA and DNA research on blood and 
tumour prior to treatment, during the course of 
treatment, at disease progression and at 
treatment discontinuation. 
To assess the predictive value of changes in circulating 
biomarkers on clinical efficacy endpoints. 
• 
Longitudinal changes in circulating DNA 
and/or RNA compared with PFS, OS and ORR. 
To collect and store DNA (according to each country’s 
local and ethical procedures) for future exploratory 
research into genes/genetic variation that may 
influence response (ie, distribution, safety, tolerability 
and efficacy) to study treatments and or susceptibility 
to disease (optional). 
• 
Pharmacogenetic analyses on blood samples. 
To collect and store tissue, plasma, and serum samples 
for diagnostic development and exploratory analyses. 
• 
Disease-relevant or response markers in tumour 
tissue and circulating tumour 
DNA/RNA/protein including but not limited to 
EGFR mutations and MET amplifications. 
To collect and store germline DNA for exploration of 
the role of HLA alleles in developmental toxicity. 
• 
HLA alleles associated with susceptibility to 
drug related AEs (such as but not limited to 
hypersensitivity). 

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CCI

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 67 of 207 
 
time of progression on randomised treatment. A separate informed consent form (ICF) for 
crossover patients must be signed prior to starting crossover treatment. 
Patients who cross over must not receive any other anti-cancer therapies between the initial 
assessment of PD and the addition of osimertinib. Savolitinib treatment should continue 
uninterrupted during this period. Patients should be crossed over as soon as possible after the 
assessment of PD and within 28 days of their progression scan. 
Patients who cross over will receive study medication once daily in 28-day cycles until 
objective PD by RECIST 1.1 is assessed by investigator, unacceptable toxicity occurs, consent 
is withdrawn or another discontinuation criterion is met. As in the treatment allocation/ 
randomisation part of the study, patients may continue to receive treatment with osimertinib 
plus savolitinib or osimertinib monotherapy (if savolitinib is stopped during cross over 
because of savolitinib-related toxicity) beyond RECIST 1.1 defined PD as long as they 
continue to receive clinical benefit, in the opinion of the investigator, and do not meet any of 
the discontinuation criteria. No other anti-cancer agent is permitted in combination with 
osimertinib within this study. 
If, after the planned futility analysis the savolitinib + placebo arm is declared futile, all 
patients remaining on savolitinib + placebo will be contacted and asked to return for a 
discussion of the futility findings and their options for remaining in the savolitinib + placebo 
arm (as long as, in the opinion of the investigator, they are still receiving clinical benefit and 
have not reported PD) or crossing over to the savolitinib + osimertinib arm. Patients who cross 
over must not receive any other intervening anti-cancer therapies before the addition of 
osimertinib. 
All patients who cross over to receive savolitinib + osimertinib (whether based on objective 
PD by RECIST 1.1 or a declaration of futility of the savolitinib + placebo arm) will follow the 
scheduled procedures described in Table 2. 
4.2 
Scientific rationale for study design  
Refer to Sections 2 and 2.1. 
4.2.1 
Rationale for study design  
The expansion cohort Part B of the TATTON study has demonstrated anti-tumour activity of 
osimertinib in combination with savolitinib (ORR 28%) in MET-amplified patients 
(confirmed centrally by FISH; MET gene copy ≥5 or MET/CEP7 ratio ≥2) who were treated 
with prior 3rd generation T790M-directed EGFR-TKI (Ahn et al 2017). 
This Phase II study has been designed to further assess the efficacy of osimertinib in 
combination with savolitinib by assessment of ORR in patients with EGFRm+ and 

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CCI

Clinical Study Protocol – 8.0 
AstraZeneca 
Osimertinib + savolitinib - D5084C00007 
 
CONFIDENTIAL AND PROPRIETARY 
 69 of 207 
 
be stratified by brain metastasis at baseline to account for potential impact due to imbalance of 
patients with brain metastasis across arms. 
4.2.2 
Rationale for endpoints  
ORR, PFS, duration of response (DoR) and percentage change from baseline in tumour size 
assessed by RECIST 1.1 using investigator assessment and OS are standard measures of 
clinical activity and are used to assess efficacy in solid tumour clinical studies. 
The Phase 1 TATTON study data indicated encouraging anti-tumour activity in patients with 
centrally-confirmed MET-amplified status. Responses were also observed in a small number 
of MET overexpressed tumours by IHC without centrally-confirmed MET-amplification by 
FISH. In SAVANNAH, the primary endpoint to assess the ORR in patients treated at the 
300 mg od savolitinib dose level, in combination with 80 mg od osimertinib, and whose 
tumours are FISH5+ and/or IHC50+ and had disease progression following prior osimertinib 
therapy was based on the TATTON study data. 
Under CSP version 7.0, an additional primary endpoint has been added to evaluate the 
efficacy at an alternative savolitinib dose and using a higher biomarker cut-off for MET 
amplification and/or overexpression. Emerging clinical data (including from the TATTON 
study and SAVANNAH study) and published literature support a biological rationale for the 
apparent association of increasing MET overexpression or amplification levels with 
improvement in responses to MET inhibitors in EGFRm+ NSCLC patients with MET 
amplification and/or overexpression. Therefore, an additional primary endpoint will determine 
the ORR in patients treated at the 300 mg bid savolitinib dose level in combination with 
80 mg od osimertinib, and whose tumours are FISH10+ and/or IHC90+ and have progressed 
following treatment with 1L osimertinib.   
Secondary endpoints include, but are not limited to, assessment of efficacy parameters by 
varying savolitinib dose levels in combination with 80 mg od osimertinib and varying MET 
FISH and IHC cut-offs in order to allow a thorough assessment of dose-response 
relationships. A description of the difference in response rate between the 300 mg bid 
savolitinib + 80 mg od osimertinib group and the 300 mg bid savolitinib + placebo group as 
well as an exploration of the prevalence of plasma ctDNA clearance after 6 weeks of study 
therapy are also secondary objectives of this study. 
The secondary symptoms and overall HRQoL endpoints, assessed using the European 
Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality-of-life 
questionnaire (QLQ-C30), version 3 (QLQ-C30 v3) and the complementary 13-item lung 
cancer symptoms questionnaire (QLQ-LC13), will show the overall influence of the benefits 
and toxicity of the treatment from the patient’s perspective and will aid in understanding the 

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benefit/risk evaluation. These PRO questionnaires are well-established instruments that have 
been previously included in cancer clinical studies.  
Standard safety parameters (discontinuation rate due to AEs/SAEs, vital signs, clinical 
chemistry/haematology parameters and electrocardiograms [ECGs]) will be used to assess the 
safety and tolerability of osimertinib in combination with savolitinib. To evaluate the safety 
and tolerability of savolitinib in combination with osimertinib, the proportion of patients 
discontinuing due to any AE and the proportion of patients discontinuing due to AE of 
hypersensitivity/anaphylaxis may be assessed. 
Standard PK parameters will be used to evaluate the PK of osimertinib and savolitinib when 
administered in combination in this population.  
Exploratory endpoints, including, but not limited to, circulating tumour deoxyribonucleic acid 
(ctDNA), circulating proteins and germline deoxyribonucleic acid (DNA), will be used to 
understand mechanisms of response (where response is defined broadly to include biomarker 
change, tolerability or safety) and resistance to treatment. 
4.3 
Justification for dose  
The evaluation of the recommended daily dose of osimertinib (80 mg od), which is the 
approved dose for EGFRm+ NSCLC, was based on non-clinical data in addition to PK, 
efficacy and safety data from across the clinical programme and is the approved dose for 
first-line treatment of adult patients with locally advanced or metastatic NSCLC with 
activating EGFR mutations (see Section 5.2.2 of the Investigator’s Brochure for more 
information).  
Final review of data from TATTON Part D (savolitinib 300 mg od dose) indicated that in the 
no prior third generation EGFR-TKI cohort (TATTON Part D), there was an improvement in 
overall safety profile, such as Common Terminology Criteria for Adverse Event (CTCAE) 
Grade 3 toxicity, with no apparent reduction in ORR relative to the 600 mg od dose. To date 
there were limited data available in patients who progressed on the 3rd generation EGFR-TKIs 
(such as osimertinib) when used as the 1L treatment. As such the risk-benefit of a savolitinib 
300 mg flat dose regimen, in combination with further enhanced hypersensitivity management 
guidelines introduced to this study in CSP version 2.0, was considered preferable to the 
previous weight-based dosing regimen. Following this review (per CSP version 3.0), all new 
patients entering the SAVANNAH study were to be treated with a 300 mg od dose of 
savolitinib. Patients who commenced on the study with a 600 mg od dose of savolitinib could 
either continue with treatment at this dose or could choose to change dose to 300 mg od (no 
re-escalation was permitted after changing dose to 300 mg even if disease progression 
occurred).  

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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be enrolled on the study. Under no circumstances can there be exceptions to 
this rule. Patients who do not meet the entry requirements are screen failures, refer to 
Section 5.4. 
In this protocol, “Enrolled” patients are defined as those who sign informed consent for the 
main study and are confirmed as eligible for the study.  
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3. 
5.1 
Inclusion criteria  
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply: 
Informed consent 
1 
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
2 
Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses.  
 
The ICF process is described in Appendix A 3. 
Age 
3 
Patients must be ≥18 years of age at the time of signing the ICF (≥20 years of age in 
Japan). All genders are permitted. 
 
Type of patient and disease characteristics 
4 
Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ 
NSCLC harbouring an EGFR mutation known to be associated with EGFR-TKI 
sensitivity and which is permitted in the osimertinib national label (such as exon 19 
deletion and/or L858R) which is not amenable to curative therapy.  
5 
Documented radiologic disease progression on 1L osimertinib. 
6 
MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by 
FISH (central) and IHC (central) testing on tumour sample collected following 
progression on 1L osimertinib treatment. 

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7 
Available tumour sample for central MET FISH and IHC analysis or willingness to 
collect additional sample for central testing which fulfils the following requirements: 
− 
Obtained following progression on previous osimertinib therapy 
− 
Obtained within 2 years of submission for MET analysis 
− 
Sufficient sample to meet the minimum sample requirement defined in the current 
Central Laboratory Manual. 
8 
At least 1 lesion, not previously irradiated, not biopsied during the screening period, that 
can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph 
nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) which is suitable for accurate repeated measurements. If only 
1 measurable lesion exists, it is acceptable to be used as long as baseline tumour 
assessment scans are done at least 14 days after the screening tumour sample collection is 
performed.  
9 
Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib 
treatment in metastatic setting is permitted. 
10 Adequate haematological function defined as: 
− 
Absolute neutrophil count ≥1500/μL 
− 
Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks)  
− 
Platelets ≥100,000/μL (no transfusion in the past 10 days) 
11 Adequate liver function defined as: 
− 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN) with total bilirubin (TBL) ≤ ULN 
OR 
− 
TBL >ULN to ≤1.5x ULN with ALT and AST ≤ ULN 
12 Adequate renal function defined as a serum creatinine <1.5 times the institutional ULN 
OR a glomerular filtration rate ≥50 mL/min, as assessed using the standard methodology 
at the investigating centre (eg, Cockcroft-Gault, Modification of Diet in Renal Disease or 
Chronic Kidney Disease-Epidemiology Collaboration formulae, 
ethylenediaminetetraacetic acid clearance or 24-hour urine collection). Confirmation of 
creatinine clearance is only required when creatinine is >1.5 times ULN.  
13 Adequate coagulation parameters, defined as:  
− 
International Normalisation Ratio (INR) <1.5 and activated partial thromboplastin 
time <1.5 x ULN unless patients are receiving therapeutic anti-coagulation which 
affects these parameters.  
14 Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically 
stable on low molecular weight heparin (LMWH) for ≥2 weeks. The use of direct oral 
anticoagulants such as apixaban/rivaroxaban will be accepted as treatment for 

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cancer-related thromboembolism treatment. The use of warfarin for oral anticoagulation 
is not recommended. 
15 Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) 
performance status of 0 or 1 with no deterioration over the previous 2 weeks and a 
minimum life expectancy of 12 weeks. 
16 Ability to swallow and retain oral medications. 
17 Willingness and ability to comply with study and follow-up procedures. 
 
Reproduction 
18 Females must be using highly effective contraceptive measures (see Section 5.3.2), 
should not be breast feeding, and must have a negative pregnancy test if of childbearing 
potential, or must have evidence of non-childbearing potential by fulfilling one of the 
following criteria at screening: 
− 
Post-menopausal is defined as aged 50 years or more and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments. 
− 
Women under the age of 50 years would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatments and with luteinizing hormone and follicle stimulating hormone 
levels in the post-menopausal range for the institution. 
− 
Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation. 
Further information is available in Appendix G (Definition of Women of Childbearing 
Potential and Acceptable Contraceptive Methods).  
19 Male patients with a female partner of childbearing potential should be willing to use 
barrier contraception during the study and for 6 months following discontinuation of 
study drug. Patients should refrain from donating sperm from the start of dosing until 
6 months after discontinuing study treatment. 
 
5.2 
Exclusion criteria  
Patients must not enter the study if any of the following exclusion criteria are fulfilled: 
Medical conditions 
1 
Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of 
starting study treatment with the exception of alopecia and Grade 2, prior 
platinum-therapy related neuropathy. 

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2 
As judged by the investigator, active gastrointestinal disease or other condition that will 
interfere significantly with the absorption, distribution, metabolism, or excretion of oral 
therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, 
malabsorption syndrome or previous significant bowel resection). 
3 
Any of the following cardiac diseases currently or within the last 6 months: 
− 
Unstable angina pectoris 
− 
Congestive heart failure (New York Heart Association [NYHA] ≥Grade 2)  
− 
Acute myocardial infarction 
− 
Stroke or transient ischemic attack  
− 
Uncontrolled hypertension (blood pressure [BP] ≥150/95 mmHg despite medical 
therapy). 
− 
Mean resting correct QT interval (QTcF) >470 msec for women and >450 msec for 
men at Screening, obtained from 3 ECGs using the screening clinic ECG machine 
derived QTcF value. 
− 
Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic 
events such as heart failure, chronic hypokalaemia not correctable with supplements, 
congenital or familial long QT syndrome, family history of unexplained sudden death 
under 40 years of age in first-degree relatives or any concomitant medication known 
to prolong the QT interval and cause Torsade de Pointes  
− 
Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECGs, eg, complete left bundle branch block, third degree heart block, second 
degree heart block, P-R interval >250 msec. 
− 
Acute coronary syndrome 
4 
Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy.  
5 
Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures 
≤7 days. No waiting is required following port-a-cath placement. 
6 
As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, 
including renal transplant, active bleeding diatheses or uncontrolled hypertension, which 
in the investigator’s opinion makes it undesirable for the patient to participate in the study 
or which would jeopardise compliance with the protocol.  
7 
Active hepatitis B (HBV) (positive HBV surface antigen [HBsAg] result) or hepatitis C 
(HCV). Viral testing is not required for assessment of eligibility for the study. Patients 
with a past or resolved HBV or HCV infection are eligible if: 
− 
Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc-IgG]. In 
addition, patients must be receiving anti-viral prophylaxis for 2 to 4 weeks prior to 

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study treatment and 6 to 12 months (to be determined by hepatologist) post treatment 
or  
− 
Positive for HBsAg, but for >6 months have had normal transaminases and HBV 
DNA levels < 100 IU/mL (ie, are in an inactive carrier state). In addition, patients 
must be receiving anti-viral prophylaxis for 2 to 4 weeks prior to study treatment and 
6 to 12 months (to be determined by hepatologist) post treatment. See Appendix I 2. 
− 
Patients with a past or resolved HBV infection must have monthly monitoring of 
ALT and HBV DNA (see Appendix I 2). 
− 
HBV DNA levels >2000 IU/mL but on prophylactic antiviral treatment for the past 
3 months and will maintain the antiviral treatment during the study. 
− 
Patients with positive HCV antibody are eligible only if the polymerase chain 
reaction is negative for HCV ribonucleic acid. 
8 
Known serious active infection including, but not limited to, tuberculosis, or human 
immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies). 
Testing is not required for assessment of eligibility for the study.  
9 
Presence of other active cancers, or history of treatment for invasive cancer, within the 
last 5 years. Patients with Stage I cancer who have received definitive local treatment at 
least 3 years previously and are considered unlikely to recur are eligible. All patients with 
previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients with 
history of non-melanoma skin cancer. 
10 Spinal cord compression or brain metastases unless asymptomatic, stable and not 
requiring steroids for at least 2 weeks prior to start of study treatment. 
11 Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required 
steroid treatment, or any evidence of clinically active ILD. 
12 History of liver cirrhosis of any origin and clinical stage; or history of other serious liver 
disease or chronic disease with relevant liver involvement, with or without normal LFTs, 
such as: 
− 
Haemochromatosis 
− 
Alpha-1 antitrypsin deficiency 
− 
Autoimmune hepatitis 
− 
Primary sclerosing cholangitis 
− 
Primary biliary cirrhosis 
− 
Biopsy-confirmed non-alcoholic steatohepatitis with advanced fibrosis 
− 
Biopsy-confirmed alcoholic steatohepatitis with advanced fibrosis 
− 
Wilson's disease 
− 
Hepatocellular carcinoma. 

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Prior/concomitant therapy 
13 Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib. 
14 Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, 
crizotinib, cabozantinib, onartuzumab, capmatinib). 
15 Criterion removed (duplication of information). 
16 Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the 
treatment of advanced NSCLC from a previous treatment regimen or clinical study within 
14 days prior to the first dose of study treatment with the exception of monotherapy 
osimertinib which may continue uninterrupted during screening. 
17 Patients currently receiving (or unable to stop use prior to receiving the first dose of study 
treatment) medications or herbal supplements known to be strong inducers of CYP3A4, 
strong inhibitors of CYP1A2, within 3 weeks of the first dose of study treatment 
(including St John’s Wort) will be excluded. All patients must try to avoid concomitant 
use of any medications, herbal supplements and/or ingestion of foods with known strong 
inducer effects on CYP3A4 during the study and for 3 months later the last dose intake. 
18 Criterion removed (no longer relevant). 
 
Prior/concurrent clinical study experience 
19 Participation in another clinical study with a cytotoxic, investigational product (IP), or 
other anticancer drug for the treatment of advanced NSCLC if received IP from that study 
within 14 days of the first dose of study treatment.  
20 Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or 
drugs with a similar chemical structure or class. 
 
Other exclusions 
21 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
22 Judgement 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. 
23 Previous enrolment in the present study.  
24 Criterion removed (duplication of information). 
25 Patients unable to provide the required number of samples for MET analysis. 
 
Exclusions from exploratory genetic research 
26 Previous allogeneic bone marrow transplant. 

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27 Non-leukocyte depleted whole blood transfusion within 120 days of the date of the 
genetic sample collection. 
 
5.3 
Lifestyle restrictions  
5.3.1 
Meals and dietary restrictions  
Osimertinib should be taken with water, with or without food. Savolitinib should be taken 
within 15 minutes after the start of a meal. Osimertinib and savolitinib can be taken together. 
On PK days patients should come to the clinic fasted (the patient should not eat but may drink 
beforehand) where they will be given a moderate breakfast before dosing (the same breakfast 
should be given on all PK days).  
For patients receiving savolitinib 300 mg bid, a pre-dose meal will be provided if the second 
dose of the day is given in the clinic. Patients who will take the second dose at home should 
be reminded that savolitinib should be taken within 15 minutes after the start of the meal. 
5.3.2 
Pregnancy and contraception  
Women of childbearing potential 
Females of childbearing potential should use highly effective methods of contraception from 
the time of screening until 6 weeks after discontinuing study treatment. Acceptable methods 
of contraception include full abstinence, tubal ligation, combined oral, transdermal or 
intra-vaginal hormonal contraceptives, medroxyprogesterone injections (eg, Depo-provera), 
copper-banded intra-uterine devices, hormone impregnated intra-uterine systems and 
vasectomised partners (see Appendix G). All methods of contraception (with the exception of 
total abstinence) should be used in combination with the use of a condom by their male sexual 
partner for intercourse.  
Males 
Male patients must use a condom during sexual intercourse with a female partner of 
childbearing potential during the study and for 24 weeks after discontinuing study treatment. 
If the partner is not of childbearing potential, male patients should use a condom during the 
study and for 5 elimination half-lives afterwards (48 hours after last dose of savolitinib) with 
all sexual partners.  
Male patients should refrain from donating sperm from the start of dosing until 24 weeks after 
discontinuing study treatment. 
5.3.3 
Other lifestyle restrictions  
For savolitinib, during the study therapy and for 4 weeks after the last dose of study treatment 
patients should be advised to avoid prolonged exposure to the sun, wear protective clothing, a 

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hat and seek shade from the sun as far as possible; in addition, SP30+ sunscreen should be 
used. Exposure to other sources of ultraviolet light including sun beds and tanning booths, etc, 
should be avoided. 
Patients should not donate blood or blood products during the study.  
5.4 
Screen failures  
Screen failures are defined as patients who signed the main study ICF to participate in the 
clinical study but are not subsequently assigned to study treatment(s). A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure patients to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, to 
respond to queries from regulatory authorities and to support clinical diagnostic development. 
Minimal information includes demography, screen failure details, MET status information, 
eligibility criteria and any SAE. 
Individuals who do not initially meet the criteria for participation in this study (for example, 
due to logistical constraints or slow recovery of side effects from previous treatment, ie, 
screen failures) may be rescreened. Rescreened patients retain the same patient number as for 
the initial screening. However, rescreening assessments should be documented so that its 
effect on study results, if any, can be assessed.  
These patients should have failed inclusion/exclusion criteria and the reason for study 
withdrawal recorded in the electronic case report form (eCRF). 
Pre-screen failures are defined as patients who signed the pre-screening ICF but are not 
confirmed as MET-amplified/overexpressed by central laboratory testing. If the patient is 
subsequently pre-screened again the same patient number as for the initial pre-screening will 
be retained. 
6 
STUDY INTERVENTION  
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. Study treatment in this study refers to osimertinib and/or savolitinib. 
6.1 
Study Intervention(s) administered  
6.1.1 
Investigational products  
Refer to Table 6 for information regarding the study treatments. 

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Table 6 
Study treatments  
 
Osimertinib/Placebo to Osimertinib  
Savolitinib 
IMP or 
NIMP/AxMP 
IMP 
IMP 
Provider: 
AstraZeneca 
AstraZeneca 
AxMP Auxilliary medicinal product; eCRF Electronic Case Report Form; HDPE High-density polyethylene; 
IMP investigational medicinal product; NIMP Non-investigational medicinal product; PK Pharmacokinetics. 
6.2 
Preparation/handling/storage/accountability of interventions  
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment and only authorised site staff 
may dispense study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff. 
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are 
provided in the Central Laboratory Manual.  
6.3 
Measures to minimise bias: randomisation and blinding  
Patients who sign the ICF for pre-screening MET status testing will be registered in an 
interactive web response system (IWRS) to receive an E code. Patients who have tumour 
MET-status subsequently assessed as eligible for the study will be registered as eligible in the 
IWRS prior to starting study treatment. Before the study is initiated, the log-in information 
and directions for the IWRS will be provided to each site.  
Patients will complete treatments as specified above or until objective disease progression, 
unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is 
met.  
If a patient withdraws from the study, then his/her enrolment code cannot be reused. 
Withdrawn patients will not be replaced. 
Patients enrolled under CSP versions 1.0 to 6.0 

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Patients enrolled under CSP versions 1.0 to 5.0 who had tumour MET-status subsequently 
assessed as eligible for the study were registered as eligible in the IWRS prior to starting study 
treatment. 
Under CSP versions 5.0 and 6.0, patients were centrally assigned to randomised study 
intervention (300 mg bid and 600 mg od regimens), using IWRS. Before recruitment for the 
300 mg bid and 600 mg od regimens was initiated, the telephone number and call-in directions 
and/or the log in information and directions for the IWRS were provided to each site. The site 
was to contact the IWRS prior to the start of study intervention administration for each patient 
and record the intervention assignment on the applicable eCRF for patients receiving open-
label treatment, if required. 
Patients enrolled under CSP version 7.0 
Under CSP version 7.0, all patients will be centrally assigned to randomised study 
intervention (savolitinib 300 mg bid + osimertinib or savolitinib 300 mg bid + placebo) using 
IWRS. Before recruitment is initiated, the telephone number and call-in directions and/or the 
log in information and directions for the IWRS will be provided to each site. 
Patients randomised to the savolitinib 300 mg bid + placebo arm may cross over to savolitinib 
300 mg bid plus osimertinib 80 mg od following investigator assessment of PD per 
RECIST 1.1. Once the investigator has documented progression in the eCRF, and obtained 
approval for unblinding from the study physician, the treatment code for a patient may be 
obtained from the IWRS via a dedicated option they may select in this situation. In all other 
circumstances the treatment code should not be unblinded except in medical emergencies 
when the appropriate management of the patient requires knowledge of the treatment 
allocation. The investigator documents and reports the action to the AstraZeneca study 
physician, without involvement of other personnel to maintain study integrity. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. 
Treatment codes will not be unblinded for the planned analyses of data until all decisions on 
the evaluability of the data from each individual patient have been made and documented. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, in 
which the knowledge of the specific blinded study intervention will affect the immediate 
management of the patient’s condition (eg, antidote available), the investigator has the sole 
responsibility for determining if unblinding of a patients’ treatment assignment is warranted. 
Patient safety must always be the first consideration in making such a determination. If a 
patient’s treatment assignment is unblinded, the sponsor must be notified within 24 hours after 

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breaking the blind. The investigator documents and reports the action to the AstraZeneca 
physician, without involvement of other personnel to maintain study integrity. Additionally, 
patients with investigator-assessed objective PD may be unblinded. 
The personnel analysing the PK samples will be unblinded to the investigational treatment for 
each patient. 
The AstraZeneca study team will be unblinded at the time of the primary analysis. Site staff 
and patients will remain blinded until database lock for the final analysis. 
6.4 
Study intervention compliance  
The study medication should only be used as directed in this protocol. Details of treatment 
with study medication for each patient will be recorded in the appropriate sections in the 
eCRF. Treatment compliance will be assessed by the tablet or capsule count and the 
information should be recorded in the appropriate section of the eCRF. 
Patients should return all unused medication and empty containers to the investigator. 
The study personnel at the investigational site will account for all drugs dispensed and for 
appropriate destruction. Certificates of delivery and destruction should be signed. 
It is the investigator/institution’s responsibility to establish a system for handling study 
treatments, including IPs, so as to ensure that: 
• 
Deliveries of such products from AstraZeneca or its representative are correctly received 
by a responsible person. 
• 
Such deliveries are recorded. 
• 
Study treatments are handled and stored safely and properly as stated on the label. 
• 
Study treatments are only dispensed to study patients in accordance with the protocol. 
 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 
At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock. Records of usage should include the identification of the person 
to whom the study treatment was dispensed, the quantity and date of dispensing and unused 
study treatment returned to the investigator. This record is in addition to any drug 
accountability information recorded on the eCRF. Any discrepancies must be accounted for on 
the appropriate forms. Certificates of delivery and return must be signed, preferably by the 
investigator or a pharmacist, and copies retained in the investigator site file. 

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Dispensing and accountability records will continue to be collected for as long as patients 
continue to receive study treatment, although they will not be entered on the eCRF after the 
database has closed. 
Any change from the dosing schedule, dose interruptions, dose reductions, dose 
discontinuations should be recorded in eCRF. 
Study site personnel, if applicable, or the AstraZeneca monitor will account for all study drugs 
received at the site, unused study drugs and for appropriate destruction. Certificates of 
delivery, and destruction should be signed. 
6.5 
Concomitant therapy  
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrolment or receives 
within 4 weeks prior to the first dose, during the study, and until the 28 day follow-up visit 
must be recorded along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
 
In addition, for patients continuing treatment with osimertinib during Screening the date and 
time of administration of the last dose of osimertinib prior to Cycle 1 Day 1 (prior to PK 
sampling) should be recorded. 
Medication other than that described in Appendix J, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the eCRF. 
The use of medications listed in Table 7 is restricted, these medications are permitted with 
caution and careful monitoring of patients. 
Table 7 
Restricted medications  
Medication/class of drug: 
Usage (including limits for duration permitted and special 
situations in which it’s allowed) 
Paracetamol 
The administration of acetaminophen (paracetamol) to a patient is 
restricted to 3 g per day or the maximum dose approved locally (if 
less than 3 g/day) during the study. 
Sensitive CYP2C8, CYP2C9, and 
CYP2D6 substrates 
In vitro savolitinib is an inhibitor of CYP2C8, CYP2C9, and 
CYP2D6. Those drugs defined as sensitive CYP2C8, CYP2C9, and 
CYP2D6 substrates (almost exclusively metabolised by these 
enzymes should be used with caution when co-dosed with savolitinib. 

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Table 7 
Restricted medications  
Medication/class of drug: 
Usage (including limits for duration permitted and special 
situations in which it’s allowed) 
Drugs that may possibly prolong QT 
interval 
The use of the following drugs is permitted (notwithstanding other 
exclusions and restrictions) provided the patient has been stable on 
therapy for the periods indicated: 
Alfuzosin, chloral hydrate, ciprofloxacin, dolasetron, foscarnet, 
galantamine, gemifloxacin, isridipine, ketoconazole, levofloxacin, 
mexiletine, nicardipine, octreotide, ofloxacin, ondansetron, 
quetiapine, ranolazine, telithromycin, tizanidine, vardenafil, 
venlafaxine, ziprasidone. 
Amantadine, amitriptyline, amoxapine, clozapine, doxepin, 
felbamate, flecainide, fluconazole, fosphenytoin, gatifloxacin, 
granisetron, imipramine, indapamide, lithium, moexipril/HCTZ, 
moxifloxacin, risperidone, roxithromycin, sertraline, trimethoprim-
sulfa, trimipramine, voriconazole. 
Azithromycin, citalopram, clomipramine, itraconazole, nortriptyline, 
paroxetine, solifenacin, tacrolimus 
Fluoxetine, protriptyline, tamoxifen. See Appendix J. 
 
Guidance on medicines to avoid, medications that require close monitoring, and washout 
periods is provided in Appendix J and a list of medicines to avoid is kept up to date at the 
following: http://medicine.iupui.edu/clinpharm/ddis/main-table. 
Other medication other than that described above, including denosumab, corticosteroids 
and/or bisphosphonates for the treatment of bone metastases, which is considered necessary 
for the patient’s safety and wellbeing, may be given at the discretion of the investigator and 
recorded in the appropriate sections of the eCRF. 
6.5.1 
Rescue Medicine  
Recommendations on rescue medicine, regarding hypersensitivity management or 
pre-treatment for such reactions and other AE management or prophylaxis are provided in 
Appendix I. 
The study site will supply required rescue medication that will be obtained locally.  
Although the use of rescue medications is allowable at any time during the study, the period of 
delay in rescue medication following study intervention will be decided based on study 
investigator’s discretion. The date and time of rescue medication administration as well as the 
name and dosage regimen of the rescue medication must be recorded. 

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site on each patient’s visit. Paper form process will be used for SAE reporting, all SAEs, 
overdoses and pregnancies will be reported until 30 days after the last dose. The study will 
remain open until last patient treated. Last patient last visit will be defined as the last patient’s 
treatment discontinuation. 
In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed by 
AstraZeneca with the investigator. AstraZeneca will work with the investigator to transition 
the patients to alternative supply, where possible. 
In the event that a roll-over study is available at the time of the final DCO and database 
closure, patients currently receiving study treatment may be transitioned to such a study, and 
the current study would reach its end. The roll-over study would ensure treatment continuation 
with visits assessment per its protocol. Any patient that would be proposed to move to such 
study would be given a new Informed Consent. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PATIENT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of study intervention  
Patients may be discontinued from IP in the following situations. Note that discontinuation 
from study treatment is NOT the same thing as a complete withdrawal from the study. 
• 
Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. 
• 
Adverse events. 
• 
Severe non-compliance with the Clinical Study Protocol. 
• 
Objective disease progression as per RECIST 1.1. Patients may continue to receive 
treatment with osimertinib + savolitinib beyond RECIST 1.1-defined progression as long 
as they continue to receive clinical benefit, in the opinion of the investigator, and do not 
meet any of the discontinuation criteria. 
• 
Patients incorrectly initiated on study medication. 
• 
Pregnancy. 
• 
Specific stopping criteria ie, ILD, acute anaphylaxis or QTcF interval prolongation with 
signs/symptoms of serious arrhythmia. 
 
See the SoA (Table 1 and Table 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 

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Continuing on monotherapy 
A patient can continue on savolitinib monotherapy (if osimertinib was stopped earlier or if 
randomised to the savolitinib plus placebo arm) until objective disease progression. 
Savolitinib monotherapy beyond RECIST 1.1 progression is not permitted.  
A patient who is originally randomised to savolitinib + osimertinib arm may continue to 
receive treatment with osimertinib monotherapy (if savolitinib was stopped earlier) beyond 
RECIST 1.1-defined progression as long as they continue to receive clinical benefit, in the 
opinion of the principal investigator and do not meet any of the discontinuation criteria (this 
may be beyond disease progression in the absence of clinical symptoms or signs indicating 
clinically significant disease progression; no decline in performance status; absence of rapid 
disease progression or threat to vital organs or critical anatomical sites [eg, central nervous 
system metastasis, respiratory failure due to tumour compression, spinal cord compression] 
requiring urgent alternative medical intervention; or no significant, unacceptable or 
irreversible toxicities related to study treatment), according to the SoA (Table 1).  
7.1.1 
Rechallenge  
See guidance in Appendix I for circumstances under which a patient whose study treatment 
was temporarily interrupted due to an AE can restart treatment. 
7.1.2 
Procedures for discontinuation of study treatment  
The investigator should instruct the patient to contact the site before or at the time if any study 
treatment is stopped. A patient that decides to discontinue study treatment(s) will always be 
asked about the reason(s) and the presence of any AEs. The date of last intake of study 
treatment(s) should be documented in the eCRF. All study treatment(s) should be returned by 
the patient at their next on-site study visit or unscheduled visit. Patients permanently 
discontinuing study treatment should be given locally available standard of care therapy, at the 
discretion of the investigator. 
Discontinuation of study treatment(s), for any reason, does not impact on the patient´s 
participation in the study. The patient should continue attending subsequent study visits and 
data collection should continue according to the study protocol. If the patient does not agree to 
continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information. This could be a telephone contact with the 
patient, a contact with a relative or treating physician, or information from medical records. 
The approach taken should be recorded in the medical records. A patient that agrees to 
modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study.  

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7.1.3 
Follow-up of patients post discontinuation of study intervention  
As a minimum, telephone contact should be made with the patient 28 days following the 
discontinuation of both IPs to collect new AEs and follow up on any ongoing AEs and 
concomitant medications (including any subsequent cancer therapy, if appropriate). Refer to 
Section 8.3.3 for full details on AE recordings during follow-up. 
Patients who have discontinued study intervention prior to RECIST 1.1 defined radiological 
progression will be followed up with tumour assessments as indicated in the SoA until 
RECIST 1.1-defined PD or death regardless of whether or not the patient started a subsequent 
anti-cancer therapy, unless they have withdrawn all consent to study related assessments. 
All patients will be followed for survival until the end of the study.  
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoA as an alternative. 
7.1.4 
Follow-up for survival  
Patients will be followed up for survival status as indicated in the SoA until death, withdrawal 
of consent, or the end of the study. Survival information may be obtained via telephone 
contact with the patient or the patient’s family, by contact with the patient’s current physician, 
or publicly available death registries (if available). Additional assessments to be performed at 
the time of survival follow-up are detailed in the SoA. 
7.2 
Lost to follow-up  
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule. 
• 
Before a patient is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the patient or next of kin by eg, repeat telephone calls, 
certified letter to the patient’s last known mailing address or local equivalent methods. 
These contact attempts should be documented in the patient’s medical record.  
• 
Efforts to reach the patient should continue until the end of the study. Should the patient 
be unreachable at the end of the study the patient should be considered to be lost to 
follow-up with unknown vital status at end of study and censored at latest follow-up 
contact. 
 

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7.3 
Withdrawal from the study  
A patient may withdraw from the study (eg, withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment. 
A patient who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records). 
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before consent is withdrawn. 
If a patient withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records. The AstraZeneca study team 
should be informed of withdrawn patient sample destruction by the site or at the central 
laboratory in a prompt manner.  
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs. The investigator will follow up patients as medically indicated. The patient will 
return electronic PRO (ePRO) devices. 
AstraZeneca or its delegate will request investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) during survival follow-up until the end of 
the study from publicly available sources, in accordance with local regulations. Knowledge of 
the vital status at study end in all patient is crucial for the integrity of the study.  
See SoA (Table 1 and Table 2) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. All study treatment 
should be returned by the patient. 
8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarised in the SoA (Table 1 and Table 2).  
The investigator will ensure that data are recorded on the eCRF. The Electronic Data Capture 
system will be used for data collection and query handling.  
The investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The investigator will sign the completed eCRF. A copy of the completed eCRFs 
will be archived at the study site. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment. 

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Adherence to the study design requirements, including those specified in the SoA (Table 1 and 
Table 2), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the patient’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.  
8.1 
Efficacy assessments  
8.1.1 
CT and MRI scans tumour assessments (RECIST 1.1)  
RECIST 1.1 guidelines for measurable, non-measurable, target lesions (TLs) and non-target 
lesions (NTLs) and the objective tumour response criteria are presented in Appendix H of this 
Clinical Study Protocol. 
Baseline tumour assessments should include CT/MRI of chest and abdomen (including liver 
and adrenal glands) and should be performed within 28 days of treatment start, and ideally as 
close as possible to the start of study treatment.  
At screening the MRI/CT scans will include brain imaging (MRI preferred) for all patients 
randomised under CSP version 7.0. Those determined to have brain metastases at baseline or 
those who had a history of brain metastases will have their brain rescanned at all subsequent 
tumour assessments (using the same modality as at baseline) until RECIST 1.1-defined PD, 
and lesions should be captured as non-target lesions in the RECIST 1.1 assessment. In patients 
without brain metastases at baseline and without a history of brain metastases, brain scans will 
be performed only when there is a suspected CNS progression and at the RECIST 1.1-defined 
extracranial progression. The brain scan is required for all patients at PD by investigator 
assessment per RECIST 1.1 and should be performed within 4 weeks, but preferably as soon 
as possible, to allow the assessment of new lesions in the brain. Any other regions suspected, 
or with known metastasis at baseline, will be assessed by imaging and recorded at baseline. 
The same imaging modality used for baseline tumour assessment should be used for each 
subsequent follow-up assessment throughout the study if possible. Further details of the CT 
and MRI acquisition parameters will be documented in a separate image acquisition 
guidelines document. 
Follow-up assessments should be performed every 6 weeks (±7 days) after the start of 
treatment until Cycle 7, and then every 8 weeks until objective disease progression as defined 

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by RECIST 1.1 even if a patient discontinues treatment prior to progression (unless they 
withdraw consent). 
Patients randomised to the 300 mg bid savolitinib + placebo arm may cross over to 300 mg 
bid savolitinib + 80 mg od osimertinib following investigator assessed PD per RECIST 1.1. 
For patients who cross over after PD per RECIST 1.1, scheduled imaging is not required as 
specified in the crossover SoA (Table 2).  
Patients may also cross over to 300 mg bid savolitinib + 80 mg od osimertinib based on a 
declaration of futility of savolitinib + placebo without PD per RECIST 1.1. For patients who 
cross over based on a declaration of futility of the savolitinib monotherapy arm who have not 
objectively progressed during the initial randomised treatment period, scheduled imaging will 
be performed per the crossover SoA (Table 2). 
It is important to follow the assessment schedule as closely as possible. If scans are performed 
outside of the scheduled visit ±1 week window interval and the patient has not progressed, 
every attempt should be made to perform the subsequent scans at their scheduled time points. 
Patients will be evaluated until objective radiological disease progression by RECIST as per 
the SoA (Table 1). 
Categorisation of objective tumour response at each visit will be based on the RECIST 1.1 
guidelines for response: complete response (CR), partial response (PR), stable disease (SD) 
and progression of disease (PD). For ORR, a visit response of CR or PR must be confirmed by 
a later scan conducted at least 4 weeks after the initial response is observed.  
Target lesion progression will be calculated in comparison to when the tumour burden was at 
a minimum (ie, smallest sum of diameters previously recorded on study). In the absence of 
progression, tumour response (CR, PR, SD) will be calculated in comparison to the baseline 
tumour measurements obtained before starting treatment. 
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to NTLs or the appearance of a new lesion, it is advisable to continue treatment and 
reassess the patient’s status at the next scheduled assessment or sooner if clinically indicated. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal disease progression status. 
If repeated scans confirm progression, then the date of the initial scan should be declared as 
the date of progression. 

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Patients will complete ePRO assessments at home, and sometimes at site, using the same 
handheld electronic device (ePRO). Patients will be issued with the ePRO device and given 
training on how to use it, once the patient is confirmed as eligible for the study, is registered in 
IWRS and prior to starting treatment. This may be at the Screening visit or prior to dosing on 
Cycle 1 Day 1. 
All assessments should be completed according to the following parameters: 
Each centre must allocate the responsibility for the administration of the ePROs to a specific 
individual (eg, a research nurse or study coordinator) and, if possible, assign a backup person 
to cover if that individual is absent.  
The investigator will arrange for relevant training in the set-up of the electronic device and 
training patients in how to self-administer the ePROs using the device. Patients should 
complete the PROs in accordance with the study schedule as shown in Table 1. The 
significance and relevance of the data should be explained carefully to patients so that they are 
motivated to comply with the data collection. Reminders should be sent to patients at home as 
needed to ensure compliance with the assessment schedule. 
The following guidelines should be followed: 
The research nurse or appointed site staff must explain to patients the value and relevance of 
study participation and inform them that these questions are being asked to find out, directly 
from them, how they feel. The research nurse or appointed site staff should also stress that the 
information is confidential. Therefore, if the patients have any medical problems, they should 
discuss them with the doctor or research nurse separately from the ePRO assessment. 
The research nurse or appointed site staff must train the patient on how to use the ePRO 
device, using the materials and training provided by the ePRO vendor, and provide guidance 
on whom to call if there are problems with the device when the patient is completing the 
ePROs at home. 
The research nurse or appointed site staff should remind patients that there are no right or 
wrong answers. 
If the patient is unable to read (eg, blind or illiterate), that patient is exempted from 
completing the ePROs but may still participate in the study. Patients exempted in this regard 
should be flagged appropriately by the site staff and recorded in the eCRF. 
The research nurse or appointed site staff must monitor compliance to ensure all data is 
captured. Compliance must be checked at each study visit to identify problems early.  

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8.1.3 
Survival Follow-up  
Patients who have discontinued study treatment will be followed up for survival status every 
12 weeks until death, withdrawal of consent or the end of the study ie, at the time of final 
analysis. Survival information may be obtained via telephone contact with the patient, 
patient’s family or by contact with the patient’s current physician. In addition to the survival 
status, the assessment of anti-cancer and surgical treatments are also required. 
Patients should be contacted in the week following the data cut-offs to provide complete 
survival data. 
For patients who have not actively withdrawn consent, the status of those ongoing, withdrawn 
(from the study), and “lost to follow-up” at the time of the first analysis should be obtained by 
the site personnel by checking the patients notes, hospital records, contacting the patients 
general practitioner and checking publicly available death registries. In the event that the 
patient has actively withdrawn consent to the processing of their personal data, the vital status 
of the patient can be obtained by site personnel from publicly available resources where it is 
possible to do so under applicable local laws. 
8.2 
Safety assessments  
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
Planned time points for all safety assessments are provided in the SoA (Table 1 and Table 2). 
8.2.1 
Clinical safety laboratory assessments  
See Table 10 for the list of clinical safety laboratory tests to be performed and the SoA 
(Table 1 and Table 2) for the timing and frequency.  
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF. 
The clinical chemistry (including LFTs), haematology and urinalysis and serum pregnancy 
tests will be performed at a local laboratory or near to the investigator site. Sample tubes and 
sample sizes may vary depending on laboratory method used and routine practice at the site.  

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Table 10 
Laboratory safety variables  
Clinical chemistry safety 
Haematology 
Urinalysis (dipstick)a 
S/P – Albumin 
B – Haemoglobin 
U – Glucose 
S/P – ALTb 
B – Leucocyte cell count 
U – Protein 
S/P – ASTb 
B – Haematocrit 
U – Blood 
S/P – ALPb 
B – Red blood cell count 
U – Ketones 
S/P – Bilirubin, totalb 
B – Reticulocytes 
 
S/P – Calcium, total 
B – Absolute leucocyte differential count 
 
B – Neutrophil count 
 
B – Lymphocyte count 
 
B – Eosinophil count 
U – Leukocyte esterase 
S/P – Creatinine 
 
S/P- Glucose 
 
S/P – Magnesium  
 
S/P – Sodium 
B – Platelet count 
 
S/P – Potassium 
 
 
S/P – Total protein 
 
 
S/P – Blood urea nitrogen (BUN) 
or Urea 
 
 
S/P – Lactate dehydrogenase 
 
 
S/P – Amylase 
 
 
a 
If 3+ or greater proteinuria is identified by dipstick assessment, a 24-hour urine collection for formal 
quantification of the level of protein excretion should be performed. 
b 
Designates tests that are considered liver function tests and are to be done weekly for the first 10 weeks on 
study treatment (ie, Day 1, Day 8, Day 15 and Day 22 in Cycle 1 and Cycle 2; then Day 1 and Day 8 of 
Cycle 3), then Day 1 of every cycle and at progression. 
ALP Alkaline phosphatase; ALT Alanine aminotransferase; AST Aspartate aminotransferase; B Blood; 
BUN Blood urea nitrogen; P Plasma; S Serum; U Urine. 
NB: In case a patient shows an AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN 
please refer to Appendix E ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions. 
8.2.2 
Physical examinations  
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including 
spine and extremities) and neurological systems. 
Physical examination will be performed at timelines as specified in the SoA (Table 1 and 
Table 2), investigators should pay special attention to clinical signs related to previous serious 
illnesses, new or worsening abnormalities may qualify as AEs, see Section 8.3.7 for details. 

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8.2.3 
Vital signs  
Vital signs (BP, pulse, temperature and respiration rate) will be evaluated according to the 
SoA (Table 1 and Table 2). Weight will be assessed on Day 1 of each cycle for the first 
6 cycles then every 8 weeks after; height will be assessed at screening only. 
• Temperature, pulse rate and BP will be assessed.  
• BP and pulse measurements will be assessed in the semi-supine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. 
• Vital sign measurements should be preceded by at least 10 minutes of rest for the 
patient in a quiet setting without distractions (eg, television, cell phones). 
• Measurements will be taken in a semi-supine position after 10 minutes rest and will 
include temperature, systolic and diastolic BP, and pulse.  
 
8.2.4 
Electrocardiograms  
ECGs will be collected centrally. 
• Triplicate 12-lead ECG will be obtained as outlined in the SoA (Table 1 and Table 2) 
using an ECG machine that automatically calculates the heart rate and measures RR, 
P-R, QRS, QT, and QTcF intervals. 
• Triplicate ECGs will be obtained after the patient has been rested in a supine position 
for at least 5 minutes. The 3 individual ECG tracings should be obtained in succession, 
no more than 2 minutes apart. The full set of triplicates should be completed within 
5 minutes. ECGs will be recorded at 25 mm/sec. 
• All ECGs should be assessed by the investigator as to whether they are clinically 
significantly abnormal/not clinically significantly abnormal. If there is a clinically 
significant abnormal finding during the treatment period, the investigator will record it 
as an AE on the eCRF, according to standard AE collection and reporting processes. A 
28-day follow-up assessment will be required if an on-treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm reversibility of the 
abnormality. The original ECG traces must be stored in the patient medical record as 
source data. 
 

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8.2.5 
Multi-gated acquisition (MUGA)/echocardiogram (ECHO)  
An ECHO or MUGA scan to assess left ventricle ejection fraction will be conducted during 
the main study screening period, every 12 weeks (±2 weeks) relative to randomisation 
(patients recruited under CSP version 7.0) or the first dose of study drug (patients recruited 
prior to CSP version 7.0), and at the end of treatment as indicated in the SoA (Table 1 and 
Table 2). The modality of the cardiac function assessments must be consistent within a patient 
ie, if ECHO is used for the screening assessment, then ECHOs should also be done for 
subsequent testing. A 28-day follow-up assessment will be required if an on-treatment 
assessment was abnormal at the time of discontinuation of study therapy, to confirm 
reversibility of the abnormality.  
The patients should also be examined using the same machine and operator whenever 
possible. 
8.2.6 
Pregnancy assessments  
A pregnancy test on urine or blood sample will be performed for pre-menopausal women of 
childbearing potential, at the study screening visit, and prior to the first dose of study drug on 
Cycle 1 Day 1, Day 1 of every cycle and at treatment discontinuation. Tests will be performed 
by the institutional laboratory. If results are positive the patient is ineligible/must be 
discontinued from the study. In the event of a suspected pregnancy during the study, the test 
should be repeated and if positive, the patient will be discontinued from study treatment 
immediately. 
8.2.7 
ECOG Performance Status  
ECOG performance status will be assessed as specified in the SoA and at the time of PD 
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. 

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Any significant change from baseline or screening must be reported as an AE as described in 
Section 8.3.7. 
8.3 
Collection of adverse events  
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section 
The definitions of an AE or SAE can be found in Appendix B. 
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate or the 
patient's legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see Section 8.3.3.  
8.3.1 
Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.2 
Time period and frequency for collecting AE and SAE information  
AEs and SAEs will be collected from time of signing of the main study ICF throughout the 
treatment period and including the follow-up period. The follow-up period is defined as 
28±7 days after study treatment is discontinued. 
Procedure-related AEs and SAEs for those patients who provide a new tumour sample 
occurring up to and including 21 days after the new tumour sample collection procedure will 
be captured. This procedure may be performed prior to signing the main study ICF. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Section 8.4.1. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. SAEs will be reported according to local regulations. 
Investigators are not obligated to actively seek AE or SAE in former study patients. However, 
if the investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the investigator may notify the sponsor. 
The method of defining, evaluating, and assessing causality of AE and SAE are provided in 
Appendix B. 

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8.3.3 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts. All AEs and SAEs, will be followed until resolution, 
stabilisation, the event is otherwise explained, or the patient is lost to follow-up  
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
8.3.4 
Adverse event data collection  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
The maximum on-treatment CTCAE grade (according to CTCAE version 5.0) 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP(s) (yes or no) 
• 
Action taken with regard to IP(s) 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
 
8.3.5 
Causality collection  
The investigator will assess causal relationship between each IP and each AE, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational products?’. 

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For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
8.3.6 
Adverse events based on signs and symptoms  
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study site staff: ‘Have you had any health problems since the previous 
visit/you were last asked?’ or revealed by observation will be collected and recorded in the 
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
8.3.7 
Adverse events based on examinations and tests  
The results from the Clinical Study Protocol mandated laboratory tests, ECGs and vital signs 
will be summarised in the Clinical Study Report. Deterioration as compared with baseline in 
protocol-mandated laboratory values and vital signs should therefore only be reported as AEs 
if they fulfil any of the SAE criteria or are the reason for discontinuation of treatment with the 
IP. 
If deterioration in a laboratory value/ECG/vital sign/other safety assessment is associated with 
clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result/ECG/vital sign will be considered as additional information. 
Wherever possible the reporting investigator uses the clinical, rather than the laboratory term 
(eg, anaemia versus low haemoglobin value). In the absence of clinical signs or symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study, see Sections 8.3.9 and 8.3.10. 
8.3.8 
Hy’s law  
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN may need to 

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be reported as SAEs. Please refer to Appendix E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law. 
8.3.9 
Disease-under study  
Symptoms of disease-under study are those which might be expected to occur as a direct result 
of advanced NSCLC. Events which are unequivocally due to disease under study should not 
be reported as an AE during the study unless they meet SAE criteria or lead to discontinuation 
of the IP. 
8.3.10 
Disease progression  
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 
as disease progression and not an AE. Events, which are unequivocally due to disease 
progression, should not be reported as an AE during the study. 
Progression of the malignancy under study, including signs and symptoms progression, should 
not be reported as an SAE. Hospitalisation due to signs and symptoms of disease progression 
should not be reported as SAE. 
8.3.11 
New cancers  
The development of a new cancer should be regarded as an AE and will generally meet at 
least 1 of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the patient’s inclusion in 
this study. They do not include metastases of the original cancer. 
8.3.12 
Handling of deaths  
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of IP, should be reported as follows: 
• 
Death, which is unequivocally due to disease progression, should be communicated to the 
study monitor at the next monitoring visit and should be documented in the eCRF 
module, but should not be reported as a SAE during the study. 
• 
Where death is not clearly due to disease progression of the disease under study the AE 
causing the death should be reported to the study monitor as an SAE within 24 hours. The 
report should contain a comment regarding the co-involvement of progression of disease, 
if appropriate, and should assign a single primary cause of death together with any 
contributory causes. 
• 
Deaths with an unknown cause should always be reported as a SAE but every effort 
should be made to establish a cause of death. A post-mortem may be helpful in the 

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1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day ie, immediately but no later than 24 hours of when he or she becomes aware of it. 
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed.  
Section 5.4 of the osimertinib and savolitinib investigator brochures provides information 
related to the emerging safety profile of both study treatments. For further guidance on the 
definition of a SAE, see Appendix B of the Clinical Study Protocol. 
8.4.2 
Pregnancy  
All pregnancies and outcomes of pregnancy during the course of study and within 6 weeks of 
the last dose of osimertinib should be reported to AstraZeneca except for: 
• 
If the pregnancy is discovered before the study patient has received any study drug. 
 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.2.1 
Maternal exposure  
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study. 

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If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.2) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy.  
8.4.2.2 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and 
6 months following the last dose. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality), occurring from the date of the first dose until 6 months after the 
last dose and as indicated by previous studies (pre-clinical and clinical) should, if possible, be 
followed up and documented in the Pregnancy Report Form. Consent from the partner must be 
obtained before the Pregnancy Report Form is completed.  
8.4.3 
Reporting of overdose  
A maximum tolerated dose has not been established for osimertinib or savolitinib, therefore an 
overdose is any dose which exceeds the daily dose that is defined in this clinical study 
protocol.  
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 
(Initial Fatal/Life-Threatening or follow-up Fatal/Life-Threatening) or 5 (other serious initial 
and follow-up) calendar days for overdoses associated with an SAE (see Sections 8.3.2 and 
8.4.1) and within 30 days for all other overdoses. 

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8.4.4 
Medication Error, Drug Abuse, and Drug Misuse  
8.4.4.1 
Timelines  
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
1 calendar day, ie, immediately but no later than 24 hours of when they become aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error, drug abuse, or drug misuse (see Sections 8.3.2 and 
8.4.1) and within 30 days for all other events. 
8.4.4.2 
Medication Error  
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the patient 
or has the potential to cause harm to the patient. 
The full definition and examples of medication error can be found in Appendix B 8. 
8.4.4.3 
Drug Abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix B 8. 
8.4.4.4 
Drug Misuse  
Drug misuse is the intentional and inappropriate use (by a study patient) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix B 8. 
8.4.5 
Management of IP-related toxicities  
8.4.5.1 
Management of osimertinib-related toxicities  
Potential osimertinib-related toxicities during the course of the study can be managed by 
interruption of the dose of osimertinib or dose reductions (see Appendix I Section I 1). Repeat 
dose interruptions are allowed as required. If a patient experiences a CTCAE Grade 3 
(CTCAE version 5.0) and/or unacceptable toxicity, dosing will be interrupted and supportive 
therapy administered as required in accordance with local practice/guidelines. If the toxicity 
resolves or reverts to ≤CTCAE Grade 2 after 3 weeks of onset, treatment with osimertinib 

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may be restarted at the same dose (80 mg) or a lower dose (40 mg) using the rules in 
Appendix I Section I 1 and with discussion and agreement with the AstraZeneca Study Team 
Physician as needed. There will be no individual modifications to dosing schedule in response 
to toxicity, only potential dose reduction or dose modification. If the toxicity does not resolve 
to ≤CTCAE Grade 2 after 3 weeks, then the patient should be withdrawn from the study and 
observed until resolution of the toxicity. Osimertinib can be dose reduced to 40 mg od: if the 
reduced dose of 40 mg od is not tolerable, no further dose reduction is allowed and study 
treatment should be discontinued. Once a dose is reduced escalation is not permitted. 
Dose modifications are permitted in the management of IP-related toxicities as described in 
Table 11 with further information being provided in Appendix I Section I 1. 
Dose modification guidelines for QTc prolongation are shown in Table 12. 
Table 11 
Osimertinib dose adjustment information for adverse reactions  
Target organ 
Adverse reactiona 
Dose modification 
Pulmonary 
ILD/pneumonitis 
Permanently discontinue osimertinib 
Other 
 
Grade 3 or higher adverse reaction 
Withhold osimertinib for up to 3 weeks 
If Grade 3 or higher adverse reaction 
improves to Grade 0 to 2 after withholding 
of osimertinib for up to 3 weeks 
Osimertinib may be restarted at the same 
dose (80 mg) or a lower dose (40 mg) 
 
Grade 3 or higher adverse reaction that does 
not improve to Grade 0 to 2 after 
withholding for up to 3 weeks 
Permanently discontinue osimertinib 
a 
The intensity of the clinical adverse events graded by the National Cancer Institute CTCAE Version 5.0. 
ILD  Interstitial lung disease. 
 
8.4.5.2 
Management of savolitinib-related toxicities  
Potential savolitinib-related toxicities during the course of the study can be managed as 
medically indicated and with interruption of the dose of savolitinib or dose reductions as 
appropriate, unless symptoms are associated with hypersensitivity (see Appendix I 
Section I 3). Repeat dose interruptions are allowed as required, taking into consideration the 
additional precautions for restart of savolitinib as illustrated in Appendix I. For each patient 
the savolitinib dose can be reduced a maximum of 2 times (Table 9). No dose re-escalations 
are allowed. 
Dose modification guidelines for QTc prolongation are shown in Table 12. 

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Table 12 
Dose modifications for QTc 
prolongation  
 
NCI CTCAE Toxicity 
Grade 
Action with savolitinib 
Action with osimertinib 
Grade 0, 1, or 2 
None 
None 
Grade 3 
Hold dosing and follow algorithm 
below: 
Hold dosing and follow algorithm 
below: 
Patients with QTcF 
prolongation to >500 msec 
on at least 2 separate ECGs 
Consult with cardiologist to validate 
ECG finding. Ensure cardiac 
surveillance and take actions in 
accordance with clinical standards. 
Regular ECGs performed until 
resolution to QTcF <481 msec and then 
restart drug at one reduced dose level.* 
 
Withhold until QTc interval is <481 
msec or recovery to baseline if 
baseline QTc is more than 481 
msec within 21 days of onset, then 
restart at a reduced dose (40 mg) or 
at 80 mg (at the discretion of the 
investigator). 
If the toxicity does not 
resolve to QTcF <481 msec 
within 21 days 
Permanently discontinue study drug 
and consult with a cardiologist for 
further management as clinically 
indicated. 
Permanently discontinue 
osimertinib. 
Grade 4 
 
 
QTcF ≥501 or >60 msecs 
change from baseline and 
Torsade de pointes or 
polymorphic ventricular 
tachycardia or 
signs/symptoms of serious 
arrhythmia 
Permanently discontinue study drug 
and consult with a cardiologist for 
further management as clinically 
indicated. 
Permanently discontinue 
osimertinib. 
CTCAE Common Terminology Criteria for Adverse Events; ECG  Electrocardiogram; NCI  National Cancer 
Institute; QTc  corrected QT interval; QTcF corrected QT interval using Fridericia's formulas. 
*For French sites only, as per ANSM advice, the patient must remain hospitalised with continuous cardiac 
monitoring (ECG) until specialist advice is obtained by a cardiologist.  
 
8.5 
Human biological samples  
Instructions for the collection and handling, storage and shipping of biological samples will be 
provided in the study-specific Central Laboratory Manual. Samples should be stored in a 
secure storage space with adequate measures to protect confidentiality. For further details on 
Handling of Human Biological Samples, see Appendix C. 
Samples will be stored for a maximum of 15 years from the end of the study (as defined in this 
CSP; see Section 4.4) in line with consent and local requirements, after which they will be 
destroyed/repatriated. 

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• 
Samples will be disposed of after the Bioanalytical Report finalisation or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless consented for 
future analyses. 
− 
Samples may be disposed of or anonymised by pooling. Additional analyses may be 
conducted on the anonymised, pooled samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from 
the clinical study report (CSR). 
• 
Remaining sample aliquots will be retained at AstraZeneca or its designee for a maximum 
of 15 years from the end of the study (as defined in the CSP; see Section 4.4). Additional 
use includes but is not limited to further characterisation of any anti-drug antibodies, 
confirmation and/or requalification of the assay as well as additional assay development 
work. The results from future analysis will not be reported in the CSR. 
For further details on Handling of Human Biological Samples, see Appendix C. 
8.5.1 
Pharmacokinetics  
Plasma samples will be collected for measurement of plasma concentrations of osimertinib, 
savolitinib and their metabolites as specified in Table 13. The timing of PK samples may be 
adjusted during the study if warranted and agreed upon between the investigator and the 
sponsor dependent upon emerging data to ensure appropriate characterisation of the plasma 
concentration-time profiles. Samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and sponsor. Total volume of 
blood taken from each patient will not exceed that described in Section 8. Instructions for the 
collection and handling of biological samples will be provided by the sponsor or analytical 
test site. The actual date and time (24-hour clock time) of each sample will be recorded. The 
actual date, time and amount of the last savolitinib and osimertinib doses prior to each PK 
sample will be recorded. 
For patients receiving savolitinib 300 mg bid, on PK sampling days, samples will be collected 
following the first dose of the day. 
Table 13 
Pharmacokinetic sampling schedule  
Cycle number 
Sampling pointa 
Cycle 1, Day 1 
Pre-dose, and 1, and 3 hours post-dose 
Cycle 2, Day 1 
Pre-dose, and 1, and 3 hours post-dose 
Cycle 3, Day 1 
Pre-dose, and 1, 3, 4 and 6 hours post-dose (N.B. Triplicate ECGs to be collected at 
these timepoints as described in section 8.2.4.) 
Cycle 6, Day 1 
Pre-dose 
Cycle 11, Day 1  
Pre-dose 
a 
Samples may be collected at additional timepoints. 

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On PK days patients should come to the clinic fasted where they will first be given a moderate 
breakfast (the same breakfast should be given on all PK days) and will administer the 
osimertinib and savolitinib dose at the same time. Fasting state will be collected in the eCRF. 
Pre-dose PK sample may be drawn at any time before dosing occurs (before or after 
breakfast). 
Samples will be used to evaluate the PK of osimertinib and savolitinib. The savolitinib plasma 
concentration data obtained from the samples collected in this study may be included in the 
listings of the CSR. 
Any changes in the timing or addition of time points for any planned study assessments for 
individual patients must be documented and approved by the relevant study team member and 
then archived in the sponsor and site study files, and may not constitute a protocol 
amendment. The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF and CSP. 
8.5.1.1 
Determination of drug concentration  
Samples for determination of individual drug and/or metabolite concentrations in plasma will 
be analysed by Covance Bioanalytical Laboratories on behalf of AstraZeneca, using 
appropriate bioanalytical methods. Full details of the analytical methods used will be 
described in a separate bioanalytical report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a bioanalytical report. Additional analyses may be conducted on the anonymised, 
pooled PK samples to further evaluate and validate the analytical method. Any results from 
such analyses may be reported separately from the CSR. 
8.5.2 
Immunogenicity Assessments  
Immunogenicity is not evaluated in this study. 
8.5.3 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6 
Human biological sample biomarkers  
8.6.1 
Collection of mandatory samples for biomarker analysis  
Mandatory collection of samples for other biomarker research is also part of this study. The 
following samples for biomarker research are required and will be collected from all patients 
in this study as specified in Table 1 and Table 2): 

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9.3 
Populations for analyses  
For purposes of analysis, the following populations are defined: 
Population 
Description 
Target Population Analysis Set 
(TPAS) 
All patients assigned to savolitinib 300 mg bid + osimertinib who have 
FISH10+ and/or IHC90+ status, have progressed following 1L osimertinib, 
and have taken ≥1 dose of either study drug. 
Contribution of Components 
Analysis Set (CAS) 
All patients randomised under CSP version 7.0 with treatment groups 
assigned in accordance with the randomisation, regardless of the treatment 
actually received. 
Safety Analysis Set (SAF) 
All enrolled patients who take ≥1 dose of either study drug. 
PK population 
All patients who receive at least 1 dose of savolitinib or osimertinib as per 
the protocol, for whom any post-dose PK data are available and do not 
violate or deviate from the protocol in ways that would significantly affect 
the PK analyses will be included in the PK analysis set.  
Evaluable for Response 
Dosed patients who have measurable disease at baseline. 
Evaluable for Response 2 
Dosed patients with measurable disease at baseline who have had the 
opportunity for 2 on-treatment RECIST scans. 
Safety Analysis Set 2 (SAF2) 
All enrolled patients who take ≥1 dose of either study drug who have had 
the opportunity to be treated for 6 weeks. 
CSP  Clinical study protocol; FISH  Fluorescence in situ hybridisation; IHC immunohistochemistry; PK 
Pharmacokinetic(s); RECIST  Response Evaluation Criteria in Solid Tumours. 
Patients will be assigned to each of these populations and to the diagnostic populations 
(centrally confirmed by FISH [FISH5+, FISH10+] and centrally confirmed by IHC [IHC50+, 
IHC90+]), prior to any analyses being performed.  
The Target Population Analysis Set (TPAS) will be used as the population for reporting 
efficacy and to summarise baseline characteristics for patients dosed with savolitinib 300 mg 
bid + osimertinib who are FISH10+ and/or IHC90+ and have progressed following treatment 
with 1L osimertinib (primary endpoint population).  
The Contribution of Components Analysis Set (CAS) will be used as the population for 
reporting efficacy and to summarise baseline characteristics for patients randomised under 
CSP version 7.0. 
The SAF will be used for reporting efficacy of savolitinib 300 mg od + osimertinib in FISH5+ 
and/or IHC50+ patients (primary endpoint population). The SAF will also be used as the 
population for reporting efficacy and to summarise baseline characteristics for patients dosed 
prior to CSP version 7.0. The Safety Analysis Set (SAF) will be used as the population for 
reporting safety for patients dosed under all CSP versions. 

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For the PK population, where a protocol deviation impacts only part of a patient’s data, the 
affected portion of the patient’s PK data will be excluded from PK analysis and summary 
statistics, and the remaining valid data will be utilised. 
9.4 
Statistical analyses  
9.4.1 
General considerations  
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will 
be developed and will describe the patient populations to be included in the analyses and 
procedures for accounting for missing, unused and spurious data. This section is a summary of 
the planned statistical analyses of the primary and secondary endpoints. Any deviations from 
this plan will be reported in the clinical study report. 
Descriptive statistics will be used for all variables. Continuous variables will be summarised 
by the number of observations, mean, standard deviation, median, minimum and maximum. 
Categorical variables will be summarised by frequency counts and percentages for each 
category. Unless otherwise stated, percentages will be calculated out of the population total. 
Analyses will be presented by the assigned starting dose (300 mg od savolitinib, 300 mg bid 
savolitinib and 600 mg od savolitinib in combination with osimertinib, or 300 mg bid 
savolitinib as monotherapy [savolitinib + placebo]).  
Additional subgroup analyses of efficacy and safety may be performed and will be specified 
in the SAP. 
Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued study intervention, and other protocol deviations) may be generated. More detail 
will be provided in the SAP. 
Baseline for patients allocated/ randomised to treatment will be the last assessment of the 
variable under consideration prior to the intake of the first dose, except for efficacy variables. 
For efficacy variables, baseline is defined as the last visit prior to randomisation (patients 
enrolled under CSP version 7.0) or last visit prior to first dose (patients enrolled prior to CSP 
version 7.0). For patients who cross over from savolitinib plus placebo to savolitinib plus 
osimertinib, their data will be cut off for the purposes of any savolitinib plus placebo 
assessment at the last assessment of the variable under consideration prior to the intake of the 
first dose of the combination therapy. 
9.4.2 
Stratification factor(s)  
There is one stratification factor of baseline brain metastases (Yes/No) in the randomised part 
of the study under CSP version 7.0. The stratification in the statistical analyses will be based 

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on the baseline brain scan assessed by the investigator using the values entered in the IWRS at 
randomisation, even if it is subsequently discovered that these values were incorrect. 
9.4.3 
Efficacy analyses  
Investigator RECIST based assessments 
From the investigators review of the imaging scans, the RECIST tumour response data will be 
used to determine each patient’s visit response according to RECIST Version 1.1. It will be 
used to determine the endpoints PFS, ORR, DoR and tumour size change. 
At each tumour assessment, patients will be programmatically assigned a RECIST 1.1 visit 
response of CR, PR, SD or PD depending on the status of their disease compared with 
baseline and previous assessments. If a patient has had a tumour assessment which cannot be 
evaluated, the patient will be assigned a visit response of Not Evaluable (NE; unless there is 
evidence of progression in which case the response will be assigned as PD). 
Investigator assessment of PD per RECIST 1.1 of patients receiving savolitinib + placebo is 
required prior to cross over to savolitinib plus osimertinib. 
Please refer to Appendix H for the definitions of CR, PR, SD and PD. 
Central review of RECIST 1.1 based assessments 
The BICR of radiological imaging data will be carried out using RECIST 1.1. All radiological 
scans for all patients (including those unscheduled visits, or outside visit windows) will be 
provided to the BICR. The imaging scans will be reviewed by 2 independent radiologists 
using RECIST 1.1 criteria and will be adjudicated if required. The independent reviewers will 
be blinded to study intervention. 
Further details of the BICR will be documented in the independent review charter. 
9.4.3.1 
Analysis of the primary endpoints  
The ORR will be defined as a visit response of CR or PR, with the denominator defined as 
subset of all dosed patients with measurable disease at baseline. For ORR, a visit response of 
CR or PR must be confirmed by a later scan conducted at least 4 weeks after the initial 
response is observed. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Patients who discontinue treatment without 
progression, receive a subsequent anti-cancer therapy (note that for this analysis radiotherapy 
is not considered a subsequent anti-cancer therapy) and then respond will not be included as 
responders in the ORR.  

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Progression-free survival based on investigator assessment will be analysed using a stratified 
log-rank test adjusting for the stratification used in randomisation for the generation of the 
p-value. The effect of treatment will be estimated by the HR together with its corresponding 
95% CI for the CAS. An HR less than 1 will favour savolitinib plus osimertinib. The HR and 
its CI will be estimated from a Cox Proportional Hazards model (with ties = Efron and 
baseline stratification) and the CI calculated using a profile likelihood approach. If there are 
insufficient events per strata, a log-rank test will be used to analyse PFS instead of a stratified 
log-rank test.  
Overall survival  
OS is defined as the time from randomisation (patients recruited under CSP version 7.0) or the 
start of treatment (patients recruited prior to CSP version 7.0) until death due to any cause. 
Any patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive. 
Note: Patients will be contacted for survival follow-up every 12 weeks. Patients should be 
contacted in the week after data cut-off for each analysis to establish survival status. The 
impact of cross over on OS may need to be assessed depending on the number of patients 
crossing over to savolitinib plus osimertinib. Further details will be provided in the SAP. 
Summaries of OS (n, events, medians, quartiles, proportion alive at 12 and 15 months and 
corresponding 95% CIs) and a Kaplan-Meier plot will be provided. 
9.4.3.3 
EORTC QLQ-C30 and QLQ-LC13  
Symptoms and overall quality of life will be assessed using EORTC QLQ-C30 and QLQ-
LC13 (secondary endpoints). Questionnaires will be scored according to published guidelines 
or the developer’s guidelines, if published guidelines are not available. Analyses will be 
summarised using the TPAS, the CAS and the SAF (see Section 9.3 for analysis set 
definitions). Further details of the statistical analyses will be given in the SAP. 
The QLQ-C30 consists of 30 questions, which can be combined to produce 5 functional scales 
(Physical, Role, Cognitive, Emotional, Social), 3 symptom scales (Fatigue, Pain, 
Nausea/vomiting), 5 individual items (dyspnoea, insomnia, appetite loss, constipation, 
diarrhoea) and a global measure of health status. The QLQ-LC13 is a lung cancer specific 
module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, 
dyspnoea and site-specific pain), treatment related side-effects (sore mouth, dysphagia, 
peripheral neuropathy and alopecia) and pain medication. With the exception of a multi-item 
scale for dyspnoea, all are single items. The dyspnoea scale will only be used if all 3 items 
have been scored, otherwise the items are treated as single-item measures. 
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales and the global health status/QoL scale 

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in the QLQ-C30 and for each of the symptom scales/items in the QLQ-LC13 according to the 
EORTC QLQ-C30 Scoring Manual and EORTC QLQ-LC13 instructions.  
Higher scores on the global health status and functioning scales indicate better health 
status/function. Higher scores on the symptom scales indicate greater symptom burden. For 
each subscale, if <50% of the subscale items are missing, then the subscale will be divided by 
the number of non-missing items and multiplied by the total number of items on that subscale. 
If at least 50% of the items are missing, then that subscale will be treated as missing. Missing 
single items are treated as missing. The reason for missing questionnaires will be identified 
and recorded. If there is evidence that the missing data are systematic, missing values will be 
handled to ensure that any possible bias is minimised. 
The primary PRO outcome measures will be 5 patient-reported lung cancer symptoms, namely  
• 
Dyspnoea (multi-item scale based on three questions: “Were you short of breath when 
you rested; walked; climbed stairs”) (LC13),  
• 
Cough: one item (“How much did you cough?”) (LC13),  
• 
Pain: one item (“Have you had pain in your chest”) (LC13). 
• 
Fatigue (a composite score of three items: “Did you need rest; Have you felt weak; Were 
you tired”) (C30) 
• 
Appetite loss: one individual item (“Have you lacked appetite”) (C30) 
 
Definition of clinically meaningful changes 
Changes in score compared to baseline will be evaluated. A minimum clinically meaningful 
change is defined as a change in the score from baseline of ≥10 for scales/items from the 
QLQ-LC13 and the QLQ-C30 (Osoba et al 1998). 
For example, a clinically meaningful deterioration or worsening in chest pain (as assessed by 
QLQ-LC13) is defined as an increase in the score from baseline of ≥10. A clinically 
meaningful improvement in fatigue (as assessed by QLQ-C30) is defined as a decrease in the 
score from baseline of ≥10.  
At each post-baseline assessment, change in symptoms/functioning from baseline will be 
categorised as improved, stable or worsening as shown in Table 14. 

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Table 14 
Visit Response for HRQoL and disease-related symptoms  
Score 
Change from baseline 
Visit Response 
QLQ-LC13/QLQ-C30 symptom 
scales/items 
≥+10 
Worsened 
≤-10 
Improved 
Otherwise 
Stable 
QLQ-C30 functional scales and 
Global health status/QoL 
≥+10 
Improved 
≤-10 
Worsened 
Otherwise 
Stable 
 
Time to symptom deterioration  
Time to deterioration in symptoms, functioning and global health status/QoL will be 
evaluated, more details will be specified in the SAP.  
Symptom improvement rate 
Improvement in symptoms, functioning and global health status/QoL will be evaluated, more 
details will be specified in the SAP.  
9.4.4 
Safety analyses  
The SAF will be used as the population for reporting safety for patients dosed under all CSP 
versions (see Section 9.3 for analysis set definitions). 
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs, 
ECG data and ECOG performance status. 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code AEs. AEs 
will be graded according to the National Cancer Institute CTCAE (Version 5.0). 
The number of patients experiencing each AE will be summarised by the MedDRA system 
organ class and preferred term. The number and percentage of patients with AEs in different 
categories (eg, causally related, CTCAE Grade ≥3 etc) will be summarised, and events in each 
category will be further summarised by MedDRA system organ class and preferred term. 
SAEs will be summarised separately if a sufficient number occur. 
Any AE occurring before the first dose of study drug will be included in the data listings but 
will not be included in the summary tables of AEs. AE summary tables will include only 
treatment-emergent adverse events. AEs will be defined as treatment emergent if they have an 
onset, or worsen (by investigator report of a change in intensity), during the study treatment 
period (defined from date of first dose of any study treatment to date of last dose of any study 
treatment) or safety follow-up period (28 days [±7 days] after last dose of study treatment). 

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Any events in this period that occur after a patient has received further therapy for cancer 
(following discontinuation of IP) will be flagged in the data listings. 
Discontinuation rate due to AEs will be summarised for the first 6 weeks and at any time. 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation. Based on 
the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant adverse 
events and reported as such in the clinical study report. A similar review of laboratory/vital 
signs (pulse and BP)/ECG data will be performed for identification of other significant 
adverse events. 
Examples of these could be marked haematological and other laboratory abnormalities, and 
certain events that lead to intervention (other than those already classified as serious), dose 
reduction or significant additional treatment. Tables and figures for potential Hy's Law cases 
will be produced. 
Any AE occurring within the defined 28-day follow-up period after discontinuation of study 
drug will be included in the AE summaries. AEs occurring after the 28-day follow-up period 
after discontinuation of study drug or after starting subsequent anti-cancer therapy will be 
listed separately, but not included in the summaries. 
Duration of exposure will be summarised. The number and percentage of patients with at least 
1 dose interruption/dose delay and at least 1 dose reduction will also be summarised 
separately for the first 6 weeks and at any time.  
Haematology, clinical chemistry, coagulation, urinalysis, vital signs and ECG data will be 
listed individually by patient and suitably summarised. For all laboratory variables, which are 
included in the current version of CTCAE, the CTCAE grade will be calculated.  
Details of any deaths will be listed for all patients. 
Graphical presentations of safety data will be prepared as is deemed appropriate. 
9.4.5 
Pharmacokinetic analyses  
PK analyses of the plasma concentration data for osimertinib, savolitinib and their metabolites 
(AZ5104 for osimertinib; M2 and M3 for savolitinib) will be performed by QCP, AstraZeneca 
or a delegate on behalf of QCP. The actual sampling times will be used in the parameter 
calculations and PK parameters will be derived using standard non-compartmental methods. 
Where possible, the following PK parameters will be determined for osimertinib, savolitinib 
and their metabolites: 

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
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 
(CIOMS) International Ethical Guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• 
Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, investigator’s brochure, 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 revised 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 patients.   
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 CRO but 
the accountability remains with AstraZeneca. 
The investigator will be responsible for providing oversight of the conduct of the study at the 
site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local regulations. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 

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• 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
− 
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure or state other documents and will 
notify the IRB/IEC, if appropriate according to local requirements. 
 
Regulatory Reporting Requirements for Serious Breaches of Protocol or GCP 
• 
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met. 
− 
A “serious breach” means a breach likely to affect to a significant degree the safety 
and rights of a patient or the reliability and robustness of the data generated in the 
clinical trial. 
• 
AstraZeneca will comply with country-specific regulatory requirements relating to serious 
breach reporting to the regulatory authority, IRB/IEC, and investigators. 
− 
Where the EU Clinical Trials Regulation 536/2014 applies, AstraZeneca has in place 
processes to enter details of serious breaches into the European Medicines Agency 
Clinical Trials Information System (CTIS). It is important to note that redacted 
versions of serious breach reports will be available to the public via CTIS. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately. 
• 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
• 
The investigator should have a process in place to ensure that: 
− 
The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach 
− 
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by 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 

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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 patient or 
his/her legally authorised representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary. Patients or their legally 
authorised will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
centre.  
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date and time the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
Patients 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 patient or the patient’s legally authorised 
representative.  
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study. 
If a patients’ partner becomes pregnant during or within 6 months after the study, the partner 
is asked to sign the "Adult Study Informed Consent Form for Pregnant Partners of Study 
Patients" and provide information about the pregnancy accordingly. 
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within the screening window. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorised designee will explain 
to each patient the objectives of the exploratory research. Patients will be told that they are 
free to refuse to participate and may withdraw their consent at any time and for any reason 
during the storage period. The patient will give a separate agreement to allow any remaining 
specimens to be used for exploratory research. Patients who decline to participate in this 
optional research will indicate this in the ICF. If a patient withdraws consent to the use of 
donated biological samples, the samples will be disposed of/destroyed, within a reasonable 

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timeframe, and the action documented. If samples already have been analysed at the time of 
the request, AstraZeneca will not be obliged to destroy the results of this research. 
A 4 
Data protection  
• 
Patients will be assigned a unique identifier by AstraZeneca. Any patient records or 
datasets that are transferred to AstraZeneca will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred. 
• 
The patient must be informed that their personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the patient in the informed consent.  
• 
The patient must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• 
The patient must be informed that data will be collected only for the business needs. We 
will only collect and use the minimum amount of personal data to support our business 
activities and will not make personal data available to anyone (including internal staff) 
who is not authorised or does not have a business need to know the information.  
• 
The patient must be informed that in some cases their data may be pseudonymised. The 
General Data Protection Regulation (GDPR) defines pseudonymisation as the processing 
of personal data in such a way that the personal data can no longer be attributed to a 
specific individual without the use of additional information, provided that such 
additional information is kept separately and protected by technical and organisational 
measures to ensure that the personal data are not attributed to an identified or identifiable 
natural person. 
Personal Data Breaches 
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, 
stored or otherwise processed. 
• 
In compliance with applicable laws, the Data Controller1 for the processing activity where 
the personal data breach occurred (AstraZeneca or respectively the site), will notify the 
data protection authorities without undue delay within the legal terms provided for such 
notification and within the prescribed form and content. 
 
1 The Data Controller determines the purposes for which and the means by which personal data is processed, as 
defined by the European Commission. 

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• 
Whilst AstraZeneca has processes in place to deal with personal data breaches it is 
important that investigators that work with AstraZeneca have controls in place to protect 
patient data privacy.  
The investigator should have a process in place to ensure that: 
• 
Site staff or service providers delegated by the investigator/institution are allowed to 
identify the occurrence of a (potential) personal data breach. 
• 
Any (potential) personal data breach is promptly reported to AstraZeneca or delegated 
party, through the contacts (e-mail address or telephone number) provided by 
AstraZeneca.  
AstraZeneca and the site must demonstrate that they: 
• 
have taken all necessary steps to avoid personal data breaches and 
• 
have undertaken measures to prevent such breaches from occurring in the first place and 
to mitigate the impact of occurred data breaches (eg, applying encryption, maintaining 
and keeping systems and IT security measures up-to-date, regular reviews and testing, 
regular training of employees, and developed security policies and standards). 
• 
where possible, have developed an internal data breach reporting and investigation 
process and internal protocols with guidance on how to respond swiftly and diligently to 
the occurrence of a personal data breach. 
• 
where it has not been possible to develop an internal data breach reporting and 
investigation process, the site follows AstraZeneca’s instructions.  
Notification of personal data breach to patients: 
• 
notification to patients is done by the site for the data breaches that occurred within the 
processing activities for which the site is the Data Controller and for data breaches that 
occurred within the processing activities of AstraZeneca as the Data Controller, the 
notification is done in collaboration with the site and is performed by the site and/or 
Principal Investigator, acting on behalf of AstraZeneca, so that AstraZeneca has no access 
to the identifying personal information of the patients. The site and/or Principal 
Investigator shall conduct the notification by contacting the patients using the information 
that they gave for communication purposes in clinical research. 
• 
If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course 
after discovering the breach notifies AstraZeneca and provides full cooperation with the 
investigation. In these cases, to the extent AstraZeneca is the Data Controller for the 
processing activity where the breach occurred, it will be responsible for the notification to 
data protection authorities and, if applicable, to patients. If the personal data breach needs 
to be notified to the patients, the notification to patients is done in collaboration with the 

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A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com, 
http://www.clinicaltrials.gov and https://euclinicaltrials.eu, as will the summary of the main 
study results when they are available. The clinical trial and/or summary of main study results 
may also be available on other websites according to the regulations of the countries in which 
the main study is conducted. 
A 7 
Data quality assurance  
All patient data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by 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 agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy, including definition of study-critical data items and 
processes (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 included in the Monitoring Plan.  
AstraZeneca or designee is responsible for medical oversight throughout the conduct of the 
study which includes clinical reviews of study data in accordance with the currently approved 
protocol. Monitoring details describing clinical reviews of study data from a medical 
perspective are included in more detail in the Monitoring Plan. 
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data. 
AstraZeneca assumes accountability for actions delegated to other individuals (eg, CROs). 
Study monitors will perform ongoing source data verification as per the Monitoring Plan 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 patients 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 a minimum of 25 years after study archiving or as required 

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by local regulations, according to the AstraZeneca Global Retention and Disposal (GRAD) 
Schedule. No records may be destroyed during the retention period without the written 
approval of AstraZeneca. No records may be transferred to another location or party without 
written notification to AstraZeneca.  
A 8 
Source documents  
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Definitions of what constitutes source data can be found in the Source Data Verification Plan. 
A 9 
Study and site closure  
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first subject pre-screening visit is considered the first act of recruitment and will be the 
study start date. 
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 patients 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 CRO(s) used in the study of 

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the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the patient and should assure appropriate 
patient therapy and/or follow-up. 
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 publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating 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. 

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Appendix B Adverse event definitions and additional safety information  
B 1 
Definition of adverse events  
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product 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 associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
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 treatment has been administered. 
B 2 
Definitions of serious adverse event  
A serious adverse event 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-patient 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 patient or may require medical 
treatment to prevent one of the outcomes listed above. 
 
B 3 
Life threatening  
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure). 
B 4 
Hospitalisation  
Outpatient treatment in an emergency room is not in itself a serious AE, 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 patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 

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B 5 
Important medical event or medical treatment  
Medical and scientific judgement 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 patient 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 
judgement 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 (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 
B 6 
Intensity rating scale  
The grading scales found in the revised National Cancer Institute CTCAE latest version 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 Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 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 Appendix B 2. 
B 7 
A Guide to Interpreting the Causality Question  
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 

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• 
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 8 
Medication Error, Drug Abuse, and Drug Misuse  
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the patient 
or has the potential to cause harm to the patient.  

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A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient. 
Medication error includes situations where an error.  
• 
occurred 
• 
was identified and patient received the drug 
• 
did not occur, but circumstances were recognised that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error e.g., medication prepared incorrectly, even if it was not actually given to 
the patient 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed e.g., kept in the refrigerator when it should be at room 
temperature  
• 
Wrong patient received the medication (excluding interactive response technology 
[IRT]/randomization and trial supply management [RTSM] errors) 
• 
Wrong drug administered to patient (excluding IRT/RTSM errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IRT/RTSM - including those which led to one of the 
above listed events that would otherwise have been a medication error  
• 
Patient accidentally missed drug dose(s) eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Patient failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 

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Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the data entry site (DES) using the Drug Abuse Report Form. This form should be used 
both if the drug abuse happened in a study patient or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study patient). 
Examples of drug abuse include but are not limited to: 
• 
The drug used with the intent of getting a perceived reward (by the study patient or a 
person not enrolled in the study) 
• 
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high 
 
Drug Misuse  
Drug misuse is the intentional and inappropriate use (by a study patient) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study patient or if the drug misuse regards a person not enrolled in the 
study (such as a relative of the study patient). 
Examples of drug misuse include but are not limited to: 
• 
The drug is used with the intention to cause an effect in another person 
• 
The drug is sold to other people for recreational purposes 
• 
The drug is used to facilitate assault in another person 
• 
The drug is deliberately administered by the wrong route 
• 
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole 
• 
Only half the dose is taken because the study patient feels that he/she is feeling better 
when not taking the whole dose 
• 
Someone who is not enrolled in the study intentionally takes the drug 

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Appendix C Handling of human biological samples  
C 1 
Chain of custody of biological samples  
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 
patients while in storage at the centre until shipment or disposal (where appropriate). 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
AstraZeneca 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 AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire 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. 
C 2 
Withdrawal of Informed Consent for donated biological samples  
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation. 
The investigator: 
• 
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca. 
• 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented. 
• 
Ensures the organisation(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site 
• 
Ensures that the patient and AstraZeneca are informed about the sample disposal. 
 

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AstraZeneca ensures the organisations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
C 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document  
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B. 
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 eg, Ebola, Lassa fever virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. 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 - all other materials with minimal risk of containing pathogens 
• 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
• 
Clinical trial samples will routinely be packed and transported at ambient 
• 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm) 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• 
Samples routinely transported by road or rail are patient to local regulations which require 
that they are also packed and transported in a safe and appropriate way to contain any risk 

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of infection or contamination by using approved couriers and packaging/containment 
materials at all times. The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used. 

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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 
• 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection 
 
Withdrawal of consent for genetic research 
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol. 
Collection of samples for genetic research 
The blood sample for genetic research will be obtained from the patients at screening. 
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding patients who may withdraw due to an AE, such patients would be important to 
include in any genetic analysis. If for any reason the sample is not drawn at screening, it may 
be taken at any visit until the last study visit. Only 1 sample should be collected per patient for 
genetics during the study. Samples will be collected, labelled, stored, and shipped as detailed 
in the Central Laboratory Manual. 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last patient last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached. 
An additional second code will be assigned to the blood 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 patient enrolment code (E-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 

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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 A 1. 
Informed consent 
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the patient must indicate their consent to donate an 
optional extra sample in the main study consent form. A copy of the signed and dated consent 
form must be given to the patient and the original filed at the study centre. The Principal 
Investigator(s) is responsible for ensuring that consent is given freely and that the patient 
understands that they may freely withdraw from the genetic aspect of the study at any time. 
Patient data protection 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data. In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
Data management 
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples. 
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) 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 patient data or any personal identifiers.  

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Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. 
Statistical methods and determination of sample size 
The number of patients that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate. 

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Appendix E Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law  
E 1 
Introduction  
This appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law and Hy’s Law cases. It is not intended to be a comprehensive guide 
to the management of elevated liver biochemistries.  
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets 
potential PHL criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria 
could be met by an elevated ALT and/or elevated TBL from a local laboratory.  
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
E 2 
Definitions  
Potential Hy’s Law 
Aspartate aminotransferase or ALT ≥3×ULN together with TBL ≥2×ULN at any point 
during the study following the start of study intervention irrespective of an increase in alkaline 
phosphatase.  
Hy’s Law 
AST or ALT ≥3×ULN together with TBL ≥2×ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 

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E 3 
Identification of Potential Hy’s Law cases  
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥3×ULN 
• 
AST ≥3×ULN 
• 
TBL ≥2×ULN 
 
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will: 
• 
Notify the AstraZeneca representative 
• 
Determine whether the patient meets PHL criteria (see Section E 2 Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory eCRF 
 
E 4 
Follow-up  
E 4.1 
Potential Hy’s Law criteria Not Met  
If the patient does not meet PHL criteria the investigator will: 
• 
Inform the AstraZeneca representative that the patient has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP. 
 
E 4.2 
Potential Hy’s Law Criteria Met  
If the patient does meet PHL criteria the investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
intervention (See Section E 6) 
• 
Notify the AstraZeneca representative who will then inform the central Study Team  
• 
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criterion “Important medical event” and causality assessment “yes/related” 
according to CSP process for SAE reporting. 
• 
For patients that met PHL criteria prior to starting study intervention, the investigator is 
not required to submit a PHL SAE unless there is a significant change# in the patient’s 
condition.  

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• 
The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up (including any further laboratory testing) and 
the continuous review of data. 
• 
Subsequent to this contact the investigator will: 
− 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 
− 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study physician.  
− 
Complete the 3 Liver eCRF Modules as information becomes available.  
 
#A “significant” change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty. 
E 5 
Review and Assessment of Potential Hy’s Law Cases  
The instructions in this section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the study 
physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study intervention, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date PHL criteria was met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
• 
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes. 

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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study intervention: 
• 
Send updated SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes.  
− 
The “Medically Important” serious criterion should be used if no other serious 
criteria apply. 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned. 
 
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provides any further update to the previously submitted SAE of PHL, (report term now 
“Hy’s Law case”) ensuring causality assessment is related to study intervention and 
seriousness criterion is medically important, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 
E 6 
Actions Required When Potential Hy’s Law Criteria Are Met 
Before And After Starting Study Intervention  
This section is applicable to patients with liver metastases who meet PHL criteria on study 
intervention ,having previously met PHL criteria at a study visit prior to starting study 
intervention. 
At the first on-study intervention occurrence of PHL criteria being met, the investigator will 
determine if there has been a significant change in the patient’s condition compared with the 
last visit where PHL criteria were met.  
• 
If there is no significant change, no action is required 
• 
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section E 4.2 of this 
Appendix. 
 

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E 7 
Actions Required For Repeat Episodes Of Potential Hy’s Law  
This section is applicable when a patient meets PHL criteria on study intervention, and has 
already met PHL criteria at a previous on study intervention visit. 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), or did the patient meet PHL criteria prior to starting study intervention and at first 
on-study intervention visit, as described in Section E 6 of this Appendix? 
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE. 
If Yes: Determine if there has been a significant change in the patient’s condition compared 
with when PHL criteria were previously met. 
• 
If there is no significant change no action is required. 
• 
If there is a significant change follow the process described in Section E 4.2 for reporting 
PHL as an SAE. 
 
E 8 
Laboratory Tests  
Hy’s Law lab tests suggested for local laboratories 
Additional standard chemistry and coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HCV DNAa 
IgM and IgG anti-HCV 
HCV RNAa  
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate-deficient transferrinb 

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Autoimmune hepatitis 
Antinuclear antibody 
Anti-liver/kidney microsomal antibody 
Anti-smooth muscle antibody 
Metabolic diseases 
Alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrinb 
Transferrin saturation 
CMV=cytomegalovirus; DNA=deoxyribonucleic acid; EBV=Epstein-Barr virus; GGT=gamma glutamyl transferase; 
HAV=hepatitis A virus; HBc=hepatitis B core antigen; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; 
HCV=hepatitis C virus; HEV=hepatitis E virus; HSV=herpes simplex virus; IgG=immuno-globulin G; 
IgM=immuno-globulin M; INR=international normalised ratio; LDH=lactate dehydrogenase; RNA=ribonucleic acid. 
a 
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive. 
b 
Carbohydrate-deficient transferrin and transferrin are not available in China. Study teams should amend this list 
accordingly. 
 

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Appendix F New York Heart Association classification of heart disease  
F 1 
NYHA classification of heart disease  
NYHA class 
Symptoms 
I 
No symptoms and no limitation in ordinary physical activity, eg, shortness of breath when 
walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
eg, walking short distances (20 to 100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
 
F 2 
References  
New York Heart Association 1994  
The Criteria Committee of the New York Heart Association: Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th edition. Boston, MA: Little, Brown 
& Co; 1994:253-256. 

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Appendix G Definition of women of childbearing potential and acceptable 
contraceptive methods  
Definition of Women of Childbearing Potential 
Women of Childbearing Potential (WoCBP): 
Women between menarche and menopause who have not been permanently or surgically 
sterilised and are capable of procreation. 
Women NOT of Childbearing Potential: 
Women who are permanently or surgically sterilised or post-menopausal (definitions below): 
Permanent sterilisation includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion. Tubal occlusion is considered a highly 
effective method of birth control but does not absolutely exclude possibility of pregnancy. 
(The term occlusion refers to both occluding and ligating techniques that do not physically 
remove the oviducts). 
• 
Women who have undergone tubal occlusion should be managed on trials as if they are of 
WoCBP (eg, undergo pregnancy testing etc, as required by the study protocol). 
• 
Women will be considered post-menopausal if they are amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
• 
Women under 50 years old will be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range. 
• 
Women aged 50 years or more will be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments. 
 
Acceptable contraception methods 
Highly effective method of birth control is defined in Note 3 in ICH Guidance M3 
(Nonclinical Safety Studies for the conduct of Human Clinical trials for Pharmaceuticals) as 
one that results in a low failure rate (eg, less than 1 percent per year) when used consistently 
and correctly. 
Note that women should have been stable on their chosen method of birth control for a 
minimum of 2 weeks before entering the study. Generic names and examples of trade names 
are given. As trade names may vary, investigators should check the generic name of any 
contraception to ensure suitability. 

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Acceptable contraception methods are: 
• 
Total sexual abstinence (abstinence must be for the total duration of the study and the 
follow-up period) 
• 
Vasectomised sexual partner plus male condom (with patient assurance that partner 
received post-vasectomy confirmation of azoospermia) 
• 
Tubal occlusion plus male condom 
• 
Intra-uterine Device (IUD) - provided coils are copper-banded, plus male condom 
• 
Intra-uterine system (IUS) Levonorgestrel Intra Uterine System (eg, Mirena), plus male 
condom 
• 
Medroxyprogesterone injections (Depo-Provera) plus male condom 
• 
Etonogestrel implants (eg, Implanon, Norplan) plus male condom 
• 
Normal and low dose combined oral contraceptive pills, plus male condom 
• 
Norelgestromin / ethinylestradiol transdermal system plus male condom 
• 
Intravaginal device (eg ethinylestradiol and etonogestrel ) plus male condom 
• 
Cerazette (desogestrel) plus male condom. Cerazette is currently the only highly 
efficacious progesterone based pill 
 
Unacceptable contraception methods 
The following methods are considered not to be highly effective and are therefore not 
acceptable contraceptive methods in AstraZeneca clinical trials: 
• 
Triphasic combined oral contraceptives (COCs) 
• 
All progesterone only pills except, Cerazette 
• 
All barrier methods, if intended to be used alone 
• 
Non-copper containing Intra-Uterine Devices (IUDs) 
• 
Fertility awareness methods 
• 
Coitus interruptus 
 

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Appendix H Guidelines for evaluation of objective tumour response using 
RECIST 1.1  
H 1 
Introduction  
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009) 
for the study with regards to investigator assessment of tumour burden including 
protocol-specific requirements for this study. 
H 2 
Definition of measurable, non-measurable, target and non-target 
lesions  
At least 1 lesion, not previously irradiated, not biopsied during the screening period, that can 
be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes 
which must have short access ≥15 mm) with CT or MRI which is suitable for accurate 
repeated measurements. 
H 2.1 
Measurable lesions  
A lesion, not previously irradiated and not chosen for biopsy during the screening period that 
can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph 
nodes which must have a short axis ≥15 mm) with CT or MRI and which is suitable for 
accurate repeated measurements. 
H 2.2 
Non-measureable lesions  
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis at baseline. Nodes with <10 mm short 
axis are considered non-pathological and should not be recorded as non-target lesions 
(NTLs). 
• 
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that are not measurable by CT or MRI. 
• 
Previously irradiated lesions as localised post-radiation changes, which affect lesion sizes, 
may occur. Therefore, lesions that have been previously irradiated will not be considered 
measurable and should be selected as NTLs at baseline and followed up as part of the 
NTL assessment 
• 
Skin lesions assessed by clinical examination 
• 
Lesions biopsied within the screening period 
• 
Brain metastasis 
 

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H 2.3 
Special cases  
• 
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 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 patient, these non-cystic lesions should be selected as the target lesions (TLs). 
 
H 2.4 
Target lesions  
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. 
H 2.5 
Non-target lesions  
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. 
H 3 
Methods of assessment  
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up.  
The methods to be used for RECIST assessment are summarised in Table 15 and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided. 
Table 15 
Summary of methods of assessment (RECIST)  
Target lesions 
Non-target lesions 
New lesions 
CT (preferred) 
CT (preferred) 
CT (preferred) 
MRI 
MRI 
MRI 
 
Plain X-ray (includes chest X-ray) 
Plain X-ray (includes chest X-ray) 
 
 
 
 
 
 
 
 
Bone scan (scintigraphy) 
 
 
FDG-PET 
CT  Computed tomorgraphy; FDG-PET  Fluorodeoxyglucose-positron emission tomography; MRI  Magentic 
resonance imaging; RECIST  Response Evaluation Criteria in Solid Tumours. 
 

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H 3.1 
CT and MRI  
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TLs selected for response assessment and to assess NTLs and 
identification of new lesions. 
In this study it is recommended that CT examinations will be used to assess tumour burden at 
baseline and then every 6 weeks (±7 days) relative to the start of treatment until Cycle 7 then 
every 8 weeks until objective radiological progression or withdrawal from the study. CT 
examination with intravenous contrast media administration is the preferred method. MRI 
should be used where CT is not feasible or it is medically contra-indicated. For assessment of 
brain lesions MRI is the preferred method. 
H 3.2 
Clinical examination  
Clinical examination will not be used for assessment of TLs. Clinically detected lesions can be 
selected as TLs if they are then assessed by CT or MRI scans. Clinical examination can be 
used to assess NTLs in patients that also have other lesions assessable by CT, MRI or plain 
X-ray and to identify the presence of new lesions. 
H 3.3 
X-rays  
H 3.3.1 
Plain X-ray  
Plain X-rays may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions. 
H 3.3.2 
Chest X-rays  
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination. Chest X-rays can, however, be used to assess NTLs and to identify the presence 
of new lesions. 
H 3.4 
Ultrasound  
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is patient 
and operator dependent. If new clinical symptoms occur and an ultrasound is performed then 
new lesions should be confirmed by CT or MRI examination. 
H 3.5 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements. 

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H 3.6 
Tumour markers  
Tumour markers will not be used for tumour response assessments per RECIST 1.1. 
H 3.7 
Cytology and histology  
Histology will not be used as part of the tumour response assessments per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease. In such circumstances, the cytology is necessary to differentiate between 
response/stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed). Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or the appearance of a 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTLs or disease progression due to new lesions. 
H 3.8 
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 as per 
baseline assessment. 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. New lesions will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study. The investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion. Confirmation by CT, MRI and X-ray is recommended where bone scan 
findings are equivocal. 
H 3.9 
FDG-PET  
FDG-PET (fluorodeoxyglucose positron emission tomography) scans may be used as a 
method for identifying new lesions, according with the following algorithm: New lesions will 
be recorded where there is positive FDG uptake (defined as when an uptake greater than twice 
that of the surrounding tissue is observed) not present on baseline FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit. If there is no 
baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then 
follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical 
indicated, in order to confirm new lesions. 

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H 4 
Tumour response evaluation  
H 4.1 
Schedule of evaluation  
Baseline tumour assessments should include CT/MRI of lung and abdomen (including liver 
and adrenal glands) and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients and should be performed no more than 28 days 
before the start of study treatment. CT/MRI scan of the brain should be performed in patients 
with known or suspected brain metastases. Follow-up assessments should be performed every 
6 weeks (±7 days) after the start of treatment for the first 6 cycles then every 8 weeks 
(±7 days) until objective disease progression as defined by RECIST 1.1 or withdrawal of 
consent. Any other sites at which new disease is suspected should also be adequately imaged 
at follow-up. 
H 4.2 
Target lesions  
H 4.2.1 
Documentation of target lesions  
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved, should be identified as TLs at baseline. 
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis 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, which can be measured reproducibly, should be selected. 
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis 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 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. 
• 
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 longest diameter should be recorded as 0 mm. 
• 
If a TL splits into 2 or more parts, then record the sum of the diameters of those parts. 
• 
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). 

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• 
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. 
• 
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. 
• 
When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc, during 
the study, the size of the TL should still be provided where possible. 
 
H 4.2.2 
Evaluation of target lesions  
Table 16 provides the definitions of the criteria used to determine objective tumour visit 
response for TLs. 
Table 16 
Overall visit response for target lesions  
Complete response (CR) 
Disappearance of all TLs since baseline. Any 
pathological lymph nodes selected as TLs must have 
a reduction in short axis to <10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of diameters of 
TLs, taking as reference the baseline sum of 
diameters. 
Stable disease (SD)  
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD. 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of 
TLs, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase 
of at least 5 mm. 
Not evaluable (NE) 
Only relevant if any of the TLs were not assessed or 
not evaluable or had a lesion intervention at this visit. 
Note: If the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not 
evaluable as a TL response. 
CR  Complete response; PD  Progression of disease; PR  Partial response; NTL  Non-target lesion; TL  Target 
lesion. 
 
H 4.3 
Non-target lesions  
All other lesions (or sites of disease) not recorded as TL 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 

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recorded by the investigator. Table 17 provides the definitions of the criteria used to determine 
and record overall response for NTLs at the investigational site at each visit. 
Table 17 
Evaluation of non-target lesions  
Complete response (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. 
Progressive Disease (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. 
Not evaluable (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 patients 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. 
CR  Complete response; PD  Progression of disease; NTL  Non-target lesion; TL  Target lesion. 
 
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 stable disease or PR 
in TLs, the overall tumour burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of 1 or more NTLs is usually not sufficient to qualify 
for unequivocal progression status. 
H 4.4 
New lesions  
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.  
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion 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 new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 

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H 4.5 
Symptomatic deterioration  
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy. 
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time will continue to be followed until 
objective disease progression by RECIST 1.1 or withdrawal of consent. 
H 4.6 
Evaluation of overall visit response and best overall response  
The overall visit response will be derived using the algorithm shown in Table 18. 
Table 18 
Overall visit response  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
A 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD  
No 
PR 
CR 
NE 
No  
PR 
PR 
Non PD or NE 
No 
PR 
SD  
Non PD or NE 
No 
SD 
NA 
Non CR/Non PD 
No 
SD (Non CR/Non PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR  Complete response, SD  Stable disease, PD  Progression of disease, PR  Partial response, NE  Not evaluable, 
NA  Not applicable (only relevant if there were no target lesions/non-target lesions at baseline, however at least 
one target lesion is an entry criterion for the study). 
 
H 5 
Specifications for radiological imaging  
These notes are recommendations for use in clinical studies. The use of standardised protocols 
for CT and MRI allows comparability both within and between different studies, irrespective 
of where the examination has been undertaken. 

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H 5.1 
CT scan  
CT scans of the chest and abdomen (including liver and adrenal glands) should be contiguous 
throughout all the anatomical regions of interest. 
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval. 
Anatomic coverage 
Optimal anatomic coverage for most lung tumours is the chest and abdomen (including liver 
and adrenal glands). 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 patients. The brain should be imaged 
by MRI or CT in patients with known or suspected brain lesions. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, 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. 
Intravenous contrast administration 
Optimal visualisation and measurement of metastases in solid tumours requires consistent 
administration (dose and rate) of intravenous contrast as well as timing of scanning. Typically, 
most abdominal imaging is performed during the portal venous phase and (optimally) about 
the same time frame after injection on each examination. An adequate volume of a suitable 
contrast agent should be given so that the metastases are demonstrated to best effect and a 
consistent method is used on subsequent examinations for any given patient. 
It is very important that the same technique be used at baseline and on follow-up examinations 
for a given patient. For patients who develop contraindications to contrast after baseline 
contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumour type, anatomic 
location of the disease and should be optimised to allow for comparison to the prior studies if 
possible. Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward. Care must be taken in measurement of TLs on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may appear to 
have a different size using a new modality. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study, then the recommended methods are: CT thoracic examination without 

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contrast and abdominal and pelvic MRI with contrast. If MRI cannot be performed then CT 
without intravenous contrast is an option for the thorax, abdomen and pelvic examinations. 
For assessment of brain lesions MRI is the preferred method however CT is acceptable in this 
study. 
Slice thickness and reconstruction material 
It is recommended that CT scans be performed at 5 mm contiguous slice thickness and this 
guideline presumes a minimum 5 mm thickness in recommendations for the measurable lesion 
definition. Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm. If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline 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 TLs should be measured on the same 
window setting for repeated examinations throughout the study. All images from each 
examination should be included in the assessment and not “selected” images of the apparent 
lesion. 
H 5.2 
MRI scan  
MRI has excellent contrast, spatial and temporal resolution; 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. Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed. The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimised for the specific body part being imaged as 
well as the scanner utilised. It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques 
if possible. 
For these reasons, CT is the imaging modality of choice. 
H 5.3 
FDG-PET scans  
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies. If FDG-PET scans are included in a protocol, an FDG uptake period of 60 min 
prior to imaging has been decided as the most appropriate for imaging of patients with 
malignancy. Whole-body acquisition is important since this allows for sampling of all areas of 
interest and can assess if new lesions have appeared thus determining the possibility of 

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interval progression of disease. Images from the base of the skull to the level of the mid-thigh 
should be obtained 60 min post injection. PET camera specifications are variable and 
manufacturer specific, so every attempt should be made to use the same scanner, or the same 
model scanner, for serial scans on the same patient. Whole-body acquisitions can be 
performed in either 2- or 3-dimensional mode with attenuation correction, but the method 
chosen should be consistent across all patients and serial scans in the clinical trial. 
H 5.3.1 
PET/CT scans  
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted 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 is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the PET–CT can be used for RECIST measurements. 
However, this is not recommended because the PET portion of the CT introduces additional 
data that may bias an investigator if it is not routinely or serially performed. 

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Appendix I 
Dose modifications for the management of adverse events  
I 1 
Osimertinib dose modification and guidance  
Osimertinib management should be in accordance with the local label in the first instance. 
If a patient experiences a CTCAE Grade 3 and/or unacceptable toxicity dosing will be 
interrupted and supportive therapy administered as required in accordance with local 
practice/guidelines. 
If a toxicity resolves or reverts to ≤ CTCAE Grade 2 within 3 weeks of onset, treatment with 
osimertinib may be restarted at the same dose (80 mg) or a lower dose (40 mg) using the rules 
below for dose modifications (Table 19) and with discussion and agreement with the 
AstraZeneca Study Team Physician as needed. There will be no individual modifications to 
dose regimen in response to toxicity, only potential dose reduction or dose interruption.  
If the toxicity does not resolve to ≤CTCAE Grade 2 after 3 weeks, then the patient should be 
withdrawn from the study and observed until resolution of the toxicity (Table 20). 
Table 19 
Dose reduction for osimertinib to manage adverse events  
 
Starting osimertinib dose 80 mg  
Reduced dose -1 
40 mg 
 
On resolution of toxicity within 3 weeks: 
If an AE subsequently requires dose interruption, osimertinib may restart at the same dose or 
the reduced dose, on resolution/improvement of the AE at the discretion of the investigator. 

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Table 20 
Osimertinib Dose Adjustment Information for Adverse Reactions  
Target organ 
Adverse reactiona 
Dose modification 
Pulmonary 
ILD/pneumonitis 
Permanently discontinue osimertinib 
Cardiac 
QTc interval > 500 msec on at least 
2 separate ECGs 
Withhold osimertinib until QTc interval is 
< 481 msec or recovery to baseline if 
baseline QTc is ≥ 481 msec within 3 weeks 
of interruption, then restart at a reduced dose 
(40 mg) or at 80 mg (at the discretion of the 
investigator), to allow for situations where 
causality in relation to osimertinib may be 
difficult to determine). 
QTc interval prolongation with 
signs/symptoms of serious arrhythmia, 
symptomatic congestive heart failure  
Permanently discontinue osimertinib 
Other 
Grade ≥ 3 adverse reaction 
Withhold osimertinib for up to 3 weeks 
If Grade ≥ 3 adverse reaction improves to 
Grade 0 – 2 after withholding osimertinib for 
up to 3 weeks 
Osimertinib may be restarted at the same 
dose (80 mg) or at a lower dose (40 mg) 
Grade ≥ 3 adverse reaction that does not 
improve to Grade 0 – 2 after withholding 
osimertinib for up to 3 weeks 
Permanently discontinue osimertinib 
a 
The intensity of the clinical adverse events graded by the NCI CTCAE version 5.0. 
CTCAE  Common Terminology Criteria for Adverse Events; ECG  Electrocardiogram; ILD  Interstitial lung 
disease; NCI  National Cancer Institute. 
 
I 1.1 
ILD/Pneumonitis-like toxicity  
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormality 
suggestive of ILD is observed, an interruption in study treatment dosing is recommended, and 
the AstraZeneca study team should be informed. It is strongly recommended to perform a full 
diagnostic workup, to exclude alternative causes such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic oedema or pulmonary haemorrhage. The results of full 
diagnostic workup (including high resolution computed tomography (HRCT), blood and 
sputum culture, haematological parameters) will be captured by eCRF. All image data should 
be provided to AstraZeneca. In the presence of confirmatory HRCT scans where other causes 
of respiratory symptoms have been excluded, a diagnosis of interstitial lung disease should be 
considered and study treatment permanently discontinued. 
I 1.2 
QTcF prolongation  
In light of the potential for QT changes associated with osimertinib, and in accordance with 
good clinical practice, it is recommended that correction of clinically significant electrolyte 

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abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia) to within normal ranges 
takes place prior to first dose and during study treatment with osimertinib.  
Table 21 
Dose Modifications for Osimertinib-Related QTc Prolongation  
NCI CTCAE version 5 toxicity grade 
Action 
Grade 0, 1, or 2 
None 
Grade 3 
Hold dosing and follow algorithm below 
• 
Patients with QTcF prolongation to > 500 msec 
on at least 2 separate ECGs 
 
• 
Consult with cardiologist to validate ECG 
finding. Ensure cardiac surveillance and take 
actions in accordance with clinical standards. 
Regular ECGs performed until resolution to 
QTcF < 481 msec. Restart drug at a reduced 
dose of 40 mg or at the same dose 80 mg at the 
discretion of the investigator 
• 
If the toxicity does not resolve to QTcF 
< 481 msec within 21 days 
• 
Discontinue osimertinib and consult with a 
cardiologist for further management as clinically 
indicated 
Grade 4 
 
• 
QTcF ≥ 501 or > 60 msec change from baseline 
and Torsade de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia 
• 
Discontinue osimertinib and consult with a 
cardiologist for further management as clinically 
indicated 
CTCAE = Common Terminology Criteria for Adverse Events; ECG = Electrocardiogram; NCI = National 
Cancer Institute; QTcF = QT corrected according to Fridericia’s formula. 
 
I 1.3 
Keratitis  
Patients presenting with signs and symptoms suggestive of keratitis such as acute or 
worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red 
eye should be referred promptly to an ophthalmology specialist. 
I 1.4 
Erythema Multiforme and Stevens-Johnson syndrome  
Case reports of Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) have been 
uncommonly and rarely reported, respectively, in association with osimertinib treatment. 
Before initiating treatment, patients should be advised of signs and symptoms of EM and SJS. 
If signs and symptoms suggestive of EM develop, close patient monitoring and drug 
interruption or discontinuation of osimertinib should be considered. If signs and symptoms 
suggestive of SJS appear, osimertinib should be interrupted or discontinued immediately.  
I 1.5 
Changes in cardiac contractility  
Based on the available clinical trial data, a causal relationship between effects on changes in 
cardiac contractility and osimertinib has not been established. In patients with cardiac risk 
factors and those with conditions that can affect left ventricular ejection fraction (LVEF), 

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cardiac monitoring, including an assessment of LVEF at baseline and during treatment, should 
be considered. In patients who develop relevant cardiac signs/symptoms during treatment, 
cardiac monitoring including LVEF assessment should be considered. 
I 1.6 
Permanent discontinuation due to toxicity  
Patients experiencing ILD or QTcF prolongation with signs/symptoms of serious arrhythmia 
will not be permitted to restart study treatment. 
I 1.7 
Aplastic anaemia  
Rare reports of aplastic anaemia have been reported in association with osimertinib treatment. 
Some cases had a fatal outcome. Before initiating treatment, patients should be advised of 
signs and symptoms of aplastic anaemia including but not limited to persistent fever, bruising, 
bleeding, and/or pallor. If signs and symptoms suggestive of aplastic anaemia develop, close 
patient monitoring and drug interruption or discontinuation of osimertinib should be 
considered. Osimertinib should be discontinued in patients with confirmed aplastic anaemia. 
I 2 
Hepatitis B viral reactivation management guideline  
In patients with resolved or chronic hepatitis B infection (inactive carrier state) or active 
controlled HBV infection on treatment with osimertinib: 
• Recommend monthly monitoring of ALT/AST, HBV DNA levels and HBsAg (if negative 
at baseline) 
• Where liver signs and symptoms of viral reactivation appear (HBV DNA levels exceeding 
10-fold from baseline or ≥100 IU/ml (if baseline HBV DNA levels are undetectable) or 
conversion of HBsAg negative to positive): 
- 
Expert hepatologist/specialist oversight of the patient is required 
- 
Consider interruption or discontinuation of study treatment, based on risk-benefit 
assessment 
I 3 
Savolitinib dose modification and guidance  
I 3.1 
Savolitinib dose modification and guidance  
Substantial acute toxicities should be managed as medically indicated and with temporary 
suspension of savolitinib, as appropriate unless due to suspected hypersensitivity (See section 
I 2.4).  
Dose reductions or holds are allowed as clinically indicated by the treating physician and in 
line with Table 22 and Table 23. For each patient, a maximum of 2 dose reductions of 

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I 3.3 
Hepatoxicity management guideline  
• 
Promptly evaluate patients with elevated LFTs during study treatment for alternative 
aetiologies and potential Hy’s law criteria, and discontinue potential contributing 
concomitant medications or alternative causal agents, as well as anti-coagulants, if 
appropriate.  
• 
If a patient discontinues due to LFT abnormality, LFT monitoring should continue until 
resolved to Grade 1 or baseline or an apparent plateau has been reached. 
 
I 3.3.1 
Dose modification due to drug-related hepatotoxicity  
• 
Permanently discontinue drug if: 
− 
ALT or AST >8 × ULN with total bilirubin elevation above baseline or ULN, or 
− 
ALT or AST >5 × ULN for up to 1 week (<7 days) with total bilirubin elevation 
above baseline or ULN, following immediate withholding of savolitinib. Repeat LFT 
testing within 2 to 3 days and at least twice a week until improvement to Grade 1 or 
baseline. 
− 
ALT or AST >3 × ULN and (total bilirubin >2 × ULN or INR >1.5 if not on 
anticoagulants that elevate the INR), or 
− 
AST or ALT >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia >5% 
• 
Withhold dosing if ALT or AST >5 x ULN for > 2 weeks or 8 × ULN without total 
bilirubin elevation above baseline or ULN, repeat LFT testing twice a week for 1 week:  
− 
If improved to Grade 1 or baseline in 1 week, resume at reduced dose with LFT 
testing twice a week for 6 weeks 
− 
If not, discontinue 
• 
Withhold dosing if ALT or AST >3 × ULN and concurrent total bilirubin >1.5 × ULN, 
repeat LFT testing twice a week for 1 week: 
− 
If both ALT/AST and total bilirubin improved to Grade 1 or baseline in 1 week, 
resume at reduced dose with LFT testing twice a week for 6 weeks 
− 
If not, discontinue 
• 
Withhold dosing if ALT or AST >3 × ULN and concurrent total bilirubin >1 × ULN to 
1.5 × ULN. Repeat LFT testing twice a week for 1 week: 
− 
If both ALT/AST and total bilirubin improve to normal range (< Grade1) or baseline 
in 1 week, resume at same dose with LFT testing twice a week for 6 weeks 
− 
If not, resume at reduced dose, (as per bullet 3 above). 
• 
Continue dosing if ALT or AST >3 × ULN without total bilirubin elevation above 
baseline or ULN, repeat LFT testing every week 

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− 
If ALT or AST trending upward, withhold dosing and repeat LFT twice a week for 
1 week 
− 
If improve to Grade 1 or baseline in 1 week, resume at same dose with LFT testing 
every week for 6 weeks 
− 
If improve to Grade 1 or baseline in 2 weeks, resume at reduced dose with LFT 
testing every week for 6 weeks 
− 
If not, discontinue 
• 
Discontinue for recurrent ALT or AST >5 × ULN 
• 
Discontinue for recurrent ALT or AST >3 × ULN and total bilirubin >1.5 × ULN 
• 
Withhold dosing for recurrent ALT or AST >3 × ULN without total bilirubin elevation 
above baseline or ULN, repeat LFT testing twice a week for 1 week 
− 
If improve to Grade 1 or baseline in 1 week, resume at reduced dose with LFT testing 
every week for 6 weeks; if not, discontinue 
 
I 3.4 
Guidance for management of savolitinib specific toxicities  
Dermatologic: A case of Stevens-Johnson syndrome (SJS) has been reported in temporal 
association with savolitinib. Patients who show symptoms or signs suggesting emerging SJS 
while on study treatment (eg, progressive skin rash often with blisters or mucosal lesions), 
must discontinue savolitinib immediately and receive appropriate treatment. If emerging SJS 
is suspected, re-challenge with savolitinib must be avoided. 
Hypersensitivity: Hypersensitivity, which may manifest as a constellation of symptoms such 
as but not limited to pyrexia, allergic skin reaction, increased liver enzymes, cytopenia, or 
myalgia and/or arthralgia has been reported after savolitinib dosing. These reactions have 
occurred within days to weeks after the first dose but the majority of reactions have occurred 
in the first six weeks of therapy. Patients with suspected savolitinib-related hypersensitivity 
(excluding confirmed infective aetiology), may be managed with corticosteroids, 
antihistamines and antipyretics (doses and duration of treatment according to local practice at 
the discretion of the investigator). Dose interruption with savolitinib should be avoided, if 
possible. Some patients who experienced the initial hypersensitivity reaction also reported 
severe acute hypersensitivity reactions, including anaphylaxis, upon restarting savolitinib 
treatment following a short period of interruption. If patients do need dose interruption, 
restarting savolitinib must be done under controlled conditions as per below. If the patient 
experiences an acute hypersensitivity or anaphylactic reaction, immediate intervention must 
be instituted and treatment with savolitinib should be permanently discontinued. 
Restarting savolitinib: acute hypersensitivity including anaphylaxis has been observed in a 
number of patients mostly upon savolitinib restart. If interruption of savolitinib occurs in the 
first 6 weeks of study treatment due to savolitinib-related general toxicities, or specific 

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hypersensitivity toxicities occur at any time, dosing with savolitinib may be resumed but at a 
reduced dose, only after consultation with and approval from the study physician and with the 
following management: 
• 
Treatment: 
− 
Pre-treatment with systemic corticosteroids must be started at least 24 hours before 
the restart of savolitinib;  
− 
Pre-treatment with antipyretics and antihistamines on the day of restart of savolitinib;  
− 
Doses of antihistamines, corticosteroids and antipyretics should be according to 
labelling instructions/product information.  
− 
These medications must be continued daily until discontinuation of savolitinib, but 
doses of steroids may subsequently be tapered according to local practice 
 
• 
Intense medical monitoring (restart at the institution); 
− 
The restart of savolitinib must be performed in the hospital/institution where the 
clinical study is carried out with medical equipment readily available for resuscitation 
and management of anaphylaxis  
− 
Vital status recording (blood pressure, temperature, respiratory rate, heart rate, etc.) 
before administration of study drug, every 15 mins after savolitinib dosing for the 1st 
hour, every 30 mins for the next hour and hourly for a total of at least 4 hours.  
− 
Patient must be observed in the clinic for 24 hours before discharge. 
− 
Should the symptoms recur, or an acute anaphylactic reaction occurs, immediate 
intervention must be instituted for appropriate management of event and savolitinib 
must be permanently discontinued. 
Any recommendations regarding hypersensitivity management or pre-treatment should be 
used as guidelines only. Final decisions concerning management of individual patients reside 
with the investigator or the treating physician. 
 
QTC prolongation: 
Table 24 
Dose modifications for savolitinib-related QTc prolongation  
NCI CTCAE version 5.0 Toxicity Grade 
Action 
Grade 0, 1, or 2 
None 
Grade 3 
Hold dosing and follow algorithm below: 
• 
Patients with QTcF prolongation to >500 msec 
on at least 2 separate ECGs 
• 
Consult with cardiologist to validate ECG finding. 
Ensure cardiac surveillance and take actions in 
accordance with clinical standards. Regular ECGs 
performed until resolution to QTcF <481 msec 
and then restart drug at one reduced dose level 

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Table 24 
Dose modifications for savolitinib-related QTc prolongation  
NCI CTCAE version 5.0 Toxicity Grade 
Action 
• 
If the toxicity does not resolve to 
QTcF <481 msec within 21 days 
• 
Discontinue study drug and consult with a 
cardiologist for further management as clinically 
indicated 
Grade 4 
 
• 
QTcF ≥501 or >60 msecs change from 
baseline and Torsade de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia 
• 
Discontinue study drug and consult with a 
cardiologist for further management as clinically 
indicated 
CTCAE Common Terminology Criteria for Adverse Events; ECG  Electrocardiogram; NCI  National Cancer 
Institute; QTcF  corrected QT interval using Fridericia's formulas. 
 
I 3.5 
Guideline for the Management of Overlapping Toxicities Between 
Osimertinib and Savolitinib  
QTc Prolongation 
QT prolongation is a recognised toxicity of osimertinib and savolitinib; management of this 
toxicity is summarised in Table 25. 
Table 25 
Management of QTc prolongation  
CTCAE Grade  
Instructions for 
osimertinib 
Instructions for 
savolitinib 
Further investigation 
required 
CTCAE Grade 1 or 
Grade 2 
• 
No action 
required 
• 
No action required 
• 
Review 
concomitant 
treatments and co-
morbidities for risks 
of QT prolongation 
or risk for TdP a 
CTCAE Grade 3 
(QTc interval >500 msec 
or >60 msec change from 
baseline on at least 2 
separate ECGs) 
• 
Withhold 
osimertinib until 
QTcF interval is 
<481 msec within 
21 days of onset, 
then restart 
osimertinib at a 
reduced dose of 
40 mg. Dose may 
be resumed at 80 
mg at the 
discretion of the 
investigator if the 
event of QTc 
interval is 
considered to be 
non-related to 
osimertinib 
treatment 
• 
Withhold 
savolitinib until 
QTcF interval is 
<481 msec. If the 
QTcF resolves to 
<481 msec in 21 
days, restart 
savolitinib at a 
reduced dose 
• 
Review 
concomitant 
treatments and co-
morbidities for risks 
of QT prolongation 
or risk for TdPa 
• 
Consult with a 
cardiologist to 
validate ECG 
finding 
• 
Ensure cardiac 
surveillance and 
take actions in 
accordance with 
clinical standards 
• 
Regular ECGs 
performed until 
resolution to QTcF 
<481 msec 

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CTCAE Grade  
Instructions for 
osimertinib 
Instructions for 
savolitinib 
Further investigation 
required 
• 
If the QTcF does 
not resolve to 
<481 msec in 21 
days, discontinue 
osimertinib. 
• 
If the QTcF does 
not resolve to <481 
msec in 21 days, 
discontinue 
savolitinib 
• 
Consult with a 
cardiologist for 
further management 
as clinically 
indicated 
CTCAE Grade 4 
(TdP, polymorphic 
ventricular, tachycardia, 
signs and symptoms of 
serious arrhythmia) 
• 
Discontinue 
osimertinib 
• 
Discontinue 
savolitinib 
• 
Consult with a 
cardiologist for 
further management 
as clinically 
indicated 
a 
For guidance regarding potential interactions with concomitant medications known to prolong the QT 
interval, see Section J 5. 
CTCAE  Common Terminology Criteria for Adverse Events; ECG  Electrocardiogram; QTcF  QT interval 
calculated using Fridericia’s correction; TdP  Torsades de Pointes. 
 
In light of the potential for QT changes associated with osimertinib, electrolyte abnormalities 
(hypokalaemia, hypomagnesaemia, hypocalcaemia) must be corrected to within normal ranges 
prior to first dose and electrolyte levels monitored during study treatment. 
The QTc interval prolongation potential of savolitinib 600 mg was assessed in a thorough QT 
study in healthy volunteers. Analysis of the data showed that it was a positive study, as the 
upper bounds of the 2-sided 90% CI for the mean ΔΔQTcF were up to 13.6 msec and 
14 msec, at 4 hours and 5 hours, respectively. QTcF will be assessed frequently on triplicate 
ECG assessments performed at regular intervals throughout the study according to the SoA 
(Section 1.1). 
Erythema Multiforme and Stevens-Johnson Syndrome 
Case reports of EM (including Erythema Multiforme Major [EMM]) and SJS have been 
uncommonly and rarely reported, respectively, in association with osimertinib treatment. 
Before initiating treatment, patients should be advised of signs and symptoms of EM/EMM 
and SJS. If signs and symptoms suggestive of EM/EMM develop, close patient monitoring 
and drug interruption or discontinuation of osimertinib should be considered. If signs and 
symptoms suggestive of SJS appear, osimertinib should be interrupted or discontinued 
immediately. 
A case of SJS has been reported in temporal association with savolitinib. Patients who show 
symptoms or signs suggesting emerging SJS while on study treatment (eg, progressive skin 
rash often with blisters or mucosal lesions) must discontinue savolitinib immediately and 
receive appropriate treatment. If emerging SJS is suspected, re-challenge with savolitinib must 
be avoided. 

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Appendix J 
Guidance regarding potential interactions with concomitant 
medications  
The use of any permitted concomitant medications must be recorded in the eCRF. Any 
investigational anti-cancer therapy, concurrent chemotherapy, radiotherapy, immunotherapy, 
or biologic or hormonal therapy for cancer treatment other than those under investigation in 
this study must not be given concomitantly while the patient is on study intervention. 
Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and 
hormone replacement therapy) is acceptable. Local treatment of isolated lesions, excluding 
target lesions, for palliative intent is acceptable (eg, by local surgery or radiotherapy). 
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (mahuang), 
gingkobiloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should 
stop using these herbal medications 3 weeks prior to first dose of study drug (3 weeks for St. 
John’s wort). 
Based upon studies of in vitro liver microsomes and S9 fractions, savolitinib is metabolised by 
several metabolic enzymes, including both CYP450 enzymes (CYP3A4, CYP1A2) and some 
non-CYP enzymes (aldehyde oxidase, UDP-glucuronosyltransferases). Additionally, 
osimertinib is mainly metabolised by CYP3A4/5. 
J 1 
Drugs inducing CYP3A4 metabolism that AstraZeneca strongly 
recommend are not combined with osimertinib or savolitinib  
Drug-drug interaction (DDI) studies of osimertinib or savolitinib evaluated in patients showed 
that there is potential for osimertinib or savolitinib being a victim when co-administered with 
strong inducers of CYP3A4 (osimertinib or savolitinib concentrations are decreased when 
co-dosed with rifampicin). 
The following potent inducers of CYP3A4 must not be used during this study for any patient 
receiving osimertinib or savolitinib. Additionally, the use of moderate CYP3A4 inducers may 
be permitted with caution. 
Table 26 
Drugs inducing CYP3A4  
Strong CYP3A4/5 inducers 
(should not be combined) 
Moderate CYP3A4/5 inducers 
(permitted with caution) 
Avasimibe, carbamazepine, enzalutamide, mitotane, 
nevirapine, phenobarbital, phenytoin, rifabutin, 
rifampin, rifapentine, St John’s Wort 
 semagacestata, talviralinea, bosentan, efavirenz, 
etravirine, genistein, lersivirine, lopinavir, modafinil, 
nafcillin, thioridazine, tipranavir, ritonavirb 
a 
Not available on the US market. 
b 
Ritonavir has dual effects of simultaneous CYP3A inhibition and induction; the net pharmacokinetic outcome during 

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chronic ritonavir therapy is inhibition of CYP3A activity. 
CYP = Cytochrome P450. 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to be strong inducers of CYP3A4. Appropriate medical judgement is required. 
Please contact AstraZeneca with any queries you have on this issue. 
J 2 
Drugs inhibiting CYP1A2 metabolism that AstraZeneca strongly 
recommend are not combined with savolitinib  
Table 27 
Drugs inhibiting CYP1A2  
Contraindicated drugs 
Withdrawal period prior to savolitinib start 
Ciprofloxacin, enoxacin, clinafloxacin, fluvoxamine 
3 weeks  
CYP = Cytochrome P450. 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to strongly inhibit CYP1A2 activity. Appropriate medical judgement is 
required. Please contact AstraZeneca with any queries you have on this issue. 
J 3 
Medicines whose exposures may be affected by osimertinib that 
AstraZeneca considers may be allowed with caution  
Osimertinib may increase the concentrations of sensitive breast cancer resistance protein 
(BCRP) or P-glycoprotein (P-gp) substrate (concentrations of sensitive BCRP substrate, 
rosuvastatin or P-gp substrate, fexofenadine is increased). 
Table 28 
Exposure, pharmacological action and toxicity may be increased or 
decreased by osimertinib  
Warning of possible interaction 
Advice 
Rosuvastatin  
Sulfasalazine 
Doxorubicin 
Daunorubicin  
Topotecan 
Aliskerin 
Dabigatran etixelate 
Digoxin 
Drugs are permitted but caution should be exercised 
and patients monitored closely for possible drug 
interactions. Please refer to full prescribing 
information for all drugs prior to co-administration 
with osimertinib. 
 

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screening, the drugs that patients are currently prescribed should be checked opposite the 
Arizona Center website above. 
J 5.1 
Drugs with a known risk of Torsades de Pointes (TdP)  
The following drugs prolong QT interval and are clearly associated with a known risk of TdP 
even when taken as recommended. These drugs must have been discontinued prior to the start 
of administration of study treatment, in accordance with guidance provided in Table 29 and 
should not be co-administered with savolitinib or osimertinib and for a period of one week 
after discontinuing study treatment. 
The list of drugs may not be exhaustive and is subject to change as new information becomes 
available. As such, investigators are recommended to search the Arizona Center website to 
confirm the most up to date information. Recommended withdrawal periods following 
cessation of treatment with these agents are provided in Table 29. 
Table 29 
Drugs with a known risk of Torsades de Pointes (TdP)  
Contraindicated drug 
Withdrawal period prior to osimertinib startb 
Aclarubicin, anagrelide, ciprofloxacin, 
clarithromycin, cocaine, droperidol, erythromycin, 
levofloxacin, ondansetron, papaverine hydrochloride, 
procainamide, sulpiride, sultopride, terfenadine, 
terlipressin. 
2 days 
Cilostazol, cisapride, disopyramide, dofetilide, 
domperidone, flecainide, gatifloxacin, grepafloxacin, 
ibutilide, moxifloxacin, oxaliplatin, propofol, 
quinidine, roxithromycin, sevoflurane, sotalol, 
sparfloxacin, thioridazine 
7 days 
Bepridil, chlorpromazine, halofantrine, haloperidol, 
mesoridazine 
14 days 
Donepezil, terodiline 
3 weeks 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxidea, ibogaine 
6 weeks 
Pentamidine 
8 weeks 
Astemizole, probucol, vandetanib 
4 months 
Amiodarone, chloroquine 
1 year 
a 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied. 
b 
Values determined from comprehensive review (internal to AstraZeneca) of each compounds 
pharmacokinetic half-life and determination of the washout period 
This list should be checked against the full and most current list presented in the CredibleMeds® website 
(https://www.crediblemeds.org/).). 

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J 5.2 
Drugs that may possibly prolong QT interval  
The use of the following drugs is permitted (notwithstanding other exclusions and restrictions) 
provided the patient has been stable on therapy for the periods indicated. 
Table 30 
Drugs that may prolong QT interval  
Drug 
Minimum treatment period on medication prior to 
osimertinib start 
Alfuzosin, chloral hydrate, ciprofloxacin, dolasetron, 
foscarnet, galantamine, gemifloxacin, isridipine, 
ketoconazole, levofloxacin, mexiletine, nicardipine, 
octreotide, ofloxacin, ondansetron, quetiapine, 
ranolazine, telithromycin, tizanidine, vardenafil, 
venlafaxine, ziprasidone 
2 days 
Amantadine, amitriptyline, amoxapine, clozapine, 
doxepin, felbamate, flecainide, fluconazole, 
fosphenytoin, gatifloxacin, granisetron, imipramine, 
indapamide, lithium, moexipril/HCTZ, moxifloxacin, 
risperidone, roxithromycin, sertraline, trimethoprim-
sulfa, trimipramine, voriconazole 
7 days 
Azithromycin, citalopram, clomipramine, 
itraconazole, nortriptyline, paroxetine, solifenacin, 
tacrolimus 
14 days 
Fluoxetine  
5 weeks 
Protriptyline 
6 weeks 
Tamoxifen 
8 weeks 
 
J 6 
References  
The Arizona Center for Education and Research on Therapeutics website  
Available at URL: https://www.crediblemeds.org. 

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Appendix K Patient reported outcome assessments  
This appendix includes example copies of the following PRO questionnaires:  
• 
EORTC QLQ-C30 v3 (core questionnaire) 
• 
EORTC QLQ-LC13 (lung cancer module) 
• 
PGIS 
• 
PRO-CTCAE 
• 
EQ-5D-5L 
 

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Patient Reported Outcomes questionnaires EORTC QLQ-C30 removed due to copyrights.

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Patient Reported Outcomes questionnaires EORTC QLQ-C30 removed due to copyrights.

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RI
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Patient Reported Outcomes questionnaires EORTC QLQ-LC13 removed due to copyrights.

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K 3 
PGIS  
 

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$VWUD=HQHFD
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Patient Reported Outcomes questionnaire PRO-CTCAE removed due to copyrights.

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Patient Reported Outcomes questionnaire EQ-5D-5L removed due to copyrights.

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RI
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Patient Reported Outcomes questionnaire EQ-5D-5L removed due to copyrights.

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Appendix L Abbreviations  
 
Abbreviation or special 
term 
Explanation 
1L 
First line 
2L 
Second line 
3L 
Third line 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BICR 
Blinded independent central review 
bid 
Twice daily 
BP 
Blood pressure 
CAS 
Contribution of Components Analysis Set 
CI 
Confidence interval 
C1h 
Plasma concentration at 1 hour post-dose 
C3h 
Plasma concentration at 3 hours post-dose 
Cmax 
Maximum observed plasma drug concentration 
Cmin 
Minimum observed plasma drug concentration 
Cpre-dose 
Pre-dose plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete response 
CRF 
Case report form (electronic/paper) 
CRO 
Contract research organisation 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTIS 
Clinical Trials Information System 
CTSQ-16 
Cancer Therapy Satisfaction Questionnaire-16 
CYP 
Cytochrome P450 
DCO 
Data cut-off 
DILI 
Drug-induced liver injury 
DNA 
Deoxyribonucleic acid  
DoR 
Duration of response 

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Abbreviation or special 
term 
Explanation 
EC 
Ethics committee, synonymous to institutional review board and independent 
ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EGFRm 
Epidermal growth factor receptor mutation 
EGFRm+ 
Epidermal growth factor receptor mutation positive 
EGFR-TKI 
Epidermal growth factor receptor-tyrosine kinase inhibitor 
EM 
Erythema Multiforme 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 
EORTC-QLQ-LC13 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Lung Cancer 13 
EQ-5D-5L 
EuroQol 5 dimensions, 5 levels 
FACT-L 
Functional Assessment of Cancer Therapy - Lung Cancer 
FDG-PET 
Fluorodeoxyglucose-positron emission tomography 
FFPE 
Formalin fixed and paraffin embedded 
FISH/ FISH+ 
Fluorescence in situ hybridisation/ fluorescence in situ hybridisation positive 
FISH5+; FISH10+ 
≥5 MET gene copies or MET:CEP7 signal ratio ≥2 by FISH; ≥10 gene copies by 
FISH 
GCP 
Good clinical practice 
GDPR 
General Data Protection Regulation 
GMP 
Good Manufacturing Practice 
GRAD 
Global Retention and Disposal 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HDPE 
High density polyethylene 
HGF 
Hepatocyte growth factor 
HL 
Hy’s Law 
HLA 
Human leukocyte antigen 
HR 
Hazard ratio 
HRCT 
High resolution computed tomography 
HRQoL 
Health-related quality of life 

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Abbreviation or special 
term 
Explanation 
IA1 
Interim Analysis 1 
IA2 
Interim Analysis 2 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IHC50+; IHC90+ 
≥50% of tumour cells staining at strong 3+ intensity by IHC; ≥90% of tumour cells 
staining at strong 3+ intensity by IHC 
ILD 
Interstitial lung disease 
I(M)P 
Investigational (medicinal) product 
INR 
International normalised ratio 
International 
Co-ordinating investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or activities 
internationally.  
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IWRS 
Interactive web response system 
LFT 
Liver function test 
LMWH 
Low molecular weight heparin 
LVEF 
Left ventricular ejection fraction 
MET 
Mesenchymal epithelial transition factor 
MET/CEP7   
Mean MET per cell and chromosome 7 centromere ratio 
MRI 
Magnetic resonance imaging 
MUGA 
Multi-gated acquisition 
NA 
Not applicable 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NGS 
Next generation sequencing 
NIMP 
Non-investigational medicinal product 
NSCLC 
Non-Small Cell Lung Cancer 
NTL 
Non-target lesion 
NYHA 
New York Heart Association 
od 
Once daily 

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Abbreviation or special 
term 
Explanation 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PHL 
Potential Hy’s Law 
PI 
Principal investigator  
PK 
Pharmacokinetic(s) 
PK-PD 
Pharmacokinetic-pharmacodynamic 
PR 
Partial response 
PRO 
Patient reported outcomes 
PRO-CTCAE 
Patient reported outcomes version of the Common Terminology Criteria for 
Adverse Events 
QLQ-LC13 
Quality of Life Questionnaire-Lung Cancer 13 
QTcF 
QT interval corrected for heart rate using Fridericia's formulas 
RECIST (1.1) 
Response Evaluation Criteria in Solid Tumours (version 1.1) 
RNA 
Ribonucleic acid 
RTSM 
Randomization and trial supply management 
SAE 
Serious adverse event  
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SJS 
Stevens-Johnson syndrome 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected adverse reaction 
TBL 
Total bilirubin 
TdP 
Torsades de Pointe 
TKI 
Tyrosine kinase inhibitor 
TL 
Target lesion 
TPAS 
Target Population Analysis Set 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 

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11 
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