APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients
Phase: PHASE2
Conditions: NSCLC
Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

EORTC 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België – Belgique 
Tel: +32 2 774 16 11 
e-mail: eortc@eortc.org 
www.eortc.org 
EORTC protocol 1613-LCG 
APPLE trial: Feasibility and activity of AZD9291 
(osimertinib) treatment on Positive PLasma T790M in 
EGFR mutant NSCLC patients 
(EudraCT 2016-001834-82) 
(NCT02856893) 
Study Coordinator: 
Study co-Coordinator: 
This document contains confidential information. The information is provided to you and your study staff in 
confidence and cannot be used for any other purpose than the evaluation or conduct of the project 
described in this protocol. The information contained in the protocol should not be disclosed to others, 
without the prior written approval from EORTC, unless required to be made public by any applicable law. 
Version 4.0 / 29 April, 2022 
©Copyright EORTC 2022 

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Document history 
Protocol version 
Date of PRC 
approval/notification 
Amendment reference 
N° 
Classification  
Outline 
August 2, 2016 
--- 
--- 
1.0 
September 21, 2016 
--- 
--- 
2.0 
March 17, 2017 
1 
Scientific 
3.0 
October 13, 2021 
4 
Scientific 
4.0 
April 29,2022 
5 
Scientific 
 
Contacts 
Writing Committee: 
 
EORTC Headquarters Team, Brussels, Belgium 
Study Steering Committee: 
Study Coordinators, Chair and secretary of the LCG, Chair of the 
NSCLC subcommittee, Chair of Translational Research and 
representative persons from the EORTC Headquarters 
Study Coordinator: 
 
Study co-Coordinator: 
 
Medical Representative: 
 
  
Clinical Operations Manager: 
 
 
 
  
  
 
Data Manager: 
 
 
 
Statisticians: 
 
 
 
 
  

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Pharmacovigilance Unit: 
Phone: ( +32 ) 2 774 16 76 
Fax: 
 ( +32 ) 2 772 80 27 
E-Mail: pharmacovigilance@eortc.org 
 
 

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Sponsor signatory page 
 
Protocol EORTC 1613 
 
Sponsor: EORTC 
 
___________________________________________________ 
__________________ 
  
 
 
 
 
 
(Date) 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator: 
 
___________________________________________________ 
__________________ 
 
 
 
 
 
 
 
(Date) 
 
 
 
 
 
 
 
 
Investigator:  
 
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Investigator’s full name (in capitals)  
 
(Signature) 
 
 
(Date) 
 
 
18 May 2022 | 13:59:38 CEST
16 May 2022 | 15:44:09 CEST

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Table of contents 
Protocol summary ......................................................................................................................................... 10 
1 
Background and introduction ............................................................................................................... 20 
1.1 
Incidence ....................................................................................................................................... 20 
1.2 
EGFR mutant advanced NSCLC patients: First-line treatment ...................................................... 20 
1.3 
Osimertinib. Efficacy and Safety ................................................................................................... 21 
1.4 
Rationale and relevance for patients and the scientific community ............................................ 22 
2 
Objectives of the trial ............................................................................................................................ 23 
2.1 
Primary objective .......................................................................................................................... 23 
2.2 
Secondary objectives ..................................................................................................................... 23 
2.3 
Exploratory objectives ................................................................................................................... 23 
2.4 
Endpoints ....................................................................................................................................... 24 
2.4.1 Primary endpoint ...................................................................................................................... 24 
2.4.2 Secondary endpoints ................................................................................................................. 24 
2.4.3 Exploratory endpoints ............................................................................................................... 24 
3 
Patient selection criteria ....................................................................................................................... 24 
3.1 
Inclusion criteria ............................................................................................................................ 24 
3.1.1 Registration ............................................................................................................................... 24 
3.1.2 Randomization .......................................................................................................................... 25 
3.2 
Exclusion criteria at randomization ............................................................................................... 26 
4 
Trial Design ............................................................................................................................................ 27 
4.1 
Treatment beyond progression ..................................................................................................... 28 
5 
Therapeutic regimens, expected toxicity, dose modifications ............................................................. 28 
5.1 
Osimertinib .................................................................................................................................... 28 
5.1.1 General information .................................................................................................................. 28 
5.1.2 Drug supply ............................................................................................................................... 29 
5.1.3 Packaging, dispensing and storage ........................................................................................... 29 
5.1.4 Drug reconciliation procedures ................................................................................................. 29 
5.2 
Gefitinib ......................................................................................................................................... 29 
5.2.1 General information .................................................................................................................. 29 
5.2.2 Drug supply ............................................................................................................................... 30 
5.2.3 Packaging, dispensing and storage ........................................................................................... 30 
5.2.4 Drug reconciliation procedures ................................................................................................. 30 
5.3 
Initial dose and schedule ............................................................................................................... 31 
5.4 
Treatment duration ....................................................................................................................... 31 
5.5 
Withdrawal criteria ....................................................................................................................... 31 

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5.6 
Dose and schedule modifications ................................................................................................. 32 
5.6.1 Osimertinib ................................................................................................................................ 32 
5.6.2 Gefitinib ..................................................................................................................................... 34 
5.7 
Concomitant treatments ............................................................................................................... 35 
5.7.1 Osimertinib ................................................................................................................................ 35 
5.7.2 Gefitinib ..................................................................................................................................... 35 
5.7.3 Supportive care in case of toxicity ............................................................................................ 36 
5.7.4 Other concomitant therapies .................................................................................................... 36 
6 
Clinical evaluation, laboratory tests and follow-up .............................................................................. 36 
6.1 
Arm A ............................................................................................................................................. 36 
6.1.1 Before randomization ............................................................................................................... 36 
6.1.2 During treatment ...................................................................................................................... 37 
6.1.3 At the end of treatment ............................................................................................................ 38 
6.1.4 During Follow-up ....................................................................................................................... 38 
6.2 
Arm B ............................................................................................................................................. 39 
6.2.1 Before randomization ............................................................................................................... 39 
6.2.2 During treatment on gefitinib ................................................................................................... 39 
6.2.3 During treatment on osimertinib .............................................................................................. 40 
6.2.4 At the end of treatment ............................................................................................................ 41 
6.2.5 During Follow-up ....................................................................................................................... 41 
6.3 
Arm C ............................................................................................................................................. 42 
6.3.1 Before randomization ............................................................................................................... 42 
6.3.2 During treatment on gefitinib ................................................................................................... 42 
6.3.3 During treatment on osimertinib .............................................................................................. 43 
6.3.4 At the end of treatment ............................................................................................................ 44 
6.3.5 During Follow-up ....................................................................................................................... 44 
6.4 
Summary tables ............................................................................................................................. 45 
6.4.1 Arm A ......................................................................................................................................... 45 
6.4.2 Arm B ......................................................................................................................................... 47 
6.4.3 Arm C ......................................................................................................................................... 49 
7 
Criteria of evaluation ............................................................................................................................. 51 
7.1 
Evaluation of efficacy .................................................................................................................... 51 
7.1.1 Measurability of tumor lesions at baseline ............................................................................... 51 
7.1.2 Tumor response evaluation ...................................................................................................... 52 
7.1.3 Oligoprogression ....................................................................................................................... 54 
7.1.4 Reporting of tumor response .................................................................................................... 54 

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7.2 
Endpoints Definition ...................................................................................................................... 54 
7.2.1 Progression Free Survival Rate at 18 months (PFSR-OSI-18) .................................................... 54 
7.2.2 PFS by RECIST 1.1 while receiving osimertinib (PFS-OSI) .......................................................... 54 
7.2.3 Proportion of patients receiving osimertinib based on the determination of cfDNA T790M 
mutation positive .................................................................................................................................. 55 
7.2.4 Time to progression on osimertinib (TTP-OSI) .......................................................................... 55 
7.2.5 PFS-2 .......................................................................................................................................... 56 
7.2.6 Overall Response Rate (ORR) to osimertinib ............................................................................ 56 
7.2.7 Treatment duration ................................................................................................................... 56 
7.2.8 Overall Survival (OS) .................................................................................................................. 56 
7.2.9 Brain progression free survival (BPFS) ...................................................................................... 56 
7.2.10 
Exploratory endpoint: change in tumor size ......................................................................... 56 
7.3 
Evaluation of safety ....................................................................................................................... 57 
7.3.1 Adverse events .......................................................................................................................... 57 
7.3.2 General evaluation of adverse events ...................................................................................... 57 
7.3.3 Serious adverse events .............................................................................................................. 57 
7.3.4 Toxic deaths............................................................................................................................... 57 
7.3.5 Evaluability for safety ................................................................................................................ 57 
7.4 
Evaluation of frailty using the G8 geriatric screening tool ............................................................ 58 
7.4.1 Background ................................................................................................................................ 58 
7.4.2 Assessments .............................................................................................................................. 58 
7.4.3 Objective ................................................................................................................................... 58 
8 
Statistical considerations ...................................................................................................................... 59 
8.1 
Statistical design ............................................................................................................................ 59 
8.1.1 Sample size ................................................................................................................................ 59 
8.1.2 Power to detect a difference in brain progression free survival (BPFS) ................................... 59 
8.1.3 Randomization and stratifications ............................................................................................ 59 
8.2 
Statistical analysis plan .................................................................................................................. 60 
8.2.1 Analysis populations .................................................................................................................. 60 
8.2.2 Statistical methods .................................................................................................................... 60 
8.2.3 Pre-planned sensitivity or exploratory analyses ....................................................................... 61 
8.2.4 Prognostic factor analyses ........................................................................................................ 61 
8.2.5 Data recoding and display ......................................................................................................... 62 
8.3 
Interim analyses ............................................................................................................................ 62 
8.4 
End of study ................................................................................................................................... 62 
9 
Trial Governance and Data Monitoring................................................................................................. 63 

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9.1 
Study committees ......................................................................................................................... 63 
9.1.1 Study Management Group (SMG) ............................................................................................. 63 
9.1.2 Study Steering Committee (SSC) ............................................................................................... 63 
9.1.3 Independent Data Monitoring Committee (IDMC) ................................................................... 63 
9.2 
Data Monitoring ............................................................................................................................ 63 
9.2.1 Monitoring during medical review meetings ............................................................................ 63 
9.2.2 Monitoring by the IDMC ........................................................................................................... 64 
10 Translational research ........................................................................................................................... 64 
10.1 
Main objectives ............................................................................................................................. 64 
10.2 
Human Biological material ............................................................................................................ 64 
10.3 
Data storage, transfer and development of technical appendices ............................................... 65 
10.4 
General principles for human biological material (HBM) collection ............................................. 65 
11 Investigator authorization procedure ................................................................................................... 66 
12 Patient randomization procedure ......................................................................................................... 67 
12.1 
Registration (step 1) ...................................................................................................................... 67 
12.2 
Central lab review procedure of baseline sample (step 2) ........................................................... 68 
12.3 
Randomization procedure (step 3) ............................................................................................... 68 
13 Forms and procedures for collecting data ............................................................................................ 68 
13.1 
Case report forms and schedule for completion .......................................................................... 68 
13.2 
Data flow ....................................................................................................................................... 69 
13.3 
HBM* sample registration and tracking ....................................................................................... 70 
14 Reporting of Serious Adverse Events .................................................................................................... 70 
14.1 
Definitions ..................................................................................................................................... 70 
14.2 
Exceptions ..................................................................................................................................... 71 
14.3 
Severity assessment ...................................................................................................................... 72 
14.4 
Causality assessment ..................................................................................................................... 72 
14.5 
Expectedness assessment ............................................................................................................. 72 
14.6 
Reporting procedure for investigators .......................................................................................... 72 
14.7 
Reporting responsibilities for EORTC ............................................................................................ 73 
14.8 
Pregnancy reporting ...................................................................................................................... 73 
15 Quality assurance .................................................................................................................................. 74 
15.1 
Control of data consistency ........................................................................................................... 74 
15.2 
On-site monitoring ........................................................................................................................ 74 
15.3 
Audits ............................................................................................................................................. 74 
15.4 
Quality assurance and quality control in imaging ......................................................................... 75 
15.4.1 
Control of data completeness ............................................................................................... 75 

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15.4.2 
Imaging guidelines “read and understood” acknowledgment page signature .................... 75 
15.4.3 
Scan quality control ............................................................................................................... 75 
15.4.4 
Central review ....................................................................................................................... 75 
16 Ethical considerations ........................................................................................................................... 75 
16.1 
Patient protection ......................................................................................................................... 75 
16.2 
Subject identification .................................................................................................................... 76 
16.3 
Informed consent .......................................................................................................................... 76 
17 Administrative responsibilities .............................................................................................................. 77 
17.1 
The study coordinator ................................................................................................................... 77 
17.2 
The EORTC Headquarters .............................................................................................................. 77 
17.3 
The EORTC group ........................................................................................................................... 77 
18 Trial sponsorship and financing ............................................................................................................ 78 
19 Trial insurance ....................................................................................................................................... 78 
20 Results dissemination policy ................................................................................................................. 78 
20.1 
Study disclosure ............................................................................................................................ 78 
20.1.1 
Trial Registration ................................................................................................................... 78 
20.1.2 
Final Analysis Report ............................................................................................................. 79 
20.2 
Publication policy .......................................................................................................................... 79 
20.3 
Data sharing................................................................................................................................... 79 
 
 
Table of appendices 
Appendix A: References ................................................................................................................................ 81 
Appendix B: Abbreviations ............................................................................................................................ 84 
Appendix C: WHO performance status scale ................................................................................................ 86 
Appendix D: G8 geriatric screening tool (Version 1.0 - December 2010) ..................................................... 87 
Appendix E: Guidance regarding Potential Interactions With Concomitant Medications ........................... 88 
Appendix F: Specific protocol instructions during the COVID-19 crisis ........................................................ 91 
 
List of tables 
Table 1: Integration of Target, non-Target and New lesions into response assessment ............................. 53 
 
 
 
 

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Protocol summary 
Title of the Study 
APPLE trial: Feasibility and activity of AZD9291 (osimertinib) treatment on 
Positive PLasma T790M in EGFR mutant NSCLC patients 
Objective(s) 
Primary objective 
To evaluate the best strategy for delivering osimertinib (AZD9291) in NSCLC 
patients with EGFR mutation. The objective is assessed by Progression Free 
Survival rate at 18 months (PFSR-OSI-18). 
Secondary objectives 
• To evaluate PFS on osimertinib measured from randomization by RECIST 
criteria 1.1. 
• To evaluate PFS measured from switching to osimertinib by RECIST criteria 
1.1. 
• To determine the proportion of patients receiving osimertinib based on the 
determination of cfDNA T790M mutation positive.  
• To evaluate PFS-2. 
• To evaluate Overall Response Rate (ORR) to osimertinib. 
• To evaluate the Treatment duration. 
• To evaluate Time to progression (TTP) on osimertinib (measured from 
switching to osimertinib). 
• To evaluate Overall Survival (OS). 
• To evaluate brain progression free survival (BPFS). 
• Safety. 
Exploratory objectives 
• To assess the feasibility of prospective cfDNA T790M mutation testing 
during treatment with gefitinib as a predictor of treatment progression and 
its correlation with RECIST 1.1 progression.  
• To assess the feasibility of prospective cfDNA T790M mutation testing 
during treatment with osimertinib as a predictor of efficacy. 
• To assess the change in tumor size upon switching to osimertinib. 
• To describe the treatments and outcomes of the treatments administered 
after osimertinib. 
• To evaluate the resistance mechanisms to osimertinib (by optional biopsy 
at disease progression on osimertinib).  
• To evaluate osimertinib efficacy in patients with acquired resistance to 
gefitinib based on RECIST progression with blinded T790M status.  
• To monitor the activating EGFR mutation levels in cfDNA. 

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Methodology 
This is a randomized, open-label, multicenter, three-arms, phase II study in 
advanced, EGFR mutant and EGFR TKI naïve NSCLC patients, to evaluate the 
best strategy for delivering osimertinib. 
Advanced EGFR mutant NSCLC and EGFR-TKI naïve patients, will be randomized 
to: 
• arm A: first-line treatment with osimertinib until RECIST progression 
• arm B: gefitinib until emergence of cfDNA T790M positive status ("cfDNA 
T790M positive progression") and then switch to osimertinib until second 
RECIST progression.  
as of protocol version 4.0, patients in Arm B on gefitinib will switch to 
osimertinib on RECIST 1.1 progression only 
• arm C: gefitinib until RECIST progression and then switch to osimertinib 
until second RECIST progression 
In all arms, plasmatic cfDNA T790M test will be performed as exploratory 
analysis. However, only in arm B it will be used as a predictive marker for 
making treatment decision. Moreover, as an optional test, a re-biopsy at 
RECIST progression to osimertinib will be strongly encouraged to investigate 
the mechanisms of AR to osimertinib. 
The estimated duration of the study is 6 years, given that all patients have 
ended their treatment according to End of Study definition. 
Number of patients  
Number planned 
(Statistical design) 
Number analyzed 
This study is designed with an understanding of the difficulty of having a 
primary endpoint which solidly covers all arms. The primary endpoint PFSR-
OSI-18, will be assessed in all arms, yet this endpoint will be used to evaluate 
arm B and arm C. With this restriction, the below criteria for a success of the 
arm (applicable B and C) should be viewed as exploratory and further 
information from secondary endpoints as well as the costs should be 
considered if the arm is judged as feasible to be further explored. 
The study design is a 1-Stage Ahern Design - Single Proportion, with 
Progression Free Survival rate at 18 months (PFSR-OSI-18) as primary endpoint. 
It was designed with a 1-sided alpha = 0.08 and 92% power (beta = 8%). 
In arm B and C of this trial, if the result is compatible with a progression free 
survival rate at 18 months (PFSR-OSI-18) of 60% in the studied population, the 
strategy should be further explored. However, if we are unable to demonstrate 
that the PFSR-OSI-18 in the studied population is at least 40%, the strategy 
should be rejected from further exploration. 
49 eligible patients who started treatment are needed in each arm. To declare 
the arm worthwhile for further exploration, at least 25 out of 49 patients 
should be a success at 18 months.  
Additional 5% patients will be accrued to take into account patients who might 
be ineligible or not starting treatment. Hence, using a 1:1:1 ratio for 
randomization, a total of 156 patients will be accrued in this study (52 pts in 
each arm) within 26 months and an additional 24 months of follow up after the 
last patient entry is needed to allow the assessment of the primary endpoint. 

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In this study a minimum of 18 months of follow up is needed after the last 
patient entry.  
Diagnosis and main 
criteria for inclusion 
Inclusion criteria  
Registration 
• Pathological diagnosis of adenocarcinoma of the lung carrying common 
EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or 
L858R); performed locally; no other EGFR mutations will be allowed. In case 
of other (than EGFR) concomitant mutations, discussion with EORTC 
Headquarters is mandatory; 
• Stage IV NSCLC; 
• Blood sample available for cfDNA EGFR T790M central testing; 
• Adequate tissue sample in quantity and quality for translational research; 
• Age ≥18 years; 
• EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR 
TKI; 
• Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, 
radiotherapy, investigational agents) if performed more than 12 months 
before registration; 
• Before patient registration, written informed consent must be given 
according to ICH/GCP, and national/local regulations. 
Maximum time elapsed between registration and treatment start should be 
four weeks, although every effort should be made to start treatment as quickly 
as possible. 
Randomization 
• Report of adequacy sample for cfDNA EGFR T790M test by central 
laboratory; 
• Prior palliative radiotherapy or surgical procedures are allowed if 
completed at least 4 weeks before the randomization; 
• Patients with brain metastases are allowed provided they are stable (i.e., 
without evidence of progression by imaging for at least two weeks prior to 
the first dose of trial treatment and without deterioration of any neurologic 
symptoms), and have not received steroids for at least 7 days before 
randomization; 
• Baseline tumor assessment scans are done within 21 days before 
randomization; 
• Evaluable disease as defined below; 
• At least one lesion, not previously irradiated and not chosen for biopsy 
during the study screening period, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes which 
must have a short axis of ≥15 mm) with computed tomography (CT) or 
magnetic resonance imaging (MRI), and which is suitable for accurate 
repeated measurements.  
• WHO Performance Status 0-2, with no clinically significant deterioration 
over the previous 2 weeks and a minimum life expectancy of 12 weeks; 

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• Adequate bone marrow, renal, hepatic and liver function within 21 days 
form randomization and defined as follows: 
• Absolute neutrophil count ≥1.5 x 109/L; 
• Platelet count ≥100 x 109/L; 
• Hemoglobin ≥9 g/dL; 
• Alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN) if 
no demonstrable liver metastases or ≤5xULN in the presence of liver 
metastases; 
• Aspartate aminotransferase (AST) ≤2.5xULN if no demonstrable liver 
metastases or ≤5xULN in the presence of liver metastases; 
• Total bilirubin ≤1.5xULN if no liver metastases or ≤3xULN in the 
presence of documented Gilbert’s Syndrome (unconjugated 
hyperbilirubinaemia) or liver metastases; 
• Serum creatinine ≤1.5xULN concurrent with creatinine clearance ≥50 
mL/min (measured or calculated by Cockcroft and Gault equation). 
• No significant comorbidity that according to the investigator would hamper 
the participation on the trial; 
• Female patients should be using adequate contraceptive measures, as 
defined by the investigator, during the treatment until 6 weeks after last 
dose of osimertinib. They should not be breastfeeding, and must have a 
negative pregnancy test (serum or urine) prior to first dose of study drug 
(within 72 hours); or female patients must have an evidence of non-child-
bearing potential by fulfilling one of the following criteria at screening:  
• Post-menopausal defined as aged more than 50 years and amenorrheic 
for at least 12 months following cessation of all exogenous hormonal 
treatments. 
• Women under 50 years old would be consider postmenopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and with luteinizing hormone (LH) and 
follicle-stimulating hormone (FSH) levels in the post-menopausal range 
for the institution. 
• Documentation of irreversible surgical sterilization by hysterectomy, 
bilateraloophorectomy, or bilateral salpingectomy but not tubal 
ligation. 
• Male patients should be willing to use barrier contraception, i.e., condoms 
as defined by the investigator, during the treatment until 4 months after 
last dose of osimertinib; 
• Male patients will be advised to arrange for the freezing of sperm 
samples prior to the start of the study should they wish to father 
children, and not to donate sperm until 6 months after discontinuation 
of study treatment. (as per Investigator Brochure, IB) 
• Absence of any psychological, familial, sociological or geographical 
condition potentially hampering compliance with the study protocol and 

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follow-up schedule; those conditions should be discussed with the patient 
before registration in the trial. 
Important note: All eligibility criteria must be adhered to, in case of deviation 
discussion with Headquarters and study coordinator is mandatory. Patients 
with a buffer range from the normal values of +/- 5 % for hematology and +/- 
10% for biochemistry are acceptable. A +/- 3 days deviation is also allowed 
except for the pregnancy test. 
Exclusion criteria at randomization 
• Treatment with any of the following: 
• Prior treatment with any systemic anti-cancer therapy for locally 
advanced/metastatic NSCLC including chemotherapy, biologic therapy, 
immunotherapy, or any investigational drug; 
• Prior treatment with an EGFR-TKI; 
• Major surgery (excluding placement of vascular access) within 4 weeks 
before randomization; 
• Radiotherapy treatment to more than 30% of the bone marrow or with 
a wide field of radiation within 4 weeks before randomization. 
• Patients currently receiving (or unable to stop use at least 1 week prior 
to receiving the first dose of study drug) medications or herbal 
supplements known to be potent inhibitors or inducers of cytochrome 
P450 (CYP) 3A4; antiacids could be taken in a time-separate manner, at 
least 8 hours from gefitinib;  
• Other anti-cancer therapies and alternative medications such as 
homeopathy, etc;  
• Treatment with an investigational drug within five half-lives of the 
compound or any of its related material, if known; 
• Leptomeningeal carcinomatosis; spinal cord compression;  
• Any unresolved toxicities from prior systemic therapy (e.g., adjuvant 
chemotherapy) greater than CTCAE grade 2 at the time of randomization; 
• Patients will not be eligible if they have evidence of active malignancy 
(other than non-melanoma skin cancer or localized cervical cancer or 
localized and presumed cured prostatic cancer) within 2 years before 
randomization and are not receiving specific treatment for these 
malignancies at baseline assessment; 
• Any evidence of severe or uncontrolled systemic diseases, including 
uncontrolled hypertension and active bleeding diatheses, which in the 
Investigator’s opinion makes it undesirable for the patient to participate in 
the trial or which would jeopardize compliance with the protocol;  
• Active infection including hepatitis B, hepatitis C and human 
immunodeficiency virus (HIV). Active infection will include any patients 
receiving intravenous treatment for infection; active hepatitis B infection 
will, at a minimum, include all patients who are Hepatitis B surface antigen 
positive (HbsAg positive) based on serology assessment. Screening for 
chronic conditions is not required;  

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• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability 
to swallow the formulated product, or previous significant gastrointestinal 
resection that would preclude adequate absorption of osimertinib or 
gefitinib; 
• Any of the following cardiac criteria: 
• Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 
ECGs using local clinic ECG machine-derived QTcF value 
• Any clinically important abnormalities in rhythm, conduction, or 
morphology of resting ECG, e.g., complete left bundle branch block, 
third-degree heart block, second-degree heart block, PR interval >250 
msec or history of episodes of bradycardia (<50 BPM); 
• Any factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as heart failure, hypokalaemia, congenital long 
QT syndrome, family history of long QT syndrome, or unexplained 
sudden death under 40 years of age in first-degree relatives or any 
concomitant medication known to prolong the QT interval. 
• Abnormal cardiac function: LVEF <50% (assessed by MUGA or ECHO) 
• Past medical history of ILD (Interstitial Lung Disease), drug-induced ILD, 
radiation pneumonitis which required steroid treatment, or any evidence 
of clinically active ILD. 
Treatment 
Test product, dose 
and mode of 
administration 
Duration of 
treatment 
Arm A (intervention): osimertinib 80 mg QD until RECIST progression. 
Arm B (intervention): gefitinib 250mg QD until cfDNA T790M positive test 
(criteria for defining progression disease), irrespective of RECIST 1.1 criteria, 
then patients will receive osimertinib 80 mg QD until RECIST progression. If 
patients have RECIST progression without cfDNA T790M positive test, they will 
be switched to osimertinib.  
Note: as of protocol version 4.0, patients in Arm B on gefitinib will switch to 
osimertinib on RECIST 1.1 progression only 
Reference therapy, 
dose and mode of 
administration 
Arm C (active control arm): gefitinib 250mg QD until RECIST progression, 
irrespective of cfDNA T790M test, then patients will receive osimertinib 80 mg 
QD until second RECIST progression. 
Criteria for 
evaluation 
Efficacy 
Progression Free Survival Rate at 18 months (PFSR-OSI-18)  
The endpoint is evaluated primarily in arm B and arm C. 
The primary endpoint, Progression Free Survival Rate at 18 months (PFSR-OSI-
18) is defined as the proportion of patients at 18 months who are alive and 
non-progressing after switching to osimertinib. Patients who are still on 
gefitinib, alive and without progression at 18 months will be counted as a 
success with respect to the primary endpoint.  
Practically, the time point of disease evaluation corresponding to the primary 
endpoint is 18 months after randomization. Therefore, disease evaluation at 18 
months (+/- 14 days) is required for all patients who are still alive and without 
progression on osimertinib at the 18th month. The above disease evaluation is 

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also required if patients are without progression and are still on gefitinib at 18 
months. 
Patients without adequate disease assessment at 18 months will be considered 
as failures. The adequacy of the disease assessments will be subject to the 
medical review plan which will be completed prior to the interim/final analysis 
of the study. 
The baseline to determine disease progression at 18 months is the baseline at 
randomization. For patients switching to osimertibnib, the nadir of the 
measurements to determine progression is defined as the nadir after switching 
to osimertinib. 
Progression of the disease will be defined based on one or several of the 
following criteria: 
Documented radiological progression as defined by RECIST 1.1, using baseline 
at randomization; 
Development of new lesions after switching to osimertinib; 
Unequivocal (according to physician's assessment) deterioration of non-
measurable lesions after switching to osimertinib. 
Safety 
Adverse events 
 
All adverse events will be recorded; the investigator will assess whether those 
events are related to osimertinib (reasonable possibility, no reasonable 
possibility) or gefitinib (reasonable possibility, no reasonable possibility) and 
this assessment will be recorded in the database for all adverse events. 
The collection period will start from randomization and all adverse events must 
be followed until resolution or stabilization. 
General evaluation of adverse events 
This study will use the International Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0, for adverse event reporting. A copy of the CTCAE 
can be accessed from the EORTC home page 
https://www.eortc.be/services/doc/ctc/. 
Hematological toxicity will be assessed on the basis of regular blood tests. The 
nadir count will be computed at each study medication administration and 
graded according to the CTCAE version 4.0.  
Non hematological acute side effects will be assessed and reported separately 
for each study medication administration, and graded according to the CTCAE 
version 4.0. 
Planned safety analysis and tabulations are described in the statistics section. 
Serious adverse events 
Serious adverse events are defined by the Good Clinical Practice Guideline. 
Serious adverse events should be immediately reported according to the 
procedure detailed in this protocol. 

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Toxic deaths 
Toxic death is defined as death due to toxicity (defined as adverse events that 
are not confirmed as unrelated). The cause of death must be reported as 
"toxicity". 
The evaluation of toxic deaths is independent of the evaluation of response 
(patients can die from toxicity after a complete assessment of the response to 
therapy). 
Evaluability for safety 
All patients who have started the treatment (either gefitinib or osimertinib) 
will be included in overall safety analyses. 
For hematological events, the medical review team may decide that blood 
counts have not been performed and/or reported according to the protocol 
and are therefore inadequate for the evaluation of one/several hematological 
parameters in some patients. 
Parameters that will be identified and monitored will be the following: 
• Any grade 3-4 non hematological or grade 4 hematological toxicity at least 
possibly related to the treatment; 
• % of treatment interruptions, schedule modifications and dose 
modifications; 
• Compliance to the requirement of minimum dose intensity of 70% 
(treatment tolerability rule); 
• Unexpected grade 2 toxicity at least possibly related to the treatment; 
• Worsening of toxicity if data will be available at the time of DSM. 
Patients who have discontinued treatment because of toxicity will always be 
included in the safety analyses. 
Statistical methods 
Analysis populations 
• Intention-to-treat population: All randomized patients will be analyzed in 
the arm they were allocated by randomization. 
• Per protocol population: All patients who are eligible and have started their 
allocated treatment (at least one dose of the study drug(s) in 
chemotherapy trials) 
• Safety population: All patients who have started their allocated treatment 
(at least one dose of the study drug(s) in chemotherapy trials) 
A patient will be considered to be eligible if he/she did not have any deviation 
from the patient entry criteria listed in the protocol. Potential eligibility 
problems will be assessed by the Clinical Research Physician at time of medical 
review. 
Statistical methods 
Analysis of the primary endpoint 
The primary analysis will be performed to per-protocol population. 

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Patients with success is defined by the primary endpoint. The PFSR-OSI-18 in 
each arm and their 84% confidence intervals will be provided. In case the 
number of patients analyzed in each arm exceeds or less than what is foreseen 
above, the 84% confidence interval will be used for the decision. 
Time to event endpoints 
The analyses of the primary and secondary endpoints will be performed on 
per-protocol population. 
Estimates and confidence intervals  
Estimates of the median PFS-OSI, TTP-OSI, PFS2-OSI and OS are obtained by 
the Kaplan Meier technique. The 84% and 95% confidence intervals (CI) for the 
median will be calculated using the reflected CI method. 
Estimates of the event-free rate at fixed time point (18 months) will be 
obtained using the Kaplan Meier technique and 84% 2-sided CI will be 
calculated by Greenwood’s estimation of the standard deviation. Estimates of 
hazard ratios and their 84% 2-sided CI will be obtained by Cox regression. In 
addition 95% 2-sided CI will be provided for both the estimates of event rates 
and hazard ratios. Kaplan Meier Curves will be drawn for both the 
experimental and control arms on the same plot.  
Inference: Test statistics for comparisons 
Cox regression (Score Test) will be used to compare the experimental versus 
the control arms adjusted by the stratification factors in randomization (except 
for centers) at 1-sided 10% significant level. 
Toxicity 
Analysis for toxicity is based on the safety population. The worst grade of 
toxicity/adverse events observed over the whole treatment period (excluding 
re-challenge period for Arm A) according to CTCAE version 4 will be displayed. 
No formal statistical analysis will be performed to compare toxicity in both 
arms.  
Response Rate 
Patients with response categories progression, early death and unknown will 
be considered as failing to respond to treatment. The response rates in each 
arm and their 95% confidence intervals will be provided. In addition, response 
rates in the 2 arms will be compared using a two-sample test at 5% 2-sided 
level. 
Translational 
research 
The translational research is mandatory for this protocol. Any patient who 
consent to enter the trial will have to consent for the translational research. 
Objectives 
The main objectives of translational research study are, but not limited to, the 
following: 
• to describe quantitatively the presence of T790M EGFR mutations and 
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gefitinib and osimertinib longitudinally within the arms and to compare the 
presence of these mutations across the arms A, B and C. 
• to describe the associations between the presence of these mutations and 
response evaluations by RECIST 1.1 longitudinally within the arms. 
• to describe the associations between the presence of these mutations and 
response and PFS to osimertinib in Arm A, B and C. 
• to assess mechanisms of resistance to osimertinib in formalin-fixed 
paraffin-embedded (FFPE) samples obtained from patients at baseline and 
at the time of progress on osimertinib by next generation sequencing and 
compare the presence of molecular resistance alterations in tissue samples 
and plasma samples taken on progression. 
Human Biological material 
• plasma sample taken during screening visit and each treatment visit (every 
4 weeks) while patients are within active treatment with gefitinib or 
osimertinib. Note: if gefitinib or osimertinib is temporarily discontinued 
due to toxicity, plasma sample should still be obtained. The last plasma 
sample should be taken from patients who progress on osimertinib by 
RECIST 1.1 evaluation (all three arms).  
• FFPE processed biopsy samples at baseline (residual tumor from diagnostic 
sample) and from progressing tumor lesions obtained from patients 
receiving osimertinib. 
 
 

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1 Background and introduction 
1.1 
Incidence 
Lung cancer is the third most frequent cancer worldwide with 1.8 million new cases diagnosed in 2012, 
and the leading cause of cancer-related death worldwide (1.59 million deaths in 2012) [Ref. 1, Ref. 2]. The 
SEER database currently shows that 60% of non-small-cell lung cancers (NSCLC) are diagnosed in 
advanced stage [Ref. 3]. Platinum-based doublet chemotherapy is the standard first-line treatment for 
non-selected patients with advanced NSCLC who have a good performance status [Ref. 4], with a median 
survival that rarely exceeds 10 months without maintenance treatment [Ref. 5]. 
Recent progress has been achieved in the management of patients with advanced NSCLC with the 
identification of tumor-specific molecular alterations, especially in adenocarcinoma histologic subtype, 
and the development of drugs that target the respective deregulated signaling pathways [Ref. 6, Ref. 7], 
establishing tumor genotyping as an essential routine diagnostic tool in clinical practice [Ref. 8]. 
Approximately 50% of advanced NSCLC tumors have a genetic alteration but only 20%-25% of them are 
actionable oncogenic driver mutations [9]. Moreover, it has been reported that NSCLC patients whose 
tumor harbors a known oncogenic drivers and receive a matched targeted agent live significantly longer 
than those who have a driver mutation but do not receive personalized treatment (hazard ratio [HR]: 
0.69; 95% confidence interval [CI]: 0.53–0.9; p = 0.006) [Ref. 10], supporting the clinical benefit of this 
policy [9]. The most frequent genetic alterations in advanced NSCLC are KRAS mutation ~29% of tumors, 
EGFR mutation ~11%, ALK rearrangement ~5%, BRAF and PIK3CA mutations in ~2%, respectively; and 
HER2 mutation in 1% of tumors [Ref. 9]. Also, MET mutation (exon 14) [Ref. 11] and ROS1 
rearrangements [Ref. 12] have been reported in 4% and 1% of patients with NSCLC, respectively. These 
oncogenic drivers are almost always mutually exclusive in patients with NSCLC [Ref. 10]. 
1.2 
EGFR mutant advanced NSCLC patients: First-line treatment 
There are several classes of activating somatic EGFR mutations being the in-frame deletions in exon 19 
(Del19) and single point mutations in exon 21 (L858R) the most common EGFR mutation subtypes. EGFR 
mutations are more frequent in Asian than Caucasian population (~50% vs. 10%) [Ref. 13]. EGFR 
mutations predict sensitivity to first-generation reversible EGFR tyrosine kinase inhibitors (TKI) erlotinib 
and gefitinib, and the second-generation irreversible EGFR-TKI such as afatinib. These drugs 
demonstrated to improve the response rate (RR), progression-free survival (PFS) and quality of life over 
standard first-line platinum-doublet chemotherapy in several randomized phase III trials in EGFR mutant 
advanced NSCLC patients. To date, no differences in overall survival (OS) versus standard platinum-
doublet chemotherapy have been reported in these trials, possibly due to the high crossover rate to the 
TKI arm following disease progression in chemotherapy-treated patients [Ref. 14]. However, despite 
initial dramatic responses and substantial PFS to EGFR TKI observed in phase III clinical trials, most of 
EGFR mutant NSCLC patients develop acquired resistance (AR) after a median of approximately 12 
months from treatment initiation [Ref. 14]. The substitution of threonine to methionine at amino acid 
position 790 (T790M) in exon 20 of the EGFR gene is the most common type of AR mutation observed, 
which accounts for 49-70% of AR to EGFR-TKIs using different detecting methods [Ref. 15, Ref. 16,  
Ref. 17]. Originally T790M mutation was thought to represent an acquired mutation, however, 
sequencing technologies have revealed the presence of this mutation in EGFR TKI-naïve lung cancer 
patients, with a variable frequency, from <1% to 79.9% by different tests [Ref. 18, Ref. 19, Ref. 20]. 
For those EGFR mutant lung cancer patients who progress on EGFR TKI, discontinuation of EGFR TKI and 
the addition of alternative systemic treatment are common in daily clinical practice, and chemotherapy is 
the standard of care. In a recent phase III trial (IMPRESS) in EGFR mutant lung cancer patients, mainly 

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Asian population, with RECIST progression on EGFR TKI, the pemetrexed and platinum-based second-line 
chemotherapy conferred a 34% of RR with a median PFS of 5.4 months, but with a grade ≥ 3 adverse 
events in 42% of patients [Ref. 21]. Biomarker analysis from the IMPRESS trial, reported only benefit of 
continuing EGFRTKI beyond progression in combination with chemotherapy among T790M negative 
patients, with a trend toward improvement in PFS of 6.7 months vs. 5.4 months [Ref. 22]. 
1.3 
Osimertinib. Efficacy and Safety 
Osimertinib (AZD9291, Tagriso ®) is an oral, irreversible, mutant-selective EGFR TKI designed to have 
activity against tumors bearing sensitizing EGFR mutations and T790M resistance mutations that spares 
the wild type form of the receptor [Ref. 23]. 
The phase I AURA trial with osimertinib [Ref. 24] enrolled 253 advanced EGFR mutant NSCLC patients 
with acquired resistance to erlotinib or gefitinib into dose escalation and expansion cohorts. Prospective 
T790M status by central laboratory testing was required in expansion cohorts and T790M status was 
optional for dose escalation cohorts. Patients were included in doses of osimertinib of 20 mg up to 240 
mg daily. The ORR was 51% with no differences according to each dose levels of osimertinib. The dose of 
80 mg daily was considered as optimal to maximize efficacy and minimize skin and gastrointestinal 
adverse events observed at the higher doses. According to T790M status, the ORR and PFS were 71% and 
9.7 months for T790M positive tumors versus 24.6% and 3 months for T790M negative tumors, 
respectively [Ref. 10]. In the updated result of the trial with 283 patients (31 patients dose escalation and 
252 in expansion cohorts, and 163 T790M positive by central testing) confirmed an ORR of 59% and 23% 
in the T790M positive and negative patient groups, respectively. At 80 mg the T790M positive cohort 
achieved an ORR of 54% and a median PFS 13.5 months by centrally reviewed data monitoring [Ref. 25].  
In an expansion cohort form the phase I AURA trial (NCT01802632), osimertinib at doses of 80 mg/day or 
160 mg/day (sequential cohorts) was administered to 60 treatment-naïve patients with EGFR mutant 
advanced NSCLC patients (30 patients per arm). The central mutation test reported T790M in 8% of 
patients. The ORR was 75% (95% CI 66 - 82). The median PFS has not been reached. Overall, the 12-
month PFS rate was 71.7%. Grade ≥ 3 AEs were reported by 33% of patients, mainly skin rash and 
diarrhea, especially with the higher doses [Ref. 26], supporting the efficacy of osimertinib in first-line 
setting at dose of 80 mg/day. The ongoing FL-AURA (NCT02296125) phase III trial will compare the 
efficacy measured by PFS and safety of osimertinib (80 mg/d) as first-line treatment to standard of care 
EGFR TKI (gefitinib 250 mg/d or erlotinib 150 mg/d) in advanced NSCLC patients with common EGFR 
mutations. In the control arm, crossover to osimertinib will be allowed in case of progression.  
In the AURA 2 phase II study, osimertinib 80 mg/day in 199 pre-treated T790M positive advanced NSCLC 
patients reported a 71% of RR with an immature PFS of 8.6 months and the frequency of treatment-
related Grade ≥3 AEs was low (11%) [Ref. 27]. 
Osimertinib 80 mg once daily has an acceptable safety profile for the intended advanced NSCLC 
population. In the Phase II studies: 
The majority of all causality adverse events (AEs) reported with osimertinib were mild to moderate. 
Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 events were reported in 29.4% of 
patients, with 11.7% of CTCAE ≥Grade 3 considered related to osimertinib by the investigator. 
Serious adverse events (SAEs) were reported in 20.2% of patients; 5.1% of SAEs were considered causally 
related to osimertinib by the investigator. 
Thirteen patients (3.2%) experienced an AE with the outcome of death; 4 of these deaths (3 patients had 
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related to treatment with osimertinib. In 8 patients, the investigator considered the death to be due to 
both NSCLC (disease under investigation) and a fatal AE. 
The most commonly reported adverse events were low-grade gastrointestinal disturbances primarily: 
diarrhea (42.3% all grades; 1.0% ≥Grade 3); rash and acne (grouped term: 41.4% all grades; 4.4% Grade 
≥3); dry skin (grouped term: 30.9% all grades; none ≥Grade 3), and paronychia 17.5% all grades; none 
≥Grade 3). 
Nowadays, osimertinib prescription as second-line treatment is restricted to patients with AR to EGFR TKI 
based on RECIST progression criteria and T790M positivity in a re-biopsy. However, patients whose 
tumors have progressed on EGFR TKI may be unable or unwilling to provide an additional biopsy for 
testing of T790M status. Genotyping of cell free circulating plasma DNA (cfDNA) may provide an early and 
non-invasive option to identify patients who progress to EGFR TKI unable to provide tissue biopsies. 
Moreover, plasma T790M genotyping results might mirror tumor heterogeneity [Ref. 28]. 
1.4 
Rationale and relevance for patients and the scientific 
community 
Other than radiological techniques are awaited to indicate disease progression and switch treatment in 
lung cancer patients, particularly where new treatment prescription at AR requires a new tissue biopsy 
that may lead to potential complications. Moreover, in clinical trials, tumor tissue for treatment eligibility 
is a significant barrier to trial enrollment and delays treatment initiation [Ref. 7]. 
A new challenge in the treatment of EGFR mutant NSCLC patients with AR to EGFR TKI is to know whether 
plasmatic progression (T790M positive in cfDNA, a liquid biopsy) occurs earlier than RECIST progression 
and whether switching to osimertinib based only on plasmatic progression could improve the overall 
outcome of patients compared with standard procedure (treatment switching based on RECIST 
progression in a Computed Tomography (CT) scan). Recent results reported equal efficacy of third-
generation EGFR TKI independently whether the T790M research was performed in plasma or in the 
tissue in EGFR mutant patients with RECIST progression on first-generation EGFR TKI [Ref. 29], suggesting 
that liquid biopsies could become new standard tests in the near future. Liquid biopsies could also serve 
as dynamic predictive marker of efficacy on third generation EGFR TKI and also a tool to anticipate 
radiological progression. Indeed, switch to osimertinib as second-line treatment in EGFR mutant NSCLC 
patients based only on RECIST progression is justified by the fact that in T790M negative patients the 
efficacy of osimertinib as second-line treatment appears similar to standard second-line chemotherapy 
with a better toxicity profile. 
At the moment there is no data from randomized phase III trials supporting osimertinib as first-line 
treatment in EGFR mutant NSCLC patients. However, the efficacy of osimertinib to cover the pre-existing 
T790M mutation in EGFRTKI-naïve patients (as contrary to gefitinib or afatinib, chronic treatment with 
osimertinib did not cause acquired resistance in PC-9 –Del19- cells in vitro through gain of T790M  
[Ref. 30]), the efficacy of osimertinib in sensitizing EGFR mutations, and the promising 9 month PFS of 
81% with osimertinib in first-line, even when only 8% of tumors were de novo T790M positive, compared 
with other EGFR TKI in first-line (9 months PFS of 55% with gefitinib in EGFR mutant lung cancer patients 
in the IPASS trial [Ref. 31], or 68% with afatinib in EGFR mutant NSCLC patients with common mutations 
in LUX-Lung 3 trial [Ref. 32]), suggest the choice of osimertinib as investigational first-line treatment in 
EGFR mutant NSCLC patients. No trial so far has proposed plasma levels as a predictive dynamic marker 
for making treatment decisions in EGFR mutant NSCLC patients to EGFR TKI compared with classical 
RECIST criteria. Also it is unknown whether switch strategy is better than upfront third-generation 
irreversible EGFR TKI. 

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Based on of these new challenges we hereby propose a phase II study in EGFR mutant and EGFR-TKI 
naïve NSCLC patients. Patients will be randomized to first-line treatment with osimertinib until RECIST 
progression (arm A) or gefitinib until cfDNA T790M positive progression (arm B) or RECIST progression 
(arm C) and then switch to osimertinib until second RECIST progression.  
The proposed trial will answer several questions: are liquid biopsies the new standard treatment for 
defining disease progression in this population? What is the association between biological progression 
and radiological progression? What is the best treatment approach with third generation EGFR TKI as 
first-line treatment: upfront or sequential?.  
In conclusion, the phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a 
new standard for testing tumor progression compared with conventional radiological procedure in EGFR 
mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment we 
will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering 
osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC 
patients. Finally, the trial will also explore the mechanisms of acquired resistance to osimertinib based on 
the results of an optional biopsy upon progression. 
2 Objectives of the trial 
2.1 
Primary objective 
To evaluate the best strategy for delivering osimertinib (AZD9291) in NSCLC patients with EGFR mutation. 
The objective is assessed by Progression Free Survival rate at 18 months (PFS-18) in arm B and arm C (see 
further details in Chapter 8). No direct comparison with respect to the primary endpoint is planned 
between any arms. 
2.2 
Secondary objectives 
• To evaluate PFS on osimertinib measured from randomization by RECIST criteria 1.1 [Ref. 33]. 
• To evaluate PFS measured from switching to osimertinib by RECIST criteria 1.1 [Ref. 33]. 
• To determine the proportion of patients receiving osimertinib based on the determination of cfDNA 
T790M mutation positive.  
• To evaluate PFS-2. 
• To evaluate Overall Response Rate (ORR) to osimertinib. 
• To evaluate the Treatment duration. 
• To evaluate Time to progression (TTP) on osimertinib (measured from switching to osimertinib). 
• To evaluate Overall Survival (OS). 
• To evaluate brain progression free survival (BPFS). 
• Safety. 
2.3 
Exploratory objectives 
• To assess the feasibility of prospective cfDNA T790M mutation testing during treatment with gefitinib 
as a predictor of treatment progression and its correlation with RECIST 1.1 progression.  
• To assess the feasibility of prospective cfDNA T790M mutation testing during treatment with 
osimertinib as a predictor of efficacy. 
• To assess the change in tumor size upon switching to osimertinib. 
• To describe the treatments and outcomes of the treatments administered after osimertinib. 
• To evaluate the resistance mechanisms to osimertinib (by optional biopsy at disease progression on 
osimertinib). 

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• To evaluate osimertinib efficacy in patients with acquired resistance to gefitinib based on RECIST 
progression with blinded T790M status.  
• To monitor the activating EGFR mutation levels in cfDNA. 
2.4 
Endpoints 
2.4.1 
Primary endpoint 
PFS Rate at 18 months. Details and definition of the primary endpoint can be found in Section 7.2.1 
2.4.2 
Secondary endpoints 
• PFS measured from switching to osimertinib by RECIST criteria 1.1 [Ref. 33]. 
• Proportion of patients receiving osimertinib based on the determination of cfDNA T790M mutation 
positive.  
• Time to progression on osimertinib. 
• PFS-2. 
• Overall Response Rate (ORR) to osimertinib. 
• Treatment duration. 
• Overall Survival (OS). 
• Brain progression free survival (BPFS). 
• Safety. 
2.4.3 
Exploratory endpoints 
• Prospective for cfDNA T790M mutation testing on treatment with gefitinib;  
• Prospective for cfDNA T790M mutation testing on treatment with osimertinib; 
• PFS and OS taking into account treatments administered after osimertinib; 
• Resistance mechanisms to osimertinib;  
• RECIST 1.1 progression to osimertinib with blinded T790M status [Ref. 33]. 
• Activating EGFR mutation levels in cfDNA. 
3 Patient selection criteria 
3.1 
Inclusion criteria  
3.1.1 
Registration 
• Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations 
associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations 
will be allowed. In case of other (than EGFR) concomitant mutations, discussion with EORTC 
Headquarters is mandatory; 
• Stage IV NSCLC; 
• Blood sample available for cfDNA EGFR T790M central testing; 
• Adequate tissue sample in quantity and quality for translational research; 
• Age ≥18 years; 
• EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI; 
• Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational 
agents) if performed more than 12 months before registration; 
• Before patient registration, written informed consent must be given according to ICH/GCP, and 
national/local regulations. 

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Maximum time elapsed between registration and treatment start should be four weeks, although every 
effort should be made to start treatment as quickly as possible. 
3.1.2 
Randomization 
• Report of adequacy sample for cfDNA EGFR T790M test by central laboratory; 
• Prior palliative radiotherapy or surgical procedures are allowed if completed at least 4 weeks before 
randomization; 
• Patients with brain metastases are allowed provided they are stable (i.e. without evidence of 
progression by imaging for at least two weeks prior to the first dose of trial treatment and without 
deterioration of any neurologic symptoms), and have not received steroids for at least 7 days before 
randomization; 
• Baseline tumor assessment scans are done within 21 days before randomization; 
• Evaluable disease as defined below; 
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening 
period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except 
lymph nodes which must have a short axis of ≥15 mm) with computed tomography (CT) or 
magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.  
• WHO Performance Status 0-2, with no clinically significant deterioration over the previous 2 weeks 
and a minimum life expectancy of 12 weeks; 
• Adequate bone marrow, renal, hepatic and liver function within 21 days from randomization and 
defined as follows: 
• Absolute neutrophil count ≥1.5 x 109/L; 
• Platelet count ≥100 x 109/L; 
• Hemoglobin ≥9 g/dL; 
• Alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN) if no demonstrable liver 
metastases or ≤5xULN in the presence of liver metastases; 
• Aspartate aminotransferase (AST) ≤2.5xULN if no demonstrable liver metastases or ≤5xULN in the 
presence of liver metastases; 
• Total bilirubin ≤1.5xULN if no liver metastases or ≤3xULN in the presence of documented Gilbert’s 
Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; 
• Serum Creatinine ≤1.5xULN concurrent with creatinine clearance ≥50 mL/min (measured or 
calculated by Cockcroft and Gault equation);  
• No significant comorbidity that according to the investigator would hamper the participation on the 
trial; 
• Female patients should be using adequate contraceptive measures as defined by the investigator, 
during the treatment until 6 weeks after last dose of osimertinib. They should not be breastfeeding, 
until 12 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to 
first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-
bearing potential by fulfilling one of the following criteria at screening: 
• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months 
following cessation of all exogenous hormonal treatments. 
• Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 
12 months or more following cessation of exogenous hormonal treatments and with luteinizing 
hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the 
institution. 

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• Documentation of irreversible surgical sterilization by hysterectomy, bilateraloophorectomy, or 
bilateral salpingectomy but not tubal ligation. 
• Male patients should be willing to use barrier contraception, i.e., condoms as defined by the 
investigator, during the treatment until 4 months after last dose of osimertinib.  
• Male patients will be advised to arrange for the freezing of sperm samples prior to the start of the 
study should they wish to father children, and not to donate sperm until 6 months after 
discontinuation of study treatment. (as per Investigator Brochure, IB) 
• Absence of any psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should be discussed 
with the patient before registration in the trial. 
Important note: All eligibility criteria must be adhered to, in case of deviation discussion with 
Headquarters and study coordinator is mandatory. Patients with a buffer range from the normal values 
of +/- 5 % for hematology and +/- 10% for biochemistry are acceptable. A +/- 3 days deviation is also 
allowed except for the pregnancy test. 
3.2 
Exclusion criteria at randomization 
• Treatment with any of the following: 
• Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC 
including chemotherapy, biologic therapy, immunotherapy, or any investigational drug; 
• Prior treatment with an EGFR-TKI; 
• Major surgery (excluding placement of vascular access) within 4 weeks before randomization; 
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation 
within 4 weeks before randomization. 
• Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of 
study drug) medications or herbal supplements known to be potent inhibitors or inducers of 
cytochrome P450 (CYP) 3A4 (see Appendix E); antiacids could be taken in a time-separate manner, at 
least 8 hours from gefitinib. 
• Other anti-cancer therapies and alternative medications such as homeopathy, etc;  
• Treatment with an investigational drug within five half-lives of the compound or any of its related 
material, if known; 
• Leptomeningeal carcinomatosis; spinal cord compression;  
• Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than 
CTCAE grade 2 at the time of randomization; 
• Patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin 
cancer or localized cervical cancer or localized and presumed cured prostatic cancer) within 2 years 
before randomization and are not receiving specific treatment for these malignancies at baseline 
assessment; 
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and 
active bleeding diatheses, which in the Investigator’s opinion makes it undesirable for the patient to 
participate in the trial or which would jeopardize compliance with the protocol;  
• Active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Active 
infection will include any patients receiving intravenous treatment for infection; active hepatitis B 
infection will, at a minimum, include all patients who are Hepatitis B surface antigen positive (HbsAg 
positive) based on serology assessment. Screening for chronic conditions is not required;  

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• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated 
product, or previous significant gastrointestinal resection that would preclude adequate absorption of 
osimertinib or gefitinib; 
• Any of the following cardiac criteria: 
• Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs using local clinic ECG 
machine-derived QTcF value 
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., 
complete left bundle branch block, third-degree heart block, second-degree heart block, PR 
interval >250 msec or history of episodes of bradycardia (<50 BPM); 
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart 
failure, hypokalaemia, congenital long QT síndrome family history of long QT syndrome, or 
unexplained sudden death under 40 years of age in first-degree relatives or any concomitant 
medication known to prolong the QT interval. 
• Abnormal cardiac function: LVEF <50% (assessed by MUGA or ECHO) 
• Past medical history of ILD (Interstitial Lung Disease), drug-induced ILD, radiation pneumonitis which 
required steroid treatment, or any evidence of clinically active ILD. 
4 Trial Design 
This is an open-label, randomized, three-armed, multicentric, phase II study in EGFR mutant advanced 
NSCLC patients. 
Patients will first be registered into the EORTC ORTA system (registration = step 1) after signing the 
informed consent form and completion of all screening tests and confirmation of eligibility criteria for 
registration. The site will immediately send the blood samples for circulating free DNA EGFR T790M 
(cfDNA T790M) testing to the central lab (within 24 hours at maximum) at the Medical University of 
Gdansk (Poland). Once the sample is assessed and acknowledged for adequacy by the central lab, the 
result is entered in ORTA by EORTC (step 2), the site will be notified whether they can further proceed to 
patient randomization in the EORTC ORTA system. Should the sample not be deemed adequate by the 
central lab the site will be requested to send another blood sample for testing. Patients will be 
randomized (step 3) after verification of all eligibility criteria to receive one of the following:  
• Osimertinib (arm A) until PD according to RECIST 1.1; 
• Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") (arm B) 
followed by osimertinib until second PD according to RECIST 1.1;  
• Gefitinib until PD according to RECIST 1.1 followed by osimertinib until PD according to RECIST 1.1 
(arm C).  
In arm B, if patients have RECIST 1.1 progression without cfDNA T790M positive test, they will be 
switched to osimertinib.  
As of protocol v. 4.0, the T790M tests no longer need to be performed in arms A, B or C, including in Arm 
B for patients still on gefitinib. These patients should continue on gefitinib until progression by RECIST 1.1 
as in Arm C. 
Maximum time elapsed between registration and treatment start should be four weeks, although every 
effort should be made to start treatment as quickly as possible. Basal cfDNA T790M status was blinded in 
arms A and C, and only reported in arm B during the first part of treatment (gefitinib period until disease 
progression). During osimertinib treatment, T790M status was blinded in the three arms of the study - 
progression of disease on osimertinib is defined according RECIST 1.1 criteria. 

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4.1 
Treatment beyond progression 
The local investigator may choose to continue treatment with osimertinib beyond RECIST 1.1 PD, if, in 
their opinion, the patient continues to receive clinical benefit. However, this should be discussed with the 
EORTC HQ. Information on post-PD treatment needs to be provided to EORTC HQ and follow-up must 
follow chapter 6 according to the treatment arm. 
In case of oligo-progressive disease (please refer to chapter 0) in a known metastatic lesion local therapy 
(radiotherapy / surgery / cryotherapy) will be allowed after mandatory discussion with EORTC 
headquarters. This procedure will be reported in the CRF. Information on post-PD treatment needs to be 
provided to EORTC HQ and follow-up must follow chapter 6 according to the treatment arm. 
5 Therapeutic regimens, expected toxicity, dose 
modifications 
Osimertinib (AZD9291) and gefitinib are considered as Investigational Medicinal Products. 
5.1 
Osimertinib 
5.1.1 
General information 
DrugBank number: DM09330 
Other names: AZD9291 
Trade name: Tagrisso 
Molecular weight: 499.62 
Description: orally taken, beige, filmcoated tablet containing 40 mg or 80 mg of osimertinib expressed as 
free base (equivalent of 47.7 mg or 95.4 mg of osimertinib mesalate).  
Osimertinib (TAGRISSO ™1, laboratory code AZD9291) is an oral, irreversible inhibitor of the tyrosine 
kinase activity of the epidermal growth factor receptor activating mutation (EGFRm) and the resistance 
mutation (T790M) specifically. 
For more general information related to osimertinib please refer to the latest version of the Investigator 
Brochure. 

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5.1.2 
Drug supply 
Drug supplies and re-supplies will be provided free of charge by 
 (for procedures: see study 
drug guidelines that will be provided at the time of activation). 
The osimertinib drug product is provided in the high-density polyethylene bottles, 35 tablets per bottle.  
All instructions pertaining to drug management and drug supply can be found in the study drug 
guidelines (provided as a separate document). 
5.1.3 
Packaging, dispensing and storage 
Drug labels will comply with good manufacturing practice (GMP) and will be printed in the national 
language. The storage conditions for study drug will be described on the medication label. 
Osimertinib must be stored at room temperature (between 15-30◦C or 59-86◦F). 
Osimertinib tablets should not be used beyond the expiration date provided by the manufacturer.  
Study drug will be prepared and dispensed by the pharmacist at the investigator’s institution. The 
pharmacy must maintain an individual record for the patient.  
The clinical trial centers will keep a trial specific authorization list which determines the persons 
responsible for handling of the investigational drugs. The responsible person will follow the standard 
practice and directive (Annex 13).  
For more information regarding the packaging, storage and dispensing of osimertinib please refer to the 
latest version of the Investigator Brochure and the drug guidelines. 
5.1.4 
Drug reconciliation procedures 
Accountability of the investigational study drug(s) is under the responsibility of the investigator and can 
be delegated to an appropriately qualified person. 
Study drug accountability should be maintained by each site.  
In addition to internal accountability documentation on site, EORTC study-specific accountability and 
drug destruction forms will be supplied for this purpose, if site-specific forms are deemed not sufficiently 
detailed or do not provide enough information, according to EORTC Quality Assurance criteria. 
The drug accountability and destruction forms will be verified during monitoring visits. 
At the end of study, when all patients have stopped protocol treatment, complete drug reconciliation per 
batch should be available at the site for verification by EORTC in order to allow drug destruction or return 
procedure. 
Both the unused and expired study medication must be destroyed, upon authorization of the sponsor, 
according to local regulations and procedures, and a copy of the destruction form must be returned to 
the EORTC HQ. 
The medication provided for this trial is to be used only as indicated in this protocol and only for the 
patients entered in this study. 
5.2 
Gefitinib 
5.2.1 
General information 
DrugBank number: DM00317 
Other names: ZD1839 

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Trade name: IRESSA 250 
Molecular weight: 446.90 
Description: orally taken, brown, round, biconvex tablets containing 250 mg of gefitinib  
Gefitinib (IRESSA™, laboratory code) is an oral, reversible inhibitor of the tyrosine kinase activity of the 
epidermal growth factor receptor activating mutation (EGFRm). 
For more general information related to gefitinib please refer to the latest version of the Summary of 
Product Characteristics (SmPC). 
5.2.2 
Drug supply 
Drug supplies and re-supplies will be provided free of charge by 
 (for procedures: see study 
drug guidelines that will be provided at the time of activation). 
Gefitinib is provided in in the high-density polyethylene bottles, 30 tablets per bottle. 
All instructions pertaining to drug management can be found in the study drug guidelines (provided as a 
separate document). 
For more information regarding the supply of gefitinib please refer to the latest version of the SmPC. 
5.2.3 
Packaging, dispensing and storage 
Drug labels will comply with the good manufacturing practice (GMP) and will be printed in the national 
language. The storage conditions for study drug will be described on the medication label. 
Gefitinib must be stored at room temperature (between 15-30◦C or 59-86◦F). 
Gefitinib tablets should not be used beyond the expiration date provided by the manufacturer.  
Study drug will be prepared and dispensed by the pharmacist at the investigator’s institution. The 
pharmacy must maintain an individual record for the patient. 
The clinical trial centers will keep a trial specific authorization list which determines the persons 
responsible for handling of the investigational drugs. The responsible person will follow the standard 
practice and directive (Annex 13).  
For more information regarding the packaging, storage and dispensing of gefitinib please refer to the 
latest version of the SmPC. 
5.2.4 
Drug reconciliation procedures 
Accountability of the investigational study drug(s) is under the responsibility of the investigator and can 
be delegated to an appropriately qualified person. 
Study drug accountability should be maintained by each site.  
In addition to internal accountability documentation on site, EORTC study-specific accountability and 
drug destruction forms will be supplied for this purpose, if site-specific forms are deemed not sufficiently 
detailed or do not provide enough information, according to EORTC Quality Assurance criteria. 
The drug accountability and destruction forms will be verified during monitoring visits. 
At the end of study, when all patients have stopped protocol treatment, complete drug reconciliation per 
batch should be available at the site for verification by EORTC in order to allow drug destruction or return 
procedure. 

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Both the unused and expired study medication must be destroyed, upon authorization of the sponsor, 
according to local regulations and procedures, and a copy of the destruction form must be returned to 
the EORTC HQ.  
The medication provided for this trial is to be used only as indicated in this protocol and only for the 
patients entered in this study. 
5.3 
Initial dose and schedule 
Advanced EGFR mutant NSCLC and EGFR-TKI naïve patients, will be randomized to: 
• Arm A: osimertinib 80 mg QD until RECIST 1.1 progression. 
• Arm B: gefitinib 250mg QD until cfDNA T790M positive test (criteria for defining progression disease), 
irrespective of RECIST 1.1 criteria, then patients will receive osimertinib 80 mg QD until RECIST 1.1 
progression. If patients have RECIST 1.1 progression without cfDNA T790M positive test, they will be 
switched to osimertinib.  
• Arm C: gefitinib 250mg QD until RECIST 1.1 progression, irrespective of cfDNA T790M test, then 
patients will receive osimertinib 80 mg QD until RECIST 1.1 progression. 
Continuation of osimertinib post-PD is allowed on individual basis provided that in the opinion of treating 
physician, patient may benefit from this therapy (please refer also to section 4.1). 
Osimertinib or gefitinib must be swallowed with a glass of water and must not be mashed or chewed. The 
tablets can be taken preferably in the morning with or without meals 
The initial dose of osimertinib 80 mg once daily can be reduced to 40 mg once daily. The initial dose for 
gefitinib (250 mg once daily) cannot be reduced to a lower dose. 
5.4 
Treatment duration 
• In ARM A (osimertinib): Treatment should be administered until documented disease progression by 
RECIST 1.1 criteria, unacceptable toxicity, or patient refusal. Continuation of osimertinib post-PD is 
allowed on individual basis provided that in the opinion of treating physician, patient may benefit 
from this therapy. 
• In ARM B (gefitinib): Treatment should be administered until RECIST 1.1 progression at which point 
osimertinib will be started. In case of unacceptable toxicity to any of both drugs or patient refusal, 
treatment can be discontinued. Continuation of osimertinib post-PD is allowed on individual basis 
provided that in the opinion of treating physician, patient may benefit from this therapy. 
• In ARM C (gefitinib): Treatment should be administered until documented disease progression by 
RECIST 1.1 criteria, unacceptable toxicity, or patient refusal. Then patients will receive osimertinib 
until RECIST 1.1 progression. In case of unacceptable toxicity to any of both drugs or patient refusal, 
treatment can be discontinued. Continuation of osimertinib post-PD is allowed on individual basis 
provided that in the opinion of treating physician, patient may benefit from this therapy. 
5.5 
Withdrawal criteria 
Whatever the disease status, the treatment will always be discontinued in case of 
• AE or intercurrent illness that, in the opinion of the investigator, warrants the patient’s withdrawal 
from study treatment;  
• Patient refusal or lost to follow-up; 
• Excessive toxicity precluding further therapy, according to the responsible physician; 
• Any adverse events specified as a reason for permanent discontinuation as defined in the guidelines 
for dose modification due to AE in section 5.6 and subsections 

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• Significant non-compliance/non-adherence with the protocol schedule in the opinion of the 
investigator or the sponsor; 
• PD according to RECIST 1.1 to osimertinib; continuation of osimertinib post-PD is allowed on 
individual basis provided that in the opinion of treating physician, patient may benefit from this 
therapy; 
• Pregnancy; 
• Start of a new anticancer treatment. 
Patients discontinuing therapy not according to the protocol should not receive any other cancer 
treatment before their disease progresses, unless this is clearly not in the interest of the patient 
according to the local investigator. 
After progression to osimertinib, the treatment will be left to the discretion of the treating physician. Any 
anti-cancer therapy other than the study drug given as single agent will not be considered as part of the 
protocol treatment. 
5.6 
Dose and schedule modifications 
Dose modifications are required only for toxicities that are not considered to the disease or disease-
related processes under investigation. Dose modifications are not required for events that are not 
considered clinically significant such as isolated laboratory abnormalities, alopecia. 
Note: Persistent grade 1 AE, lasting longer than 10 days under appropriate treatment, should be 
considered and treated as a grade 2 event. 
5.6.1 
Osimertinib 
All patients start treatment with osimertinib at 80 mg daily irrespective if the patient received osimertinib 
as first-line treatment or as sequential treatment after gefitinib. Only 1 dose reduction with osimertinib 
(to 40 mg) will be allowed during the study.  
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade) not 
attributable to the disease or disease-related processes under investigation, where the Investigator 
considers the AE of concern to be specifically associated with the study drug 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 within 3 weeks of onset, study drug may be restarted 
at the same dose (starting dose) or a lower dose (40 mg) using the rules below for dose modification 
(Table "Recommended dose modifications with osimertinib). There will be no individual modifications to 
dosing schedule in response to toxicity, only potential dose reduction or dose interruption. If restarting at 
the same dose level, patients should be closely monitored for 3 days following the restart of treatment. If 
within 3 days there is recurrence of same toxicity, a dose reduction should be considered at the 
Investigator’s discretion. 
If the toxicity does not resolve to ≤CTCAE grade 2 after 3 weeks of withholding osimertinib, then the 
patient should be withdrawn from the study treatment and observed until resolution of the toxicity. 
There will be no individual modifications to treatment schedule in response to toxicity, only potential 
dose reduction or dose interruption. 
If an AE subsequently requires dose interruption, study drug may restart at the same dose or the reduced 
dose, on resolution/improvement of the AE at the discretion of the investigator as described above. 
 
 

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Recommended dose modifications with osimertinib 
Target Organ 
Adverse reaction 
Modification 
Pulmonary 
Interstitial lung disease 
(ILD)/Pneumonitis 
Permanently discontinue 
osimertinib 
Cardiac 
QTc† interval greater than 500 
msec on at least 2 separate 
ECGsb 
Withhold osimertinib until QTc 
interval is less than 481 msec or 
recovery to baseline if baseline 
QTc is greater than or equal to 
481 msec within 3 weeks of 
withholding osimertinib, then 
resume at 40 mg dose 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 
Permanently discontinue 
osimertinib 
Asymptomatic, absolute 
decrease in LVEFc of 10% from 
baseline and below 50% 
Withhold osimertinib for up to 2 
weeks. 
• If improved to baseline LVEF, 
resume. 
• If not improved to baseline, 
permanently discontinue. 
Symptomatic congestive heart 
failure 
Permanently discontinue 
osimertinib 
Other 
Grade 3 or higher adverse 
reaction  
Withhold osimertinib for up to 3 
weeks 
If improvement to Grade 1 
within 3 weeks  
Resume at 80 mg or 40 mg daily 
If no improvement to Grade1 
within 3 weeks 
Permanently discontinue 
osimertinib 
5.6.1.1 
Interstitial Lung Disease (ILD)/pneumonitis like toxicity 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive of 
interstitial lung disease/pneumonitis is observed, an interruption in study treatment dosing is 
recommended, and the Sponsor 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 hemorrhage. The 
results of full diagnostic workup (including high-resolution computed tomography (HRCT), blood and 
sputum culture, hematological parameters) will be captured by eCRF. 

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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. 
5.6.1.2 
QTc prolongation 
In light of the potential for QT changes associated with osimertinib, electrolyte abnormalities 
(hypokalemia, hypomagnesaemia, hypocalcemia) must be corrected to be within normal ranges prior to 
first dose and electrolyte levels monitored during study treatment. 
Patients with QTcF prolongation to >500 msec should have study treatment interrupted and regular ECGs 
performed until resolution to <481 msec or recovery to baseline if baseline QTcF is >481 msec and then 
restarted at a reduced dose of 40 mg, or 80mg at the discretion of the investigator. If the toxicity does 
not resolve to ≤ grade 1 within 21 days of withholding osimertinib the patient will be permanently 
withdrawn from study treatment. 
5.6.1.3 
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. 
5.6.1.4 
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. 
5.6.1.5 
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 LVEF, 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. 
5.6.1.6 
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. 
5.6.2 
Gefitinib 
The initial dose for gefitinib (250 mg once daily) cannot be reduced to a lower dose. The dose of gefitinib 
may be withheld or discontinued if clinically indicated at the discretion of the Investigator 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade) not 
attributable to the disease or disease-related processes under investigation, where the Investigator 

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considers the AE of concern to be specifically associated with the study drug dosing will be interrupted 
and optimal supportive therapy administered as required in accordance with local practice/guidelines. 
If the toxicity resolves or reverts to CTCAE grade to baseline within 2 weeks of onset, study drug may be 
restarted at the same dose. If restarting at the same dose level, patients should be closely monitored for 
3 days following the restart of treatment. If within 3 days there is recurrence of same toxicity patient 
should be withdrawn from the study treatment and observed until resolution of the toxicity. 
For Grade 2 dermatological events, dosing may be continued at investigator discretion with optimal and 
appropriate supportive therapy administered as required in accordance with local practice / guidelines. 
5.7 
Concomitant treatments 
5.7.1 
Osimertinib 
The use of any natural/herbal products or other “folk remedies” should be discouraged, but use of these 
products, as well as use of all vitamins, nutritional supplements, and all other concomitant medications 
must be recorded in the eCRF. In vitro data have shown that the principal CYP enzyme responsible for the 
Phase I metabolism of osimertinib is CYP3A4.Once enrolled all patients must try to avoid concomitant use 
of medications, herbal supplements and/or ingestion of foods that are known to be potent inducers of 
CYP3A4 whenever feasible, but patients may receive any medication that is clinically indicated for 
treatment of adverse events. Such drugs must have been discontinued for an appropriate period before 
they enter screening and for a period of 3 months after the last dose of osimertinib. 
All concomitant medications should be captured on the eCRF. Guidance on medicines to avoid, 
medications that require close monitoring and on washout periods is provided (see Appendix E). 
If medically feasible, patients taking regular medication, with the exception of potent inducers of CYP3A4 
(see above), should be maintained on it throughout the study period. Patients taking concomitant 
medications whose disposition is dependent upon BCRP and which have a narrow therapeutic index 
should be closely monitored for signs of changed tolerability as a result of increased exposure of the 
concomitant medication whilst receiving osimertinib. Guidance on medications to avoid, medications 
that require close monitoring and on washout periods is provided (see Appendix E). 
Patients taking rosuvastatin should have creatine phosphokinase levels monitored (due to BCRP 
mediated increase in exposure). If the patient experiences any potentially relevant AEs suggestive of 
muscle toxicity including unexplained muscle pain, tenderness, or weakness, particularly if accompanied 
by malaise or fever, rosuvastatin must be stopped and any appropriate further management should be 
taken. 
Please refer to Appendix E for any further information on guidance for concomitant medications. 
5.7.2 
Gefitinib 
Gefitinib is metabolized by the CYP3A4 and the CYP2D6. 
Drugs which inhibit CYP3A4 activity (ketoconazole, posaconazole, voriconazole, proteasome inhibitors, 
claritromicin, telitromicine) might increase plasmatic concentrations of gefitinib. There are no data about 
the concomitant treatment with drugs that inhibit CYP2D6. 
Plasmatic dose of gefitinib can be reduced when is administered concomitantly with drugs which increase 
CYP3A4 activity such as: phenytoin, rifampicin, barbiturates or St John’s Wort. 
Antiacids such as omeprazole can increase the gastric pH and it reduces plasmatic concentrations of 
gefitinib. Omeprazol and other proton pump inhibitors cannot be used in combination with gefitinib.  

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Those patients under treatment with warfarin should be monitored as per standard practice because 
there is an increased risk of hemorrhagic events or INR alteration. 
5.7.3 
Supportive care in case of toxicity 
Please refer to Appendix F. 
5.7.4 
Other concomitant therapies 
In case of RECIST 1.1 progression on a known lesion during osimertinib treatment, surgery, radiotherapy 
and cryotherapy will be allowed. 
No other systemic anticancer therapies will be allowed. 
Administration of Covid vaccine will be a treating physician decision after evaluation of benefit-risk ratio 
and depending of local vaccine availability and compliance with local regulatory guidelines. In cancer 
patients, the use of inactivated virus vaccines are usually permitted and live vaccines are generally 
prohibited in those receiving immunosuppressive treatments. Information on the mRNA based COVID-19 
vaccines when used in cancer patients is currently not available. See Appendix F for EMA 
recommendations. 
6 Clinical evaluation, laboratory tests and follow-up 
As described in chapter 4, a cycle of treatment is defined as 28 days of once daily treatment with 
osimertinib or gefitinib.  
In arm A, after 24 weeks, the duration between study visits will change from every 28 days (4 weeks) to 
every 56 days (8 weeks).  
In arm B and C, study visits will be every 28 days (4 weeks) until the switch to osimertinib. After that, one 
visit will be performed 28 days after osimertinib initiation, the second one at 8 weeks with radiological 
evaluation and then every 56 days (8 weeks) if no progression on the first CT scan after osimertinib 
initiation. 
6.1 
Arm A 
6.1.1 
Before randomization  
Baseline assessments need to be performed within 21 days prior to randomization: 
• Signature of the informed consent; 
• Assessment of eligibility criteria; 
• Assessment of the baseline signs and symptoms and adverse events based on CTCAE version 4.0, 
performance status and medical history; 
• Collection of concomitant medication; 
• Demographics, physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: white blood cell (WBC) with differential count, platelets (PLTs), hemoglobin (Hb);  
• biochemistry: blood urea nitrogen (BUN), serum creatinine and calculated creatinine clearance (by 
Cockcroft), uric acid, albumin, total bilirubin, Alkaline Phosphatase (AP), Aspartate 
AminoTransferase (AST/ASAT), Alanine AminoTransferase (ALT/ALAT), Gamma-Glutamyl 
Transferase (GGT), sodium, potassium, Lactic Dehydrogenase (LDH), total calcium, phosphorus, 
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Note: * Electrolyte abnormalities (hypokalemia, hypomagnesaemia, hypocalcemia) must be 
corrected to be within normal ranges prior to first dose and electrolyte levels monitored during 
study treatment. 
• Beta HCG (serum) for women of childbearing potential. This test must be negative within 72h 
before first dose of treatment; 
• Stick urinalysis;  
• Digital ECG with QTc interval; no alteration in QTc interval should be reported before osimertinib 
initiation;  
• LVEF assessed by MUGA or ECHO 
• Collection of plasma sample for central T790M status; 
• Collection of tumor sample for translational research (please refer to section 10.2); 
• Thoracic and upper abdomen contrasted-enhanced CT scan (including adrenal glands) and brain CT 
scan; if a patient is allergic to contrast adequate premedication as per local practice should be 
provided. Should there be any further constraint, the EORTC Headquarters should be contacted as 
soon as possible. 
• Ophthalmological examination; 
• Geriatric G8 assessment for 70 years old patients or older. 
6.1.2 
During treatment 
In women of childbearing potential, pregnancy test (serum or urine beta HCG) is to be performed every 4 
weeks (+/- 2 days) or more frequently if required by national regulations/institution guidelines. 
6.1.2.1 
Every 4 weeks (+/- 2 days) for the first 24 weeks 
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1;  
• Collection of plasma sample for central T790M status to be performed every 28 days during all 
treatment duration independently of medical visits. The results of this test will be blinded for the 
investigator; 
• Digital ECG with QT interval; 
• Ophthalmological examination if clinically indicated. 
6.1.2.2 
At week 12 (+/- 2 days) 
• LVEF assessed by MUGA or ECHO 
6.1.2.3 
Every 8 weeks (+/-3 days) after week 24  
After week 24, the duration between study visits will change from every 28 days (4 weeks) to every 56 
days (8 weeks) until discontinuation of osimertinib, please refer to criteria sections 5.4 and 5.5. 
Radiological evaluation will follow section 6.1.2.4. 
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 

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• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1. 
• Digital ECG with QT interval; 
• LVEF assessed by MUGA or ECHO if clinically indicated 
• Ophthalmological examination if clinically indicated. 
6.1.2.4 
Radiological evaluation every 8 weeks (+/- 7 days), first scan at 8 
weeks after baseline scan 
Tumor assessments by thoracic and upper abdomen contrasted-enhanced CT scan (including adrenal 
glands) and brain CT scan every 8 weeks independently of delayed or interrupted doses. If a patient is 
allergic to contrast adequate premedication as per local practice should be provided. Should there be any 
further constraint, the EORTC Headquarters should be contacted as soon as possible. 
The same schedule for radiologic assessment needs to be performed until both criteria are met: 
• end of osimertinib treatment; 
• the second documented, RECIST 1.1 radiological progression. 
6.1.3 
At the end of treatment 
Treatment is continued until objective PD to osimertinib according to RECIST 1.1, or other discontinuation 
criteria are met (such as toxicity, patient refusal, etc) please refer to sections 5.4 and 5.5. 
When the treatment is decided to be permanently stopped, an end of treatment visit needs to be 
performed at 30 days after last protocol treatment (+/- 7 days) and the following assessments are 
required: 
• Adverse event collection; 
• Performance Status and clinical examination including vital signs, height, weight and blood pressure; 
• Collection of concomitant medication; 
• In case objective progression as per RECIST 1.1 and an optional tissue biopsy can be performed, 
results will be collected in the study. 
A 28-day follow-up LVEF assessment by MUGA or ECHO will be required if an on-treatment assessment 
was abnormal at the time of discontinuation of study treatment, to confirm reversibility of the 
abnormality. 
Patients who discontinue study drug for reasons other than objective disease progression will 
additionally continue assessments for objective PD; please refer to section 6.1.2.4. 
6.1.4 
During Follow-up 
After end of treatment, patients will be followed up every 8 weeks for: 
• Any anti-cancer therapy administered after osimertinib. Response to new anti-cancer therapy will be 
collected if available; 
• Survival status; 
• Complementary examination will be performed according local physician standards. 
• Contrast-enhanced CT scan of the thorax and upper abdomen and brain CT scan should be performed 
every 8 weeks until a second progression as per RECIST 1.1. If a patient is allergic to contrast 
adequate premedication as per local practice should be provided. Should there be any further 
constraint, the EORTC Headquarters should be contacted as soon as possible. 

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6.2 
Arm B 
6.2.1 
Before randomization 
Baseline assessments need to be performed within 21 days prior to randomization: 
• Signature of the informed consent; 
• Assessment of eligibility criteria; 
• Assessment of the baseline signs and symptoms and adverse events based on CTCAE version 4.0, 
performance status and medical history; 
• Collection of concomitant medication; 
• Demographics, physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please refer to section 6.1.1; 
• biochemistry: please refer to section 6.1.1; 
• Beta HCG (serum) for women of childbearing potential. This test must be negative within 72h 
before first dose of treatment; 
• Stick urinalysis.  
• Digital ECG with QT interval; no alteration in QT interval should be reported before osimertinib 
initiation;  
• LVEF assessed by MUGA or ECHO 
• Collection of plasma sample for central T790M status; 
• Collection of tumor sample for translational research (please refer to section 10.2); 
• Thoracic and upper abdomen contrasted-enhanced CT scan (including adrenal glands) and brain CT 
scan; if a patient is allergic to contrast adequate premedication as per local practice should be 
provided. Should there be any further constraint, the EORTC Headquarters should be contacted as 
soon as possible. 
• Geriatric G8 assessment for 70 years old patients or older. 
6.2.2 
During treatment on gefitinib 
6.2.2.1 
Every 8 weeks (+/- 2 days)  
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1; 
• Pregnancy test: serum (or urine) beta HCG in women of childbearing potential or more frequently 
if required by national regulations/institution guidelines. 
6.2.2.2 
Radiological evaluation every 8 weeks (+/- 7 days), first scan at 8 
weeks after baseline scan 
Tumor assessments by thoracic and upper abdomen contrasted-enhanced CT scan (including adrenal 
glands) and brain CT scan every 8 weeks independently of delayed or interrupted doses. If a patient is 
allergic to contrast adequate premedication as per local practice should be provided. Should there be any 
further constraint, the EORTC Headquarters should be contacted as soon as possible. 

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In case of disease progression according to RECIST 1.1 criteria, patients will be switched to osimertinib at 
the next per protocol planned medical visit (4 weeks since previous medical visit as per section 6.2.2.1). 
IMPORTANT: this every 8 week schedule remains in place, as per calendar, also after the switch to 
osimertinib. 
6.2.3 
During treatment on osimertinib 
Patients must stop gefitinib 48 hours before osimertinib initiation. 
In women of childbearing potential, pregnancy test (serum or urine beta HCG) is to be performed every 4 
weeks (+/- 2 days) or more frequently if required by national regulations/institution guidelines. 
6.2.3.1 
Day 1 cycle 1 (within 3 days prior to actual osimertinib dosing) 
• Adverse events and Performance Status assessment;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Collection of concomitant medication; 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1. 
• Digital ECG with QT interval;  
• LVEF assessed by MUGA or ECHO 
• Ophthalmological examination. 
6.2.3.2 
Every 4 weeks (+/-2 days) from week 1 until week 24 
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1. 
• Digital ECG with QT interval; 
• Ophthalmological examination if clinically indicated. 
6.2.3.3 
At week 12 (+/- 2 days)  
• LVEF assessed by MUGA or ECHO 
6.2.3.4 
Every 8 weeks (+/- 3 days) from week 24 
After week 24, the duration between study visits will change from every 28 days (4 weeks) to every 56 
days (8 weeks) until discontinuation of osimertinib, please refer to criteria sections 5.4 and 5.5. 
Radiological evaluation will follow section 6.2.3.5. 
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1. 

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• Digital ECG with QT interval; 
• LVEF assessed by MUGA or ECHO if clinically indicated 
• Ophthalmological examination if clinically indicated. 
6.2.3.5 
Radiological evaluation every 8 weeks (+/- 7 days), first scan at 8 
weeks after baseline scan 
Tumor assessments by thoracic and upper abdomen contrasted-enhanced CT scan (including adrenal 
glands) and brain CT scan every 8 weeks independently of delayed or interrupted doses. If a patient is 
allergic to contrast adequate premedication as per local practice should be provided. Should there be any 
further constraint, the EORTC Headquarters should be contacted as soon as possible. 
6.2.4 
At the end of treatment 
Treatment is continued until objective PD to osimertinib according to RECIST 1.1, or other discontinuation 
criteria are met (such as toxicity, patient refusal, etc) please refer to sections 5.4 and 5.5. 
When the treatment is decided to be permanently stopped, an end of treatment visit needs to be 
performed at 30 days after last protocol treatment (+/- 7 days) and the following assessments are 
required: 
• Adverse event collection; 
• Performance Status and clinical examination; 
• Collection of concomitant medication; 
• In case of objective progression on osimertinib by RECIST 1.1 an optional tissue biopsy can be 
performed, results will be collected in the study. 
A 28-day follow-up LVEF assessment by MUGA or ECHO will be required if an on-treatment assessment 
was abnormal at the time of discontinuation of study treatment, to confirm reversibility of the 
abnormality. 
Patients who discontinue study drug for reasons other than objective disease progression will 
additionally continue assessments for objective PD; please refer to section 6.2.5. 
6.2.5 
During Follow-up 
After end of treatment, patients will be followed up every 8 weeks for: 
• Any anti-cancer therapy administered after osimertinib. Response to new anti-cancer therapy will be 
collected if available; 
• Survival status; 
• Complementary examination will be performed according local physician standards. 
If treatment was interrupted without any objective PD per RECIST 1.1 being identified, follow-up will also 
include, until objective disease progression per RECIST 1.1: 
• Contrast-enhanced CT scan of the brain, thorax and upper abdomen performed every 8 weeks. If a 
patient is allergic to contrast adequate premedication as per local practice should be provided. 
Should there be any further constraint, the EORTC Headquarters should be contacted as soon as 
possible. 
 
 

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6.3 
Arm C  
6.3.1 
Before randomization 
Baseline assessments need to be performed within 21 days prior to randomization: 
• Signature of the informed consent; 
• Assessment of eligibility criteria; 
• Assessment of the baseline signs and symptoms and adverse events based on CTCAE version 4.0, 
performance status and medical history; 
• Collection of concomitant medication; 
• Demographics, physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please refer to section 6.1.1; 
• biochemistry: please refer to section 6.1.1; 
• Beta HCG (serum) for women of childbearing potential. This test must be negative within 72h 
before first dose of treatment; 
• Stick urinalysis.  
• Digital ECG with QT interval; no alteration in QT interval should be reported before osimertinib 
initiation;  
• LVEF assessed by MUGA or ECHO  
• Collection of plasma sample for central T790M status; 
• Collection of tumor sample for translational research (please refer to section 10.2); 
• Thoracic and upper abdomen contrasted-enhanced CT scan (including adrenal glands) and brain CT 
scan; if a patient is allergic to contrast adequate premedication as per local practice should be 
provided. Should there be any further constraint, the EORTC Headquarters should be contacted as 
soon as possible. 
• Geriatric G8 assessment for 70 years old patients or older. 
6.3.2 
During treatment on gefitinib 
6.3.2.1 
Every 8 weeks (+/- 2 days)  
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1; 
• Pregnancy test: serum (or urine) beta HCG in women of childbearing potential or more frequently 
if required by national regulations/institution guidelines. 
6.3.2.2 
Radiological evaluation every 8 weeks (+/- 7 days) 
Tumor assessments by brain, thoracic and upper abdomen contrasted-enhanced CT scan (including 
adrenal glands) every 8 weeks independently of delayed or interrupted doses. If a patient is allergic to 
contrast adequate premedication as per local practice should be provided. Should there be any further 
constraint, the EORTC Headquarters should be contacted as soon as possible. 

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In case of progression on gefitinib according RECIST 1.1 criteria, independently of T790M status, patients 
will be switched to osimertinib at the next per protocol planned medical visit (4 weeks since previous 
medical visit as per section 6.3.2.1). 
IMPORTANT: this every 8 week schedule remains in place, as per calendar, also after the switch to 
osimertinib. 
6.3.3 
During treatment on osimertinib 
In case of progression on gefitinib according RECIST 1.1 criteria, independently of plasmatic T790M 
status, patients must be switched to osimertinib at the next per protocol planned medical visit (4 weeks 
since previous medical visit as per section 6.3.2.1). 
Patients must stop gefitinib 48 hours before osimertinib initiation.  
In women of childbearing potential, pregnancy test (serum or urine beta HCG) is to be performed every 4 
weeks (+/- 2 days) or more frequently if required by national regulations/institution guidelines. 
6.3.3.1 
Day 1 cycle 1 (within 3 days prior to actual osimertinib dosing)  
• Adverse events and Performance Status assessment;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Collection of concomitant medication 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1. 
• Digital ECG with QT interval; 
• LVEF assessed by MUGA or ECHO  
• Ophthalmological examination. 
6.3.3.2 
Every 4 weeks (+/-2 days) from week 1 until week 24 
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 
• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1. 
• Digital ECG with QT interval; 
• Ophthalmological examination if clinically indicated. 
6.3.3.3 
At week 12 (+/- 2 days) 
• LVEF assessed by MUGA or ECHO 
6.3.3.4 
Every 8 weeks (+/- 3 days) from week 24 
After week 24, the duration between study visits will change from every 28 days (4 weeks) to every 56 
days (8 weeks) until discontinuation of osimertinib, please refer to criteria sections 5.4 and 5.5. 
Radiological examination will follow section 6.3.3.5. 
• Adverse events and Performance Status assessment; 
• Collection of concomitant medication;  
• Physical examination, including vital signs, height, weight and blood pressure; 

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• Laboratory examination including: 
• hematology: please see section 6.1.1; 
• biochemistry: please see section 6.1.1. 
• Digital ECG with QT interval; 
• LVEF assessed by MUGA or ECHO if clinically indicated 
• Ophthalmological examination if clinically indicated. 
6.3.3.5 
Radiological evaluation every 8 weeks (+/- 7 days), first scan at 8 
weeks after baseline scan 
Tumor assessments by thoracic and upper abdomen contrasted-enhanced CT scan (including adrenal 
glands) and brain CT scan every 8 weeks independently of delayed or interrupted doses. If a patient is 
allergic to contrast adequate premedication as per local practice should be provided. Should there be any 
further constraint, the EORTC Headquarters should be contacted as soon as possible. 
6.3.4 
At the end of treatment 
Treatment is continued until objective PD to osimertinib according to RECIST 1.1, or other discontinuation 
criteria are met (such as toxicity, patient refusal, etc) please refer to sections 5.4 and 5.5. 
When the treatment is decided to be permanently stopped, an end of treatment visit needs to be 
performed at 30 days after last protocol treatment (+/- 7 days) and the following assessments are 
required: 
• Adverse event collection; 
• Performance Status and clinical examination; 
• Collection of concomitant medication; 
• In case objective progression as per RECIST 1.1 and an optional tissue biopsy can be performed, 
results will be collected in the study. 
A 28-day follow-up LVEF assessment by MUGA or ECHO will be required if an on-treatment assessment 
was abnormal at the time of discontinuation of study treatment, to confirm reversibility of the 
abnormality. 
Patients who discontinue study drug for reasons other than objective disease progression will 
additionally continue assessments for objective PD; please refer to section 6.3.5. 
6.3.5 
During Follow-up 
After end of treatment, subjects will be followed up every 8 weeks for: 
• Any anti-cancer therapy administered after osimertinib. Response to new anti-cancer therapy will be 
collected if available; 
• Survival status. 
• Complementary examination will be performed according local physician standards. 
If treatment was interrupted without any objective PD per RECIST 1.1 being identified, follow-up will also 
include, until objective disease progression per RECIST 1.1: 
• Contrast-enhanced CT scan of the thorax and upper abdomen and brain CT scan performed every 8 
weeks; if a patient is allergic to contrast adequate premedication as per local practice should be 
provided. Should there be any further constraint, the EORTC Headquarters should be contacted as 
soon as possible. 
 

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6.4 
Summary tables 
6.4.1 
Arm A 
 
Before 
randomization 
During treatment 
At the end of 
treatment 
Follow-up 
 
From week 1 to week 24 
After week 24 
Every 4 weeks  
(+/- 2 days) 
Every 8 weeks  
(+/- 7 days) 
Every 8 weeks (+/- 7 days) 
Signature of Informed Consent 
x 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
Baseline symptom assessment 
x 
 
 
 
 
 
Concomitant medication 
x 
x 
 
x 
x 
 
AE and PS assessment 
x 
x 
 
x 
x 
 
Physical examination, including vital 
signs, height, weight and blood 
pressure 
x 
x 
 
x 
x 
 
Lab exam1 
x 
x 
 
x 
x 
 
Collection of plasma sample for 
central T790M status 
x 
x 
 
 
 
 
Collection of tissue sample 
x 
 
 
 
 
 
Pregnancy test2 
x2 
every 4 weeks (+/- 2 days) or more frequently if required by 
national regulations/institution guidelines. 
 
 
Stick urinanalysis 
x 
 
 
 
 
 
ECG 
x 
x 
 
x 
 
 
LVEF assessed by MUGA or ECHO 
x 
x4 
 
x5 
 
 
Imaging evaluation3 
x3 
 
x3 
x3 
x3 
x3 

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Before 
randomization 
During treatment 
At the end of 
treatment 
Follow-up 
 
From week 1 to week 24 
After week 24 
Every 4 weeks  
(+/- 2 days) 
Every 8 weeks  
(+/- 7 days) 
Every 8 weeks (+/- 7 days) 
Ophthalmological examination 
x 
x5 
 
x5 
x5 
 
G8 assessment6 
x6 
 
 
 
 
 
Survival status 
 
 
 
 
 
x 
Optional tissue biopsy 
 
 
 
 
x7 
 
1 hematology: white blood cell (WBC) with differential count, platelets (PLTs), hemoglobin (Hb); biochemistry: blood urea nitrogen (BUN), serum creatinine and calculated creatinine clearance (by 
Cockcroft), uric acid, albumin, total bilirubin, Alkaline Phosphatase (AP), Aspartate AminoTransferase (AST/ASAT), Alanine AminoTransferase (ALT/ALAT), Gamma-Glutamyl Transferase (GGT), sodium, 
potassium, Lactic Dehydrogenase (LDH), total calcium, phosphorus, magnesium, glucose 
2 the test must be negative within 72 hours before treatment start 
3 Contrasted enhanced CT scan of the thorax and upper abdomen (including adrenal glands) and brain CT scan. The same schedule for radiologic assessment needs to be performed until both criteria are 
met: (a) end of osimertinib treatment; (b) the second documented, RECIST 1.1 radiological progression.  
4 at week 12 on osimertinib and if clinically indicated 
5 if clinically indicated 
6 for 70 years old patients or older 
7 In case of RECISTS 1.1 progression 
 
 

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6.4.2 
Arm B 
 
Before 
randomization 
During treatment with 
gefitinib 
During treatment with osimertinib* 
At the end of 
treatment 
Follow-up 
From week 1 to week 24 
After week 24 
Every 8 weeks (+/- 7 days) 
Day 1 cycle 1** 
Every 4 weeks 
(+/- 2 days) 
Every 8 weeks 
(+/- 7 days) 
Every 8 weeks  
(+/- 7 days) 
Signature of Informed 
Consent 
x 
 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
Baseline symptom 
assessment 
x 
 
 
 
 
 
 
 
Concomitant medication 
x 
x 
x 
x 
 
x 
x 
 
AE and PS assessment 
x 
x 
x 
x 
 
x 
x 
 
Physical examination, 
including vital signs, 
height, weight and blood 
pressure 
x 
x 
x 
x 
 
x 
x 
 
Lab exam1 
x 
x 
x 
x 
 
x 
x 
 
Collection of plasma 
sample for central T790M 
status 
x 
 
 
 
 
 
 
 
Collection of tissue 
sample 
x 
 
 
 
 
 
 
 
Pregnancy test2 
x2 
 
every 4 weeks (+/- 2 days) or more frequently if required 
by national regulations/institution guidelines. 
 
 
Stick urinanalysis 
x 
 
 
 
 
 
 
 
ECG 
x 
 
x 
x 
 
x 
 
 

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Before 
randomization 
During treatment with 
gefitinib 
During treatment with osimertinib* 
At the end of 
treatment 
Follow-up 
From week 1 to week 24 
After week 24 
Every 8 weeks (+/- 7 days) 
Day 1 cycle 1** 
Every 4 weeks 
(+/- 2 days) 
Every 8 weeks 
(+/- 7 days) 
Every 8 weeks  
(+/- 7 days) 
LVEF assessed by MUGA 
or ECHO 
x 
 
x 
x4 
 
x5 
 
 
Imaging evaluation3 
x3 
x3 
 
 
x3 
x3 
x3 
x3 
Ophthalmological 
examination 
 
 
x 
x5 
 
x5 
x5 
 
G8 assessment6 
x6 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
x 
Optional tissue biopsy 
 
 
 
 
 
 
x7 
 
1 hematology: white blood cell (WBC) with differential count, platelets (PLTs), hemoglobin (Hb); biochemistry: blood urea nitrogen (BUN), serum creatinine and calculated creatinine clearance (by 
Cockcroft), uric acid, albumin, total bilirubin, Alkaline Phosphatase (AP), Aspartate AminoTransferase (AST/ASAT), Alanine AminoTransferase (ALT/ALAT), Gamma-Glutamyl Transferase (GGT), sodium, 
potassium, Lactic Dehydrogenase (LDH), total calcium, phosphorus, magnesium, glucose 
2 the test must be negative within 72 hours before treatment start 
3 Contrasted enhanced CT scan of the thorax and upper abdomen (including adrenal glands) and brain CT scan. IMPORTANT: this every 8 week schedule remains in place, as per calendar, also after the 
switch to osimertinib. If treatment was interrupted without any objective PD per RECIST 1.1 being identified, imaging needs to be continued until objective disease progression per RECIST 1.1. 
4 at week 12 on osimertinib and if clinically indicated 
5 if clinically indicated 
6 for 70 years old patients or older 
7 In case of RECISTS 1.1 progression 
*Patients must stop gefitinib 48 hours before osimertinib initiation. 
** within 3 days prior to actual osimertinib dosing 
 
 

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6.4.3 
Arm C 
 
Before 
randomization 
During treatment with 
gefitinib 
During treatment with osimertinib* 
At the end of 
treatment 
Follow-
up 
From week 1 to week 24 
After week 24 
 
Every 8 weeks  
(+/- 7 days) 
Day 1 cycle 
1** 
Every 4 weeks 
(+/- 2 days) 
Every 8 weeks  
(+/- 7 days) 
Every 8 weeks (+/- 7 days) 
Signature of Informed 
Consent 
x 
 
 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
Baseline symptom 
assessment 
x 
 
 
 
 
 
 
 
 
Concomitant medication 
x 
 
X 
x 
x 
 
x 
x 
 
AE and PS assessment 
x 
 
X 
x 
x 
 
x 
x 
 
Physical examination, 
including vital signs, 
height, weight and blood 
pressure 
x 
 
X 
x 
x 
 
x 
x 
 
Lab exam1 
x 
 
x 
x 
x 
 
x 
x 
 
Collection of plasma 
sample for central T790M 
status 
x 
 
 
 
 
 
 
 
 
Collection of tissue 
sample 
x 
 
 
 
 
 
 
 
 
Pregnancy test2 
x2 
x 
 
every 4 weeks (+/- 2 days) or more frequently if required by 
national regulations/institution guidelines. 
 
 
Stick urinanalysis 
x 
 
 
 
 
 
 
 
 
ECG 
x 
 
 
x 
x 
 
x 
 
 

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Before 
randomization 
During treatment with 
gefitinib 
During treatment with osimertinib* 
At the end of 
treatment 
Follow-
up 
From week 1 to week 24 
After week 24 
 
Every 8 weeks  
(+/- 7 days) 
Day 1 cycle 
1** 
Every 4 weeks 
(+/- 2 days) 
Every 8 weeks  
(+/- 7 days) 
Every 8 weeks (+/- 7 days) 
LVEF assessed by MUGA 
or ECHO 
x 
 
 
x 
x4 
 
x5 
 
 
Imaging evaluation3 
x3 
 
x3 
 
 
x3 
x3 
x3 
x3 
Ophthalmological 
examination 
 
 
 
x5 
x5 
 
x5 
x5 
 
G8 assessment6 
x6 
 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
x 
Optional tissue biopsy 
 
 
 
 
 
 
 
x7 
 
1 hematology: white blood cell (WBC) with differential count, platelets (PLTs), hemoglobin (Hb); biochemistry: blood urea nitrogen (BUN), serum creatinine and calculated creatinine clearance (by 
Cockcroft), uric acid, albumin, total bilirubin, Alkaline Phosphatase (AP), Aspartate AminoTransferase (AST/ASAT), Alanine AminoTransferase (ALT/ALAT), Gamma-Glutamyl Transferase (GGT), sodium, 
potassium, Lactic Dehydrogenase (LDH), total calcium, phosphorus, magnesium, glucose 
2 the test must be negative within 72 hours before treatment start 
3 Contrasted enhanced CT scan of the thorax and upper abdomen (including adrenal glands) and brain CT scan. IMPORTANT: this every 8 week schedule remains in place, as per calendar, also after the 
switch to osimertinib. If treatment was interrupted without any objective PD per RECIST 1.1 being identified, imaging needs to be continued until objective disease progression per RECIST 1.1. 
4 at week 12 on osimertinib and if clinically indicated 
5 if clinically indicated 
6 for 70 years old patients or older 
7 In case of RECISTS 1.1 progression 
*Patients must stop gefitinib 48 hours before osimertinib initiation. 
** within 3 days prior to actual osimertinib dosing 

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7 Criteria of evaluation 
7.1 
Evaluation of efficacy 
Objective tumor response and time to progression will be measured according to the RECIST criteria 
(version 1.1, Ref. 33).  
Response criteria are essentially based on a set of measurable lesions identified at baseline as target 
lesions, and – together with other lesions that are denoted as non-target lesions – followed until disease 
progression. 
Imaging datasets will be collected on an ongoing basis and reviewed retrospectively (details in section 
15.4). 
The following paragraphs are a quick reference to the RECIST criteria (version 1.1). The complete criteria 
are included in the published RECIST document [Ref. 33] also available at http://www.eortc.be/RECIST. 
7.1.1 
Measurability of tumor lesions at baseline 
7.1.1.1 
Definitions 
• Measurable disease - the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
• Measurable lesions - tumor lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 20 mm with chest x-ray, and as ≥ 10 mm with CT scan or 
clinical examination [using calipers]. Bone lesions are considered measurable only if assessed by CT 
scan and have an identifiable soft tissue component that meets these requirements (soft tissue 
component > 10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be 
considered measurable; only the short axis will be measured and followed. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters) by use of a ruler or calipers. 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
• Non-measurable lesions - All other lesions (or sites of disease), including small lesions are considered 
non-measurable disease. Bone lesions without a measurable soft tissue component, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, lymphangitic involvement of lung or skin and abdominal masses followed by clinical 
examination are all non-measurable. Nodes that have a short axis <10 mm at baseline are considered 
non-pathological and should not be recorded or followed. 
• Target Lesions. When more than one measurable tumor lesion or malignant lymph node is present at 
baseline all lesions up to a maximum of 3 lesions total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. Note that pathological nodes must meet the 
criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute 
to the baseline sum. At baseline, the sum of the target lesions (longest diameter of tumor lesions plus 
short axis of lymph nodes: overall maximum of 3) is to be calculated and recorded.  
• Non-target Lesions. All non-measurable lesions (or sites of disease) including pathological nodes 
(those with short axis ≥ 10 mm but < 15 mm), plus any measurable lesions over and above those 

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listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”. 
All baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
7.1.1.2 
Methods of measurements 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Assessments should be identified on a calendar 
schedule and should not be affected by delays in therapy, which may be treatment arm dependent. 
While on study, all target lesions recorded at baseline should have their actual measurements recorded 
on the CRF at each subsequent evaluation, even when very small (e.g. 2 mm). If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the 
lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. For lesions which fragment/split add together the longest diameters of the 
fragmented portions; for lesions which coalesce, measure the maximal longest diameter for the “merged 
lesion”. 
• Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and ≥ 10 
mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging 
is preferred. 
• Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions > 20 mm on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
• CT, MRI. CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for bone scans). While PET scans are not considered adequate to 
measure lesions, PET-CT scans may be used providing that the measures are obtained from the CT 
scan and the CT scan is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 
• Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse 
effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when 
the measurable tumor has met criteria for response or stable disease is advised to differentiate 
between response or stable disease and progressive disease. 
7.1.2 
Tumor response evaluation 
All patients will have their BEST RESPONSE from the start of study treatment until the end of treatment 
classified as outlined below: 
Complete Response (CR): disappearance of all target and non-target lesions and normalization of tumor 
markers. Pathological lymph nodes must have short axis measures < 10mm (Note: continue to record the 
measurement even if < 10 mm and considered CR). Tumor markers must have normalized. Residual 
lesions (other than nodes < 10 mm) thought to be non-malignant should be further investigated (by 
cytology or PET scans) before CR can be accepted.  

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Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumor 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD 
taking as reference the smallest sum of diameters on study. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions taking as 
references the smallest sum of diameters recorded on study (including baseline) AND an absolute 
increase of ≥ 5 mm. Appearance of new lesions will also constitute PD (including lesions in previously 
unassessed areas). In exceptional circumstances, unequivocal progression of non-target disease may be 
accepted as evidence of disease progression, where the overall tumor burden has increased sufficiently 
to merit discontinuation of treatment, for example where the tumor burden appears to have increased 
by at least 73% in volume (which is the increase in volume when all dimensions of a single lesion increase 
by 20%). Modest increases in the size of one or more non-target lesions are NOT considered unequivocal 
progression. If the evidence of PD is equivocal (target or non-target), treatment may continue until the 
next assessment, but on further documentation, the earlier date must be used. 
Table 1: Integration of Target, non-Target and New lesions into response assessment 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
category also requires 
Patients with Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumor 
markers, tumor nodes < 10 
mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least once ≥ 
8 wks. from baseline  
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression [or evidence of unequivocal disease progression] at 
that time should be reported as “symptomatic deterioration”. This is a reason for stopping therapy, but 
is NOT objective PD. Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
 
 

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7.1.2.1 
Frequency of tumor re-evaluation 
Tumor evaluation is done through CT scan of the brain, thorax and upper abdomen (including adrenal 
glands) every 8 weeks.  
The baseline imaging is done within 14 days from randomization and thereafter every 8 weeks. 
For the patients in arm B that will switch their treatment based on the biological PD, the baseline imaging 
will be the most recent one (regularly done as per schedule) to the treatment start to osimertinib.  
7.1.2.2 
Date of progression 
This is defined as the first day when the RECIST (version 1.1) criteria for PD are met. Refer to Ref. 33 as 
well as below (section 7.2.1) for further information on what constitutes early progression, assessment of 
progression of non-target disease, new lesions and usage of FDG-PET to diagnose progression.  
7.1.3 
Oligoprogression 
This is defined as the first day when the RECIST (version 1.1) criteria for PD are met however the number 
of new lesions is up to 3 and amenable to local therapies (stereotactic radiotherapy or surgery). 
7.1.4 
Reporting of tumor response 
All patients included in the study must be assessed for response to treatment, even if there is a major 
protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be 
assigned one of the following categories: complete response, partial response, stable disease, 
progressive disease, early death or not evaluable. 
Early death is defined as any death occurring before the first per protocol time point of tumor re-
evaluation. 
Patients’ response will be classified as "not evaluable" if insufficient data were collected to allow 
evaluation per these criteria. 
7.2 
Endpoints Definition 
7.2.1 
Progression Free Survival Rate at 18 months (PFSR-OSI-18)  
The primary endpoint in this study is Progression Free Survival rate according to RECIST 1.1 “while 
receiving osimertinib” at 18 months (PFSR-OSI-18). This endpoint is evaluated in arm B and C. In arm A, 
the endpoint is assessed to simply provide a point estimate for PFSR-OSI-18 and the corresponding 
confidence interval.  
The primary endpoint is defined as the proportion of patients at 18 months who are alive and did not 
experience an event for PFS-OSI according to the definition in section 7.2.2. 
Practically, the time point of disease evaluation corresponding to the primary endpoint is 18 months after 
randomization. Therefore, disease evaluation at 18 months (+/- 14 days) is required for all patients who 
are still alive and without an event for PFS-OSI at the 18th month. Disease evaluation done within a 
window of +/- 2 weeks will be taken into account for the 18-month assessment. 
Progression Free Survival rate according to RECIST 1.1 “while receiving osimertinib” at 18 months (PFSR-
OSI-18) will be estimated using the Kaplan Meier technique in order to take into account possible failures 
of follow-up not due or related to the event of interest (progression or death). 
7.2.2 
PFS by RECIST 1.1 while receiving osimertinib (PFS-OSI) 
This endpoint is evaluated in arm B and C. In arm A, the endpoint is assessed to simply provide a point 
estimate for median PFS-OSI and the corresponding confidence interval. 

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ARM A: 
For patients in arm A, progression Free Survival “while receiving osimertinib” (PFS-OSI) is defined as the 
time interval between the date of randomization and the date of disease progression according to the 
RECIST criteria (version 1.1) or death whichever comes first (i.e. calculated as the difference between the 
two dates). This corresponds to the classical definition of PFS according to RECIST v1.1.  
For each patient, the value for PFS-OSI will be used in the analysis regardless of whether or not 
intercurrent events occur such as protocol treatment discontinuation or further use of other anticancer 
therapies or use of concomitant medication etc... As a consequence, tumor re-evaluation should 
continue until the event of interest despite the occurrence of any intercurrent event. 
Patients alive and free of progression prior to the analysis cut-off date are censored at the date of the last 
disease assessment before the cut-off date.  
ARM B and C: 
• For patients in arm B and C switching to osimertinib, progression Free Survival “while receiving 
osimertinib” (PFS-OSI) is defined as the time interval between the date of randomization and the date 
of disease progression or death “after switching to osimertinib” whichever comes first (i.e. calculated 
as the difference between the two dates), thus taking into account the influence of the switching 
strategy under investigation on the following treatment line.  
The baseline to determine disease progression is the baseline at randomization. For patients in arm B 
and C switching to osimertinib, the nadir of the measurements to determine progression is defined as 
the nadir after switching to osimertinib. Disease progression is defined in section 7.1.2 and date of 
progression is defined in section 7.1.2.2. 
• For patients in arm B and C who do not start osimertinib for any reason, PFS-OSI is defined as the 
time interval between the date of randomization and the date of disease progression according to the 
RECIST criteria (version 1.1) or death whichever comes first (i.e. calculated as the difference between 
the two dates). This corresponds to the classical definition of PFS according to RECIST v1.1.  
For each patient, the value for PFS-OSI will be used in the analysis regardless of whether or not 
intercurrent events occur such as protocol treatment discontinuation or further use of other 
anticancer therapies or use of concomitant medication etc... As a consequence, tumor re-evaluation 
should continue until the event of interest despite the occurrence of any intercurrent event.  
If neither event has been observed prior to the analysis cut-off date, then the patient is censored at the 
date of the last disease assessment before the cut-off date. 
7.2.3 
Proportion of patients receiving osimertinib based on the 
determination of cfDNA T790M mutation positive 
The proportion of patients receiving osimertinib based on the determination of cfDNA T790M is the 
number of patients receiving at least 1 dose of osimertinib based on the determination of cfDNA T790M 
(positive mutation). This endpoint is only defined and applicable for Arm B. 
7.2.4 
Time to progression on osimertinib (TTP-OSI) 
Time to progression on osimertinib is defined as the time interval between the date receiving osimertinib 
and the date of disease progression. Death is not counted as an event.  
The baseline to determine disease progression is the baseline at randomization. For patients in arm B and 
C switching to osimertinib, the nadir of the measurements to determine progression is defined as the 
nadir after switching to osimertinib. 

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Disease progression is defined in section 7.1.2 and date of progression is defined in section 7.1.2.2. If the 
event has not been observed or if the patient dies before the analysis cut-off date, then the patient is 
censored at the date of the last disease assessment or the date of death prior the cut-off date. Patients 
not receiving osimertinib are excluded for this endpoint. The nature of this endpoint is different in Arm A 
(first line progression) from Arm B and C (second line progression). 
7.2.5 
PFS-2  
In Arm A, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 or 
death, irrespective of treatment(s) received.  
In Arm B and C, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 
or death after switching to osimertinib, the first PD being PD by RECIST 1.1 or by positive cfDNA T790M 
status. For patients unable to start osimertinib, PFS-2 is calculated as the time between randomization 
and the second PD by RECIST 1.1 on any subsequent off protocol anticancer treatment line.  
If no PFS-2 event has been observed prior to the analysis cut-off date, then the patient is censored at the 
date of the last disease assessment before the cut-off date. 
7.2.6 
Overall Response Rate (ORR) to osimertinib 
Overall Response Rate (ORR) to osimertinib is an overall rate including patients with documented 
complete response (CR) or partial response (PR) while patients are receiving osimertinib, where CR and 
PR are defined according to the principles mentioned in section 7.1.2. Patients not receiving osimertinib 
will not be included in the ORR to osimertinib analysis. 
The nature of this endpoint is different in Arm A (first line ORR) from Arm B and C (second line ORR). 
7.2.7 
Treatment duration 
Treatment duration will be measured from the time of randomization until the protocol treatment stops. 
In Arms B and C, if patients receive osimertinib , the duration is calculated till osimertinib stops. 
7.2.8 
Overall Survival (OS)  
Overall survival (OS) is defined as the time interval between the date of randomization and the date of 
death from any cause. Patients still alive at the analysis cut-off date are censored at the last date known 
to be alive (before the cut-off date).  
7.2.9 
Brain progression free survival (BPFS) 
Brain progression free survival is defined as the time interval between the randomization and the date of 
brain progression (progression within target lesions in the brain, unequivocal progression in non-target 
lesions in the brain, or appearance of new lesions in the brain) or death whichever comes first.  
Disease progression is defined in section 7.1.2 and date of progression is defined in section 7.1.2.2. CT 
scan will be used to evaluate new or recurrence progression in the brain. If the event has not been 
observed or if the patient dies or has PD that hampered further assessment/evaluation of brain 
progression, then the patient is censored at the date of the last follow up examination or day of death. 
7.2.10 
Exploratory endpoint: change in tumor size 
Change in tumor size is defined as the difference in each tumor evaluation from the baseline 
measurement at the time of starting or switching to osimertinib. More information about this endpoint 
can be found in [Ref. 35]. 

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7.3 
Evaluation of safety 
7.3.1 
Adverse events 
All adverse events will be recorded; the investigator will assess whether those events are related to 
osimertinib (reasonable possibility, no reasonable possibility) or gefitinib (reasonable possibility, no 
reasonable possibility) and this assessment will be recorded in the database for all adverse events. 
The collection period will start from randomization and all adverse events must be followed until 
resolution or stabilization. 
7.3.2 
General evaluation of adverse events 
This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 
4.0, for adverse event reporting. A copy of the CTCAE can be accessed from the EORTC home page 
https://www.eortc.be/services/doc/ctc/. 
Hematological toxicity will be assessed on the basis of regular blood tests. The nadir count will be 
computed at each study medication administration and graded according to the CTCAE version 4.0.  
Non hematological acute side effects will be assessed and reported separately for each study medication 
administration, and graded according to the CTCAE version 4.0. 
Planned safety analysis and tabulations are described in the statistics section. 
7.3.3 
Serious adverse events 
Serious adverse events are defined by the Good Clinical Practice Guideline. 
Serious adverse events should be immediately reported according to the procedure detailed in this 
protocol (see chapter on Reporting Serious Adverse Events). 
7.3.4 
Toxic deaths 
Toxic death is defined as death due to toxicity (defined as adverse events that are not confirmed as 
unrelated). The cause of death must be reported as "toxicity". 
The evaluation of toxic deaths is independent of the evaluation of response (patients can die from 
toxicity after a complete assessment of the response to therapy). 
7.3.5 
Evaluability for safety 
All patients who have started the treatment (either gefitinib or orsimertinib) will be included in overall 
safety analyses. 
For hematological events, the medical review team may decide that blood counts have not been 
performed and/or reported according to the protocol and are therefore inadequate for the evaluation of 
one/several hematological parameters in some patients. 
Parameters that will be identified and monitored will be the following: 
• Any grade 3-4 non hematological or grade 4 hematological toxicity at least possibly related to the 
treatment; 
• % of treatment interruptions, schedule modifications and dose modifications; 
• Compliance to the requirement of minimum dose intensity of 70% (treatment tolerability rule); 
• Unexpected grade 2 toxicity at least possibly related to the treatment; 
• Worsening of toxicity if data will be available at the time of DSM. 

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Patients who have discontinued treatment because of toxicity will always be included in the safety 
analyses. 
7.4 
Evaluation of frailty using the G8 geriatric screening tool 
7.4.1 
Background 
Older cancer patients have a much more heterogeneous general health status compared to young cancer 
patients. Some older patients are in perfect general health, while others are vulnerable or frail. Frailty is a 
well-known concept in geriatric medicine [Ref. 36]. It is defined as a multi-factorial syndrome, resulting in 
a reduction of the physiological reserve and of the capability to resist stressful events (homeostatic 
capacity). Frailty is associated with an increased risk of unfavorable clinical events: disability, 
hospitalization, institutionalization, death. In oncology, the construct of frailty is as well used to describe 
patients with increased risk of treatment-associated morbidity and mortality. Presence of frailty can be 
detected by a so-called (Comprehensive) Geriatric Assessment (GA). Performance of GA is advised in 
older cancer patients by the International Society of Geriatric Oncology, SIOG [Ref. 37]. GA is time 
consuming (takes about 30 minutes). Therefore, short geriatric screening tools such as the G8 have been 
developed as a short and easy to use measurement of general health status. The G8 score has been 
specifically developed in oncology, includes 8 items, takes a few minutes to complete, and can be 
completed by any health care worker [Ref. 38]. The score ranges from 1 to 17. A score greater than 14 
indicates that there is little risk that further GA reveals significant problems in the further assessed GA 
domains. The G8 was shown to strongly predict functional decline and overall survival [Ref. 39]. G8 is by 
far the best studied geriatric screening tool in oncological patients, and also has better performance for 
detection of geriatric problems than other geriatric screening tools such as VES-13 [Ref. 40]. 
7.4.2 
Assessments 
G8 will be measured in all patients aged 70 years and above at baseline. G8 has to be completed by the 
clinician, the nurse or the trained coder. This screening tool includes 7 items of the Mini Nutritional 
Assessment and the age of the patient. The English version of G8 is included as a protocol appendix 
(Appendix D).  
7.4.3 
Objective 
The inclusion of the G8 screening tool in EORTC trials will allow a uniform, easy and established approach 
of frailty at baseline. The G8 tool itself has been developed as a screening tool, and not a tool for follow-
up. 
The treating physician may decide which actions are needed based on the G8 result (e.g. further geriatric 
assessment in case of a G8 score of less or equal to 14; geriatric interventions if specific problems are 
detected within specific geriatric domains). 
The assessment of frailty as defined by G8 in all patients aged 70 years and above entered in EORTC trials 
will allow interpretation of whether new treatment strategies have been tested in both fit and less fit 
patients which has importance for the generalizability of the study results.  

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8 Statistical considerations 
8.1 
Statistical design 
8.1.1 
Sample size 
This study is designed with an understanding of the difficulty of having a primary endpoint which solidly 
covers all arms. The primary endpoint PFSR-OSI-18 as defined in Chapter 0, will be assessed in all arms, 
yet this endpoint will be used to evaluate arm B and arm C. With this restriction , the below criteria for a 
success of the arm (applicable B and C) should be viewed as exploratory and further information from 
secondary endpoints as well as the costs should be considered if the arm is judged as feasible to be 
further explored. 
The study design is a 1-Stage Ahern Design - Single Proportion, with Progression Free Survival rate at 18 
months (PFSR-OSI-18) as primary endpoint. It was designed with a 1-sided alpha = 0.08 and 92% power 
(beta = 8%). 
In arm B and C of this trial, if the result is compatible with a progression free survival rate at 18 months 
(PFSR-OSI-18) of 60% in the studied population, the strategy should be further explored. However, if we 
are unable to demonstrate that the PFSR-OSI-18 in the studied population is at least 40%, the strategy 
should be rejected from further exploration. 
49 eligible patients who started treatment are needed in each arm. To declare the arm worthwhile for 
further exploration, at least 25 out of 49 patients should be a success (see definition of the primary 
endpoint in section 7.2.1) at 18 months.  
Additional 5% patients will be accrued to take into account patients who might be ineligible or not 
starting treatment. Hence, using a 1:1:1 ratio for randomization, a total of 156 patients will be accrued in 
this study (52 pts in each arm) within 26 months and an additional 24 months of follow up after the last 
patient entry is needed to allow the assessment of the primary endpoint. The estimated duration of the 
study is 6 years, given that all patients have ended their treatment according to End of Study definition 
(section 8.4). 
In this study a minimum of 18 months of follow up is needed after the last patient entry.  
8.1.2 
Power to detect a difference in brain progression free survival (BPFS) 
In this study, a special emphasis is given to the secondary endpoint BPFS. Formal comparison between 
arm A versus B and A versus C with respect to BPFS will be made. The power of such comparison is given 
below. 
With a 1-sided alpha = 5% (so that a 1-sided family wise error: 10%, taking into account 2 comparisons), 
and looking for an improvement in BPFS at 18 months from 75% to 87.5% (equivalent to 54% reduction in 
risk of progression, i.e. HR = 0.46), 36 BPFS events will give an approximately 70% power to detect the 
above difference. 
8.1.3 
Randomization and stratifications 
Patients will be centrally randomized (for practical details, see chapter on registration / randomization 
procedure). A minimization technique will be used for random treatment allocation stratifying by 
institution, Type of mutation (Del19 vs. L858R), Initial T790M (Yes vs. No) and Brain Metastasis (Yes vs. 
No). 

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8.2 
Statistical analysis plan 
Analyses described below will be done separately for each arm, except for the secondary endpoint BPFS 
where comparisons between the arms (i.e. A vs. B, B vs. C and A vs. C) will be conducted.  
8.2.1 
Analysis populations 
• Intention-to-treat population: All randomized patients will be analyzed in the arm they were allocated 
by randomization. 
• Per protocol population: All patients who are eligible and have started their allocated treatment (at 
least one dose of the study drug(s) in chemotherapy trials) 
• Safety population: All patients who have started their allocated treatment (at least one dose of the 
study drug(s) in chemotherapy trials) 
A patient will be considered to be eligible if he/she did not have any deviation from the patient entry 
criteria listed in chapter 3 of the protocol. Potential eligibility problems will be assessed by the Clinical 
Research Physician at time of medical review. 
8.2.2 
Statistical methods 
Analysis of the primary endpoint 
The primary analysis will be performed to per-protocol population. 
Patients with success is defined by the primary endpoint in Section 7.2.1. The PFSR-OSI-18 in each arm 
and their 84% confidence intervals will be provided. In case the number of patients analyzed in each arm 
exceeds or less than what is foreseen above (Section 8.1.1), the 84% confidence interval will be used for 
the decision.  
Time to event endpoints 
The analyses of the primary and secondary endpoints will be performed on per-protocol population. 
Comparison between arms are foreseen for BPFS endpoint only.  
Estimates and confidence intervals  
Estimates of the median PFS-OSI, TTP-OSI, PFS2-OSI and OS are obtained by the Kaplan Meier technique. 
The 84% and 95% confidence intervals (CI) for the median will be calculated using the reflected CI 
method.  
Estimates of the event-free rate at fixed time point (18 months) will be obtained using the Kaplan Meier 
technique and 84% 2-sided CI will be calculated by Greenwood’s estimation of the standard deviation. 
Estimates of hazard ratios and their 84% 2-sided CI will be obtained by Cox regression. In addition 95% 2-
sided CI will be provided for both the estimates of event rates and hazard ratios. Kaplan Meier Curves will 
be drawn for both the experimental and control arms on the same plot.  
Inference: Test statistics for comparisons (for BPFS)  
Cox regression (Score Test) will be used to compare the experimental versus the control arms adjusted by 
the stratification factors in randomization (except for centers) at 1-sided 10% significant level.  
Toxicity  
Analysis for toxicity is based on the safety population. The worst grade of toxicity/adverse events 
observed over the whole treatment period (excluding re-challenge period for Arm A) according to CTCAE 
version 4 will be displayed. No formal statistical analysis will be performed to compare toxicity in both 
arms.  

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Response Rate 
Patients with response categories progression, early death and unknown will be considered as failing to 
respond to treatment. The response rates in each arm and their 95% confidence intervals will be 
provided. In addition, response rates in the 2 arms will be compared using a two-sample test at 5% 2-
sided level. 
8.2.3 
Pre-planned sensitivity or exploratory analyses 
A sensitivity analysis of efficacy based on intent to treat (ITT) population will be conducted in addition to 
the primary analysis based on per protocol population.  
Sensitivity analyses will be conducted on PFS-OSI rate at 18 months according to RECIST 1.1 (primary 
endpoint) to verify the robustness of the results vis-à-vis the missing data. Once the main analysis is 
completed, PFSR-OSI-18 will be analyzed as binary endpoint. The following sensitivity analyses will be 
conducted: 
• Patients lost-to-follow up before 18 months, i.e. with missing assessments at 18 months (using the 
window of ± 2 weeks) and at all times thereafter will be considered as having an event at 18 months 
(worst case scenario). Only patients with the confirmation they are alive and progression free at 18 
months (status for PFS not missing at 18 months or after and status at 18 months is no progression) 
will be considered event free at 18 months.  
In details, 
• Patients alive and without any progression by RECIST 1.1 at 18 months will be counted as a 
success irrespective of treatment(s) received (still under protocol treatment or switched to 
investigator's choice standard treatment including no further systemic anticancer therapy 
documented). 
• Patients who progress on gefitinib by RECIST 1.1 or by positive cfDNA T790M status testing prior 
to 18 months and are switched to osimertinib (T790M positive) and progression free at 18 months 
after switching to osimertinib will be counted as a success.  
• Patients who progress on gefitinib by RECIST 1.1 or by positive cfDNA T790M status prior to 18 
months and are switched to osimertinib (T790M positive) and progress by RECIST 1.1 after 
switching to osimertinib prior to 18 months will be counted as a failure.  
• Patients with a progression by RECIST 1.1 prior to 18 months and not able to start osimertinib 
prior to 18 months for any reason will be counted as a failure.  
• Complete case analysis: the analysis will be restricted to patients with available PFS data at 18 months 
(complete case analysis).  
In addition, sensitivity analyses will be conducted in which patients who will have started any other 
cancer treatment before their disease progresses will be considered as having an event at the date of 
start of the other cancer treatment. 
Exploratory analysis of BPFS and OS according to the presence of T790M mutation status and the 
presence of original activating EGFR mutation in the plasma will be performed. In addition, exploratory 
endpoint on change in tumor size (see chapter 7) will be performed.  
8.2.4 
Prognostic factor analyses 
No prognostic factor (PF) analyses will be conducted. 

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8.2.5 
Data recoding and display 
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical variables by the 
levels of the variables as they appear on the CRF (with %). Categories with a text field specification will be 
tabulated as categories and then supplemented by a listing with the following information for the 
patients fulfilling the condition for the specification (patient id, institution, treatment group, value of the 
item and text field contents). 
Dates relating to events prior to entry will be presented as the delay in days (or weeks, months, or years) 
between the past event and the date of entry (date of randomization – date of past event + 1) and 
presented using the median and range. For example, on the randomization checklist, the date of last 
administration of prior treatment (or the date of first diagnosis of the cancer) will be presented as the 
time elapsed (in days, weeks, months or years, as appropriate) since the day of the last administration 
and the date of entry on study (date of randomization – last administration/diagnosis +1). 
Other delays (e.g. re-treatment delays) are presented as continuous variables using the median and 
range. 
Continuous variables for which a coding system exists (such as for laboratory data) will be recoded into 
categories (for adverse events, the grading scale specified in the protocol will be used). Whenever no 
specific scale exists, lab data will be categorized based on the normal range: for example, below the 
lower normal limit (when appropriate), within the normal range, above the upper normal limit (ULN) and 
the degree to which it is above the ULN (for example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory 
data, the nadir is generally displayed. The nadir in a given cycle is the lowest laboratory value in that 
cycle; the overall nadir for a patient is the lowest laboratory value among all cycles. 
Other continuous variables (for example age, dose …) are presented using the median and range 
(minimum, maximum).  
DI observed = 




× weeks
m
mg
2
 = 
[ ]
[
]
weeks
duration
total
dose
total
m
mg
2
 
The relative dose intensity is calculated as the ratio of the dose intensity as calculated above to the dose 
intensity indicated in the protocol. The dose intensity indicated in the protocol is obtained as the dose 
specified per cycle (in mg/m²). 
The dose intensity and the relative dose intensity are presented using median and ranges. The relative 
dose intensity can also be presented in categories (≤70%, >70-90%, >90-110%, >110-120%. 
If appropriate, continuous data may also be presented in categories (for example, age may also be 
grouped in decades). 
8.3 
Interim analyses 
No interim analysis (IA) is foreseen in this protocol.  
8.4 
End of study 
End of study occurs when all of the following criteria have been satisfied: 
1. Thirty days after all patients have stopped protocol treatment 
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol 
3. The database has been fully cleaned and frozen for this analysis 

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9 Trial Governance and Data Monitoring  
9.1 
Study committees  
9.1.1 
Study Management Group (SMG) 
The Study Management Group is set up for this study. It consists of the EORTC Headquarters team in 
charge of running the study (clinical research physician, statistician, clinical scientist, project manager and 
data managers) and the principal study coordinator.  
The EORTC Headquarter team is responsible for the day -to-day conduct of the trial. The Study 
Coordinator will assist the team in case of problems with patient evaluation (eligibility, treatment 
compliance, safety).  
The Study Management Group also performs the medical review as indicated below.  
9.1.2 
Study Steering Committee (SSC)  
The Study Steering Committee for this study is composed of the study coordinators, the representatives 
of Academic Groups collaborating to the study, at least one representative of the EORTC Headquarters 
(Study Clinical Research Physician or Clinical Scientist) and one representative of the EORTC. 
This committee provides the general oversight of the study and has the executive power. The SSC 
monitors study progress and conduct and advises on its scientific credibility. The SSC will consider and 
act, as appropriate, upon the recommendations of the independent data monitoring committee.  
9.1.3 
Independent Data Monitoring Committee (IDMC)  
The independent data monitoring committee for EORTC studies (IDMC) is in charge of the independent 
oversight of this study. The composition of the IDMC is described in EORTC Policy "Independent Data 
Monitoring Committees for EORTC studies" (ref. EORTC POL004) and its functioning is ruled by the 
charter annexed to the Policy.  
The study-specific experts on the IDMC performing this review will be selected for their relevant 
expertise with the disease and/or treatments assessed in the study.  
The IDMC reports its recommendations in writing to the Study Management Group through the project 
manager to the Study Steering Committee and other relevant parties (supporting bodies, collaborative 
groups…).  
9.2 
Data Monitoring  
9.2.1 
Monitoring during medical review meetings  
The medical review will be performed on a regular basis by the medical representative assisted as 
needed by the study management group. The main study coordinator will, in particular, support the 
Study Medical Representative during the medical review process and will assist the team in case of 
problems with patient evaluation (safety, eligibility, treatment compliance). The main study coordinator 
is also responsible for the review and approval of the medical review plan and medical review reports.  
If at any time during the course of the study, the medical review identifies safety signals or other 
elements that could affect the potential risks and benefits to the study participants. These will be 
reported to the Study Steering Committee and may trigger a review by the EORTC Independent Data 
Monitoring Committee (IDMC).  

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9.2.2 
Monitoring by the IDMC  
The IDMC will be asked to give advice on whether the accumulating data from the trial justifies 
continuing recruitment of further patients or further follow-up. 
The IDMC will review the trial whenever safety problems or other elements are identified during the 
medical review or by the SMG and/or SSC that could affect the potential risks and benefits for study 
participants.  
The IDMC will also review the intermediate reports of accumulating data according to the study interim 
monitoring plan described in the statistical section of this protocol. If a decision is made to continue 
without change, the IDMC may advise on the frequency of future reviews of the data on the basis of 
accrual and event rates. 
While the trial is ongoing the accumulating data will generally remain confidential, unless the SSC and 
IDMC agree that the data should be made public. 
10 Translational research 
The translational research is not optional for this protocol. Any patient who consent to enter the trial will 
have to consent for the translational research.  
10.1 Main objectives 
The main objectives of translational research study are, but not limited to, the following: 
• to describe quantitatively the presence of T790M EGFR mutations and original activating EGFR 
mutations in plasma of patients treated with gefitinib and osimertinib longitudinally within the arms 
and to compare the presence of these mutations across the arms A, B and C. 
• to describe the associations between the presence of these mutations and response evaluations by 
RECIST 1.1 longitudinally within the arms. 
• to describe the associations between the presence of these mutations and response and PFS to 
osimertinib in Arm A, B and C. 
• to assess mechanisms of resistance to osimertinib in formalin-fixed paraffin-embedded (FFPE) 
samples obtained from patients at baseline and at the time of progression on osimertinib by next 
generation sequencing and compare the presence of molecular resistance alterations in tissue 
samples and plasma samples taken on progression. 
• To assess pharmaco-kinetics and/or pharmaco-dynamics of the different drugs, as potential 
resistance mechanisms in blood samples taken at baseline and during the course of treatment.  
Detailed statistical analysis plan will be presented in a separate document prior to TR analysis. 
10.2 Human Biological material 
• Blood sample that would have been taken during screening visit and treatment each visit (every 4 
weeks) while patients are within active treatment with gefitinib or osimertinib. Note: if gefitinib or 
osimertinib is temporarily discontinued due to toxicity, plasma sample should still be obtained. The 
last plasma sample should be taken from patients who progress on osimertinib by RECIST 1.1 
evaluation (all three arms). Please refer to chapter 6. 
• FFPE processed biopsy samples at baseline (residual tumor from diagnostic sample) and from 
progressing tumor lesions obtained from patients receiving osimertinib. 

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10.3 Data storage, transfer and development of technical appendices 
The translational projects will be the result of the work of collaborating institutions and EORTC HQ. 
Statistical analysis plan will be jointly developed for each project. These documents will be developed and 
approved before starting any analysis. They will specify the analytical and methodological details. Clinical 
and patient-reported outcome data will be stored in the EORTC clinical database and biological 
investigational data will be stored in respective collaborating institutions. Transfer of data will be 
performed according to applicable policies in each organization (e.g. EORTC POL008) or according to 
jointly approved data transfer charters. 
10.4 General principles for human biological material (HBM) 
collection 
Human biological material (HBM) collection involves the collection and storage of biological material, 
residual biological material or derivatives in compliance with ethical and technical requirements.  
Biobanking refers to the chain of procedures that encompass the life cycle of the biological material, e.g. 
from collection, shipping to long term storage and use, and may also be subject to local regulation and/or 
national/international legislation. 
In this study, biological material will be centralized and stored at Medical University of Gdansk. From 
here, the biological material will be used or distributed to the other research laboratories involved in the 
translational research (TR) projects specified in this protocol or defined in the future.  
The following principles apply to storage of HBM: 
• The biobank will have a designated manager responsible for collection and will act as a 
communication point with the EORTC. 
• The collected HBM should be documented, i.e. the amount remaining and its location. 
• The Study Steering Committee (SSC)/Group committee will be responsible for TR project review and 
prioritization, including the consideration of newly proposed TR projects not specified in the protocol. 
In the absence of a SSC, responsibilities of the SSC are transferred to the Group and/ or EORTC HQ as 
applicable. 
• Final decisions on the use of HBM will be determined by a majority vote of the SSC/Group committee. 
Additional expertise may be sought through advisory non-SSC/Group committee members. 
Access to HBM (see EORTC Biobanking Policy POL020): HBM may be used for another purpose for which 
it was originally collected, subject to meeting ethical principles/and is covered by informed 
consent/ethics approval. In the case of secondary use of HBM, (i.e. for new TR projects that are not 
specified in the clinical study protocol and that were not foreseen at the time of protocol writing) 
interested parties may apply for the use of HBM and will follow the next steps:  
• A short description of the new TR projects will be written and submitted to EORTC HQ for 
coordination with the appropriate SSC/Group committee. 
• The SSC/Group committee will prioritize the TR projects. Access procedures defined by the SSC/Group 
committee will build on the following key points:  
• Project prioritization  
• should be strongly based on scientific merit,  
• should consider the contribution of the different investigators to the trial and TR project,  
• will take into consideration if the applicant is an EORTC member or not (whilst maintaining the 
principle of access to the wider scientific community and commitments owed to study 
participants and ethical committees). 

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• Protection of confidentiality must be respected. 
• An EORTC HQ feasibility check, including recommendations for regulatory and ethical matters and 
other restrictions on the use of the HBM, will take place. If in the event the HBM collections are still 
retained at individual clinical sites, the TR project leader and the involved EORTC Group are 
responsible for collecting and providing information on availability of HBM for the feasibility 
assessment. 
• Prioritized TR projects will then be reviewed by the Translational Research Advisory Committee 
(TRAC). 
• Once SSC/Group committee prioritization, the EORTC HQ feasibility assessment, and TRAC review are 
complete and when all applicable competent Ethics Committees approvals are in place and ethical 
principles are met, the TR project can be activated and HBM release and analysis can commence. 
• The EORTC Board will mediate any disagreements of opinion between TRAC, the EORTC HQ feasibility 
assessment, the SSC/Group committee and the TR project leader(s), as needed. 
11 Investigator authorization procedure 
Investigators will be authorized to register and/or randomize patients in this trial only once they have 
returned the following documents to the EORTC Headquarters: 
• The updated signed and dated curriculum vitae of the Principal Investigator in English (not older than 
2 years) with a GCP training proof. 
• The (updated) list of normal ranges for the investigator’s institution signed and dated by the head of 
the laboratory. Please make sure normal ranges are provided also for those tests required by the 
protocol but not routinely done at the investigator’s institution. 
• The Confirmation of interest by Principal Investigator Form (CIF), stating that the investigator will fully 
comply with the protocol. This must include an estimate of yearly accrual and a statement on any 
conflict of interest that may arise due to trial participation. 
• The Study Agreement between EORTC and investigator's institution. 
• A copy of the favorable opinion of the local or national (whichever is applicable) ethics committee 
mentioning the documents that were reviewed (including the version numbers and version dates of 
all documents). A list of all members of the ethics committee is also requested. 
• A copy of the translated and adapted (according to all national requirements) Patient Information / 
Informed Consent Sheet (PISIC). Version numbers and dates must be clearly stated on each page. The 
signature log-list of the staff members with a sample of each authorized signature and the indication 
of the level of delegations. In case patients receive treatment at a satellite institution, i.e. outside the 
authorized institution, details on the satellite institution, including the CV of the local investigator, 
normal lab ranges and the approval of an ethics committee will have to be transmitted to the EORTC 
Headquarters. Please keep in mind that all communication is done ONLY between the primary 
institution and the EORTC HQ. 
• The full name, address, phone numbers and e-mail address of the local pharmacist who will be 
responsible for the trial medication (for any trial where the drug will be provided). 
• An accreditation, a certification, an established quality control / external quality assessment or 
another validation should be provided for the own laboratory. 
The center specific list of required documents will be included in the protocol activation package, with 
proper instructions as required by this protocol, your group and / or the applicable national law. 
The new investigator will be added to the “authorization list”, and will be allowed to register/randomize 
patients in the trial as soon as 

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• All the above-mentioned documents are available at the EORTC HQ. 
• All applicable national legal and regulatory requirements are fulfilled. 
Patient registration/randomization from centers not (yet) included on the authorization list will not be 
accepted. 
12 Patient randomization procedure 
Patient randomization will only be accepted from authorized investigators (see chapter on “investigator 
authorization procedure"). 
A patient can only be randomized after verification of eligibility. Both the eligibility check and 
randomization must be done before the start of the protocol treatment. 
Subjects should be registered shortly after signing the informed consent the EORTC online 
randomization system (ORTA = online randomized trials access), accessible 24 hours a day, 7 days a 
week, through the internet. To access the interactive randomization program, the investigator needs a 
username and a password (which can be requested at http://orta.eortc.be/). 
In case of problems EORTC participants can phone the EORTC Headquarters from 9.00 am to 5.00 pm 
(Belgian local time) from Monday through Friday to randomize patients via the EORTC call center. 
Randomization via the phone is not available on Belgian holidays. A list of these holidays is available on 
the EORTC web site (http://orta.eortc.be/) and it is updated annually. 
Through Internet: 
 
 
http://orta.eortc.be/ 
In case of problems randomization by phone:  
 
+32 2 774 16 00 
12.1 Registration (step 1) 
A list of questions to be answered during the registration procedure is included in the registration 
checklist, which is part of the case report forms.  
STANDARD INFORMATION REQUESTED: 
• EORTC institution number  
• EORTC protocol number (1613) 
• Step number: (1 - New patient) 
• Name of the responsible investigator  
• Patient's code (maximum 4 alphanumerics, a unique code to help identify the patient within your 
institution - not the patient initials)  
Patient's birth date (day/month/year) or year of birth (as allowed per applicable legislation)  
PROTOCOL SPECIFIC QUESTIONS: 
• All registration criteria will be checked one by one 
• Date of written informed consent (day/month/year) 
Once registration criteria have been verified, a sequential patient identification number (“seqID”) will be 
allocated. This number will allow the identification of the patients in the VISTA/Remote Data Capture 
system (VISTA/RDC) that will be used to complete the Case Report Forms.  
All SAMPLE SHIPMENTS and REPORTS must be identified with the EORTC Id (seqID) attributed at 
registration 

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12.2 Central lab review procedure of baseline sample (step 2) 
After registration and shipment of the sample, the central laboratory will assess the blood sample for 
circulating free DNA EGFR T790M (cfDNA T790M). The cfDNA T790M results of the central lab will be 
entered in the ORTA system (step 2) by EORTC HQ. 
If the analysis failed for any technical reason, the site will be allowed to send second blood sample for 
evaluation. 
A patient who has not been registered before the cfDNA T790M central testing will not be accepted for 
the study at a later date and cannot be entered for the second step of the study. All eligibility criteria 
must be met before proceeding to step 3 (below). 
At the end of step 2, once the cfDNA T790M results have been verified, the site will be informed by a 
notification email if, following the cfDNA T790M results the patient is eligible to start the randomization 
procedure (step 3). 
12.3 Randomization procedure (step 3) 
A patient who has not been registered and had the cfDNA T790M tested by the central lab will not be 
accepted for the study at a later date and cannot be checked for eligibility by the third step of the study.  
An exhaustive list of questions to be answered during the randomization procedure is included in the 
eligibility checklist, which is part of the case report forms. 
STANDARD INFORMATION REQUESTED:  
• Institution number  
• Protocol number (1613)  
• Step number: (3 – Existing patient)  
• Name of the responsible investigator  
The patient will have to be selected in the list of patients that have already been registered in the first 
step. Once the patient has been identified in the list, select the corresponding patient’s code. The 
patient’s code and date of birth will automatically be inserted in the identification screen.  
PROTOCOL SPECIFIC QUESTIONS:  
• All eligibility criteria will be checked one by one  
• Actual values of the eligibility parameters will be requested when applicable  
• Stratification factors  
Once eligibility and stratification factors have been checked, the treatment will be randomly allocated to 
the patient (minimization technique) and the site will be informed of it by an automatic notification email 
if the patient is eligible. 
13 Forms and procedures for collecting data 
13.1 Case report forms and schedule for completion 
Data will be reported on the forms specifically designed by the EORTC Headquarters for this study. Forms 
should be electronically sent to the EORTC Headquarters through the VISTA/RDC (Remote Data Capture) 
system, with the exception of the SAE form and the Pregnancy notification form which are paper CRFs. 

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SERIOUS ADVERSE EVENTS AND PREGNANCY NOTIFICATION FORMS SHOULD BE IMMEDIATELY 
REPORTED ACCORDING TO THE PROCEDURE DETAILED IN THIS PROTOCOL (see chapter on Reporting 
Serious Adverse Events). 
A. Before the treatment starts: 
The patient must be registered/randomized in the trial by INTERNET or in case of problems by phone. 
The electronic CRFs to be completed for a patient are available on the VISTA/RDC website one hour after 
the registration/randomization on http://rdc.eortc.be/ or on http://www.eortc.org in the section 
”Research Tools”. 
The paper SAE and Pregnancy Notification forms will be made available to the institution at the time the 
institution is authorized. 
B. During/after treatment 
The list of forms to be completed for this study and their submission schedule are available on the 
VISTA/RDC website and are also described in the "guidelines for completion of case report forms" that 
are provided to each participating investigator.  
ALL Forms must be electronically approved and sent by the responsible investigator or one of his/her 
authorized staff members with the exception of the paper SAE and Pregnancy Notification forms which 
need to be signed and dated individually by the responsible investigator or one of his/her authorized 
staff members 
13.2 Data flow 
The forms must be completed electronically, with the exception of the paper forms (SAE form and 
Pregnancy Notification), according to the schedule defined in the guidelines for completion of Case 
Report Forms. 
The list of staff members authorized to enter data (with a sample of their signature) must be identified 
on the signature log and sent to the EORTC Headquarters by the responsible investigator before the start 
of the study. To enter the RDC system, the investigator or authorized staff member needs to use the 
same username and password that are used to access the interactive randomization program (ORTA). 
In all cases, it remains the responsibility of the principal investigator to check that data are entered in the 
database as soon as possible and that the electronic forms are filled out completely and correctly.  
The EORTC Headquarters will perform extensive consistency checks on the received data. Corrections of 
obvious data errors will be done by the EORTC Data Manager, as outlined on the convention list, which 
can be downloaded from the EORTC trial specific webpage: http://www.eortc.be/protoc/. Queries will be 
issued in order to resolve other inconsistent data. The queries for the electronic forms will appear in the 
VISTA/RDC system and must be answered there directly. 
The EORTC data manager will subsequently apply the corrections into the database. 
When satellite institutions are involved, all contact is made exclusively with the primary institution, for 
purposes of data collection and all other study related issues. 
If an investigator (or an authorized staff member) needs to modify a CRF after the form has been 
electronically sent to the EORTC Headquarters, he/she should create a request for data correction in the 
VISTA/RDC system. 

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13.3 HBM* sample registration and tracking  
Once the patient is registered, this procedure might take up to one hour, the investigator or his/her 
authorized staff must log on "Samples" website at https://samples.eortc.be/ or by clicking on the link 
"Samples Website" at the bottom of the page http://rdc.eortc.be.  
"Samples" is a web-based tracking tool designed to register, manage and track Human Biological 
Materials collected in the frame of EORTC clinical trials.  
Details about access the "Samples" Website, register samples and tracking shipments are described on 
the guidelines of HBM* management.  
(*) Human Biological Material 
14 Reporting of Serious Adverse Events 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors follow specific 
procedures when notifying and reporting adverse events/reactions in clinical trials. These procedures are 
described in this section of the protocol. 
14.1 Definitions 
These definitions reflect the minimal regulatory obligations; specific protocol requirements might apply 
in addition. 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment”. An adverse event can therefore be any unfavorable and 
unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal 
laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated 
with the use of the protocol treatment, whether or not considered related to the investigational 
medicinal product. 
AR: An Adverse reaction of an investigational medicinal product is defined as “any noxious and 
unintended response to a medicinal product related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal 
relationship means to convey in general that there is evidence or argument to suggest a causal 
relationship. 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of which is not 
consistent with the applicable product information" (e.g. investigator's brochure for an unapproved 
investigational product or summary of product characteristics (SmPC) for a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product information this 
adverse reaction should be considered as unexpected. 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate or severe, or as described in CTC grades); the event itself, however, may be of relative 
minor medical significance (such as severe headache). This is not the same as “serious,” which is based 
on patient/event outcome or action criteria usually associated with events that pose a threat to patient’s 
life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations.  

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SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a patient, 
whether or not considered related to the protocol treatment, that at any dose: 
• results in death 
• is life-threatening (i.e. an event in which the subject was at risk of death at the time of event; it does 
not refer to an event which hypothetically might have caused death if it was more severe) 
• requires inpatient hospitalization or prolongation of existing patient hospitalization 
• results in persistent or significant disability or incapacity 
• is a congenital anomaly or birth defect 
• is a medically important event or reaction. 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered serious such as important medical events that might not be immediately life-threatening 
or result in death or hospitalization but might jeopardize the patient or might require intervention to 
prevent one of the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. 
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the protocol 
treatment.  
SUSAR: Suspected Unexpected Serious Adverse Reaction.  
SUSARs occurring in clinical investigations qualify for expedited reporting to the appropriate Regulatory 
Authorities within the following timeframes: 
• Fatal or life-threatening SUSARs within 7 calendar days 
• Non-fatal or non-life-threatening SUSARs within 15 calendar days 
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours. 
Second primary malignancy is one unrelated to the treatment of a previous malignancy (and is NOT a 
metastasis from the previous malignancy). 
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the previous malignancy. 
14.2 Exceptions 
The following situations do not need to be reported as SAEs:  
• Elective hospitalization for pre-existing conditions that have not been exacerbated by trial treatment. 
• A hospitalization which was planned before the patient consented for study participation and where 
admission did not take longer than anticipated. 
• A hospitalization planned for protocol related treatment or protocol related procedure as per 
institutional standard timelines. 
• Social and/or convenience admission to a hospital 
• Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads to the 
procedure is an (S)AE. 
• Situations where an untoward medical occurrence did not occur (palliative care, rehabilitation, 
overdose without occurrence of an adverse event). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 

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By EORTC convention, clinical events related to the primary cancer being studied or to the primary cancer 
progression are not to be reported as SAEs, even if they meet any of the seriousness criteria from the 
standard SAE definition, unless the event is more severe than expected and therefore the investigator 
considers that their clinical significance deserves reporting.  
14.3 Severity assessment 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE v4.0 
https://www.eortc.be/services/doc/ctc/. 
14.4 Causality assessment 
The investigator is obligated to assess the relationship between protocol treatment and the occurrence 
of each SAE following the definitions in this table: 
Relationship to the protocol treatment 
Description 
Reasonable possibility 
There is a reasonable possibility that the protocol 
treatment caused the event 
No reasonable possibility 
There is no reasonable possibility that the 
protocol treatment caused the event 
The investigator will use clinical judgment to determine the relationship. Alternative causes, such as 
natural history of the underlying diseases, medical history, concurrent conditions, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the protocol treatment will be 
considered and investigated. 
The decision will be recorded on the SAE form and if necessary the reason for the decision will also be 
recorded. 
14.5 Expectedness assessment 
The expectedness assessment is the responsibility of the sponsor of the study. The expectedness 
assessment will be performed against the following reference documents: 
• For osimertinib: Investigator's Brochure (The RSI is the IB section entitled "Reference safety 
information".) 
• For gefitinib: Summary of Product Characteristics (SmPC) (The RSI is section 4.8 in the SmPC.) 
14.6 Reporting procedure for investigators 
This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a subject is 
randomized until 30 days after last protocol treatment administration and to any SAE that occurs outside 
of the SAE detection period (after the 30-days period), if it is considered to have a reasonable possibility 
to be related to the protocol treatment or study participation. 
In addition, SAEs occurring after the subject signed the study-specific informed consent and prior to the 
initial dose of study drug will be collected only if they are considered by the Investigator to be causally 
related to required study procedures. 
Signed Patient Informed Consent till 
randomization: 
Only SAE* as result of a protocol-required 
intervention 
Randomization till 30 days after last protocol 
treatment administration: 
All SAEs 

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From day 31 after last protocol treatment 
administration: 
Only related SAEs 
Any secondary malignancy should also be reported in expedited way on a SAE form with the 
appropriate seriousness criteria! 
All reporting must be done by the principal investigator or authorized staff member (i.e. on the signature 
list) to confirm the accuracy of the report. 
All SAE data must be collected on the study-specific SAE form. 
All SAEs must be reported immediately and no later than 24 hours from the time the investigator or staff 
became aware of the event. 
All SAE-related information needs to be provided in English. 
All additional documents in local language must be accompanied by a translation in English, or the 
relevant information must be summarized in a follow-up SAE report form. 
All SAE-related information must be faxed or e-mailed to: 
 
EORTC Pharmacovigilance Unit: 
 
Fax No. +32 2 772 8027 or pharmacovigilance@eortc.org  
To enable the Sponsor to comply with regulatory reporting requirements, all initial SAE reports should 
always include the following minimal information: an identifiable patient (SeqID), a suspect medicinal 
product if applicable, an identifiable reporting source, the description of the medical event and 
seriousness criteria, as well as the causality assessment by the investigator. Complete information 
requested on the SAE form of any reported serious adverse event must be returned within 7 calendar 
days of the initial report. If the completed form is not received within this deadline, the 
Pharmacovigilance Unit will make a written request to the investigator. 
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 calendar days. 
All forms need to be dated and signed by the principal investigator or any authorized staff member (i.e. 
on the signature list). 
14.7 Reporting responsibilities for EORTC 
The EORTC Pharmacovigilance Unit will forward all SAE reports to the appropriate persons within the 
EORTC Headquarters and to the pharmacovigilance contact at the pharmaceutical company as per 
pharmacovigilance agreement. 
The EORTC Pharmacovigilance Unit will provide a six-monthly summary which will be added in the Trial 
Status Report and which will be accessible to all participating investigators.  
The EORTC Pharmacovigilance Unit will take in charge the reporting of SUSARs to the Competent 
Authorities, Ethics committees, EudraVigilance Clinical Trial Module (EVCTM) and all participating 
investigators whenever applicable. 
14.8 Pregnancy reporting 
Pregnancy occurring during a patient’s participation in this trial, although not considered an SAE, must be 
notified to the EORTC Pharmacovigilance Unit within the same timelines as an SAE (within 24 hours) on a 
Pregnancy Notification Form. The outcome of a pregnancy should be followed up carefully and any 
adverse outcome to the mother or the child should be reported. This also applies to pregnancies in 
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• Any pregnancy in a female subject or in a female partner of a male subject diagnosed during the 
treatment period or within 4 months after last protocol treatment administration must be reported 
to the EORTC Pharmacovigilance Unit  
• This must be reported within 24 hours of first becoming aware of the event by fax, to the 
Pharmacovigilance Unit on a Pregnancy Notification Form  
• If an SAE occurs in conjunction with the pregnancy, please also complete an SAE form as explained in 
the SAE reporting chapter 
15 Quality assurance 
15.1 Control of data consistency 
Data forms will be entered in the EORTC Headquarters database by using the VISTA/RDC (Remote Data 
Capture) system. Computerized and manual consistency checks will be performed on newly entered 
forms; queries will be issued in case of inconsistencies. Consistent forms will be validated by the Data 
Manager. Inconsistent forms will be kept "pending" until resolution of the inconsistencies. 
15.2 On-site monitoring 
The EORTC Headquarters will perform on-site monitoring visits according to the approved study-
monitoring plan. 
The first visit in a participating site will be performed within 3 to 6 months after the first patient's 
registration / randomization at this site. Frequency and number of subsequent visits will depend on site's 
accrual and quality observed during the first visit.  
The aim of these site visits will be: 
• to verify that the site facilities remain adequate for performing the trial 
• to verify that the principal investigator and site staff involved in the trial are working in compliance 
with GCP and protocol requirements  
• to assess the consistency of data reported on the case report forms with the source data 
• to check that Serious Adverse Events have been properly reported and that follow-up information or 
queries are correctly fulfilled 
• to assist the site in resolving any outstanding queries 
• to control the drug accountability process 
15.3 Audits 
The EORTC is responsible for the performance of the EORTC investigators. 
The investigator, by accepting to participate in this protocol, agrees that EORTC, any third party (e.g. a 
CRO) acting on behalf of the EORTC, or any domestic or foreign regulatory agency, may come at any time 
to audit or inspect their site and all subsites, if applicable.  
This audit consists of interviews with the principal investigator and study team, review of documentation 
and practices, review of facilities, equipment and source data verification. 
The investigator will grant direct access to paper and/or electronic documentation pertaining to the 
clinical study (e.g. CRFs, source documents such as hospital patient charts and investigator study files) to 
these authorized individuals. All site facilities related to the study conduct could be visited during an 
audit (e.g. pharmacy, laboratory, archives …). The investigator agrees to co-operate and provide 
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If applicable, the company(ies) supplying the study drug(s) may have access to anonymized data but will 
not have access to source documents. 
If a regulatory authority inspection is announced, the investigator must inform the EORTC Headquarters 
Compliance and Audits immediately (contact at: Complianceandaudits@eortc.org). 
In this way EORTC can provide support in preparing and/or facilitating the inspection. EORTC 
representatives/delegates may also attend the inspection. 
15.4 Quality assurance and quality control in imaging 
15.4.1 
Control of data completeness 
The EORTC HQ will track all scans of all patients received from the sites and will request/query 
missing/incomplete scans. Furthermore, if the scans arrive in unacceptable quality or in a non-acceptable 
format, the site will be informed to provide substitute scans. 
Scans will be uploaded by the participating centers via the EORTC imaging platform.  
Please refer to the imaging guidelines for more details. 
15.4.2 
Imaging guidelines “read and understood” acknowledgment page 
signature 
This is the first page of the imaging guidelines. Every site participating in an EORTC study with imaging, 
must comply with the minimum requirements established as specified in the imaging guidelines. The first 
page of the imaging guidelines must be signed and returned to the EORTC HQ for every new version of 
the imaging guidelines. The page must be signed by the head of radiology department. This is mandatory 
from all institutions in this study before activation to participate in it.  
15.4.3 
Scan quality control 
• QC will be performed on an on-going basis. 
• The EORTC Imaging manager will be reviewing all scans for all patients to check for artifacts and to 
ensure compliance with the imaging guidelines and study protocol.  
• Every subsequent scan on the same patient must be done with the same scanner across all visits. In 
case of scanner breakdown or change of scanners in the department, you need to notify the EORTC 
HQ. 
15.4.4 
Central review 
Retrospective central review of the images will be organized. For more information, see the independent 
central review charter. 
16 Ethical considerations 
16.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either the 
Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) 
and/or the laws and regulations of the country, whichever provides the greatest protection of the 
patient. 
The protocol has been written, and the study will be conducted according to the ICH Harmonized 
Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 

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https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-
practice_en.pdf). 
The protocol must be approved by the competent ethics committee(s) as required by the applicable 
national legislation. 
16.2 Subject identification 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. A sequential 
identification number will be automatically allocated to each patient registered in the trial. This number 
will identify the patient and will be included on all case report forms. In order to avoid identification 
errors, the patient’s code (maximum of 4 alphanumerics) and date of birth or year of birth (as allowed 
per applicable legislation) will also be reported on the case report forms. 
16.3 Informed consent 
All patients will be informed about 
• the aims of the study 
• the possible adverse events 
• the procedures and possible hazards to which the patient will be exposed 
• the mechanism of treatment allocation 
• strict confidentiality of any patient data 
• medical records possibly being reviewed for trial purposes by authorized individuals other than their 
treating physician 
The template of the patient’s informed consent statement is given as a separate document dated and 
version controlled to this protocol. 
An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and it is the responsibility 
of the Coordinating investigators for this trial (sometimes called National Coordinators) to adapt it to 
national/local requirements where necessary. 
The translated informed consent documents are to be submitted to ethics committees for approval. The 
competent ethics committee for each institution must approve the informed consent documents before 
the center can join the study. It is the responsibility of the competent ethics committee to ensure that 
the translated informed documents comply with ICH-GCP guidelines and all applicable national 
legislation. 
It is emphasized in the patient information sheet that participation is voluntary and that the patient is 
free to refuse further participation in the protocol whenever he/she wants to. This will not have any 
impact on the patient’s subsequent care. Documented informed consent must be obtained for all 
patients included in the study before they are registered and/or randomized at the EORTC Headquarters. 
The written informed consent form must be signed and personally dated by the patient or by the 
patient’s legally acceptable representative. 
All of the above must be done in accordance with the applicable national legislation and local regulatory 
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17 Administrative responsibilities 
17.1 The study coordinator 
The Study Coordinator works closely with the study team to develop the outline and full protocol and 
discusses the contents of the reports with the study team. The Study coordinator is responsible for 
publishing the study results. He/she will assist the Clinical Research Physician for answering some clinical 
questions concerning eligibility, treatment, and contributes to the medical review of the patients. 
Study coordinator: 
 
 
 
 
 
17.2 The EORTC Headquarters 
The EORTC Headquarters will be responsible for writing the protocol and PIS/IC, reviewing the protocol, 
setting up the trial, collecting case report forms, controlling the quality of the reported data, organizing 
the medical review and generating reports and analyses in cooperation with the Study Coordinator. All 
methodological questions should be addressed to the EORTC Headquarters. 
EORTC HEADQUARTERS 
 
Avenue E. Mounierlaan 83/11 
 
Brussel 1200 Bruxelles 
 
België - Belgique 
 
Fax: +32 2 7723545 
17.3 The EORTC group 
All questions concerning ongoing membership in the group should be addressed to the chairman and/or 
secretary of the group. 
For new membership contact Membership Committee at membership@eortc.org. 
Lung Cancer Group EORTC group 
Chairman: 
 
 
 
 
 
  
 
 

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Secretary: 
 
 
 
 
 
 
18 Trial sponsorship and financing 
EORTC is the legal Sponsor for all EORTC participants. 
The contact details of the EORTC are: 
 
EORTC Headquarters 
 
Avenue E. Mounierlaan 83/11 
 
Brussel 1200 Bruxelles 
 
België - Belgique 
 
Phone: +32 2 7741611 
 
Fax: 
+32 2 7723545 
 
e-mail: eortc@eortc.org 
The trial is supported with the educational grant by 
 that also provides osimertinib and 
gefitinib for free. 
19 Trial insurance 
A clinical trial insurance has been taken out according to the laws of the countries where the study will be 
conducted. An insurance certificate will be made available to the participating sites at the time of study 
initiation.  
Clinical trial insurance is only valid in centers authorized by the EORTC Headquarters. For details please 
refer to the chapter on investigator authorization. 
20 Results dissemination policy 
20.1 Study disclosure 
20.1.1 
Trial Registration 
This trial will be registered in a public database (https://www.clinicaltrialsregister.eu). As the clinical trial 
(CT) regulation 536/2014 of the European Union (EU) becomes applicable, more information about this 
trial will be uploaded in this public database in compliance with European requirements on transparency. 
Information posted, among others, will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.  
In accordance with applicable EU regulations, a summary of the trial results will be made publicly 
available within one year of the end of study declaration.  
EORTC as Sponsor of this trial will submit the summary of the results based on the final analysis report in 
compliance with the regulations. 

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20.1.2 
Final Analysis Report 
A Final Analysis Report that reports summary statistics of all the data collected for the study and presents 
an interpretation of the study results will be issued by the EORTC Headquarters. It will form the basis for 
the manuscript intended for publication. The Final Analysis Report or a summary thereof will be 
distributed to all participating groups, the supporting companies and ethics committees and the results 
will be posted in relevant public databases (as in section 20.1.1).  
20.2 Publication policy 
All publications must comply with the terms specified in the EORTC Policy 009 “Release of Results and 
Publication Policy” version 5.0 dated November 2020.  
In accordance with the Policy 009, results of the present study will be made public once the study data 
are mature for the final analysis of the primary study endpoint (as described in the section “statistics” of 
the present protocol), irrespective of the findings (positive or negative). Deviations from the results 
disclosure rules specified in the Policy require authorization by the Independent Data Monitoring 
Committee (IDMC).  
The primary trial publication will be written on the basis of the final analysis report and shall be published 
in a peer-reviewed scientific journal within 1 year of the date of the database lock. The principal study 
coordinator is responsible for drafting the manuscript. 
All publications ((papers, abstracts, presentations…) must be reviewed and approved by at least one 
EORTC Headquarters staff prior to submission to journal or congress or presentation. Approval and 
review by third parties involved in the study comply with all contractual agreement in place.  
The authorship rules conform to the recommendations of the International Committee of Medical 
Journal Editors defining the roles of authors and contributors 
(http://icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-
contributors.html) and will be attributed for each publication in line with the EORTC Policy referred 
above. All contributors who do not meet sufficient criteria for authorship will be acknowledged in the 
publication. 
Investigators will not independently publish site-specific results about the study endpoints until results of 
the whole study are published (or after one year following database lock if there is no publication). 
Deviations from this rule are authorized by the study IDMC. 
Sources of funding or support to the study will be disclosed and acknowledged in the publication.  
The name “EORTC” must be visible in the publications title or authors list. 
20.3 Data sharing 
EORTC is committed to ensuring that the data generated from its studies be put to good use by the 
cancer research community and, whenever possible, are translated to deliver patient benefit.  
It is therefore EORTC's policy to consider for sharing upon request from qualified scientific and medical 
researchers all data generated from its research whilst safeguarding intellectual property, the privacy of 
patients and confidentiality.  
Considering that ongoing research contributing to the completion of datasets must not be compromised 
by premature or opportunistic sharing and analysis of data, the EORTC will not release the data of its 
study until the primary study results have been published; unless authorization for release has been 
granted according to the terms of EORTC Policy 009.  

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Requests for accessing the data of published trials should be filed through the data sharing tab on the 
EORTC website (www.eortc.org). 

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Ref. 32 L.V. Sequist, J.C.-H. Yang, N. Yamamoto, K. O’Byrne, V. Hirsh, T. Mok, et al., Phase III study of 
afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR 
mutations, J. Clin. Oncol. 31 (2013) 3327–3334. doi:10.1200/JCO.2012.44.2806. 
Ref. 33 E. Eisenhauer, P. Therasse, J. Bogaerts et al. New Response Evaluation Criteria in Solid Tumors: 
Revised RECIST Guideline (Version1.1). Eur J Cancer. 2009 Jan;45(2):228-47 
Ref. 34 Dancey JE, Dodd LE, Ford R, et al. Recommendations for the assessment of progression in 
randomised cancer treatment trials. Eur J Cancer 2009 Jan;45(2):281–9. 
Ref. 35 Theodore G. Karrison , Michael L. Maitland , Walter M. Stadler , Mark J. Ratain . Design of Phase 
II Cancer Trials Using a Continuous Endpoint of Change in Tumor Size: Application to a Study of 
Sorafenib and Erlotinib in Non – Small-Cell Lung Cancer, J Natl Cancer Inst. 2007 Oct 
3;99(19):1455-61. 
Ref. 36 Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013; 
381(9868): 752-62. 
Ref. 37 Wildiers H, Heeren P, Puts M, et al. International Society of Geriatric Oncology Consensus on 
Geriatric Assessment in Older Patients With Cancer. J Clin Oncol 2014. 
Ref. 38 Bellera CA, Rainfray M, Mathoulin-Pelissier S, et al. Screening older cancer patients: first 
evaluation of the G-8 geriatric screening tool. Ann Oncol 2012; 23(8): 2166-72. 
Ref. 39 Kenis C, Decoster L, Van Puyvelde K, et al. Performance of two geriatric screening tools in older 
patients with cancer. J Clin Oncol 2014; 32(1): 19-26. 
Ref. 40 Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health 
problems warranting a geriatric assessment in older cancer patients: an update on SIOG 
recommendations. Ann Oncol 2014. 

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Appendix B: Abbreviations 
AE(se)  
adverse event(s) 
ALT/ALAT  
alanine aminotransferase 
AP  
alkaline phosphatase 
AR  
acquired resistance 
AST/ASAT  
aspartate aminotransferase 
BUN  
blood urea nitrogen 
cfDNA  
cell free circulating plasma DNA 
CIF  
confirmation of interest by principal investigator form 
CR  
complete response 
CT  
computed tomography 
CTCAE  
common terminology for adverse events 
EGFR  
epidermal growth factor receptor 
EGFR 
EGFR tyrosinase kinase inhibitors 
EGFR T790M 
substitution of threonine to methionine at amino acid position 790 (T790M) in 
exon 20 of the EGFR gene 
GGT  
gamma-glutamyl transferase 
Hb  
hemoglobin 
HMB  
human biological material 
IB  
investigator’s brochure 
ICH/GCP 
international conference on harmonization/ good clinical practice 
INR  
International Normalized Ratio 
ITT  
intent to treat 
LDH  
lactic dehydrogenase  
MRI  
magnetic resonance imaging 
NSCLC  
non-small-cell lung carcinoma 
ORR  
overall response rate 
OS  
overall survival 
PD  
progressive disease 
PET  
positron emission tomography 
PF  
prognostic factor 
PFS  
progression free survival 
PFSR-OSI-18  
progression free survival rate at 18 months 

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PISIC  
patient information sheet and informed consent 
PR  
partial response 
PS  
Performance Status 
QD  
daily dose 
RDC  
remote data capture 
RECIST  
response evaluation criteria in solid tumors 
RR  
response rate 
SAE(s)  
serious adverse event(s) 
SAR  
serious adverse reaction 
SD  
stable disease 
SmPC  
summary of product characteristics 
SSC 
study steering committee 
SMG 
Study management group 
SUSAR 
suspected unexpected serious adverse reaction 
TKI  
tyrosinase kinase inhibitors 
TTP  
time to progression 
TR  
translational research 
TRAC  
translational research advisory committee 
UAR  
Unexpected adverse reaction 
ULN  
upper limit of normal 
WBC  
white blood cells 

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Appendix C: WHO performance status scale 
Grade 
Performance scale 
0 
Able to carry out all normal activity without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out light 
work 
2 
Ambulatory and capable of all self-care but unable to carry out any work; 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; cannot carry on any self-care; totally confined to bed or chair 

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Appendix D: G8 geriatric screening tool 
(Version 1.0 - December 2010) 
To be completed by: Clinician, nurse or trained coder. 
Notes: This screening tool includes 7 items of the Mini Nutritional Assessment and the age of the patient. 
Score: Total score by adding up coded answers. 
G8 Screening tool 
 
Items 
Possible answers 
Score 
A 
Has food intake declined over the past 3 months 
due to loss of appetite, digestive problems, chewing 
or swallowing difficulties? 
0: severe reduction in food intake 
1: moderate reduction in food intake 
2: normal food intake 
………... 
B 
Weight loss during the last 3 months? 
0: weight loss >3kg 
1: does not know 
2: weight loss between 1 and 3 kg 
3: no weight loss 
………... 
C 
Mobility 
0: bed or chair bound 
1: able to get out of bed/chair but does 
not go out 
2: goes out 
………... 
E 
Neuropsychological problems 
0: severe dementia or depression 
1: mild dementia or depression 
2: no psychological problems 
………... 
F 
Body Mass Index (weight in kg/height in m2) 
0: BMI less than 19 
1: BMI 19 to less than 21 
2: BMI 21 to less than 23 
3: BMI 23 or greater 
………... 
H 
Takes more than 3 medications per day 
0: yes 
1: no 
………... 
P 
In comparison with other people of the same age, 
how does the patient consider his/her health 
status? 
0: not as good 
0,5: does not know 
1: as good 
2: better 
………... 
 
Age 
0: >85 
1: 80-85 
2: <80 
………... 
 
Total score (0-17) 
 
………... 
 

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Appendix E: Guidance regarding Potential Interactions 
With Concomitant Medications 
Guidance regarding potential interactions with concomitant medications 
The use of any natural/herbal products or other “folk remedies” should be discouraged, but use of these 
products, as well as use of all vitamins, nutritional supplements, and all other concomitant medications 
must be recorded in the eCRF. 
1. Drugs inducing CYP3A4 metabolism that 
 strongly recommend are not combined with 
osimertinib 
Osimertinib is metabolised by CYP3A4 and CYP3A5 enzymes. 
A drug-drug interaction study of osimertinib evaluated in patients showed that there is potential for 
osimertinib being a victim when co-administered with strong inducers of CYP3A4 (osimertinib 
concentrations are decreased when co-dosed with rifampicin). 
The following potent inducers of CYP3A4 must not be used during this study for any patient receiving 
osimertinib. 
Table 1 
Drugs inducing CYP3A4 
 
Contraindicated drugs 
 
Withdrawal period prior to osimertinib start 
Carbamazepine, phenobarbital, phenytoin 
Rifampicin, rifabutin, rifapentin 
St John’s Wort 
3 weeks 
Phenobarbitone 
5 weeks 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that are 
known to strongly modulate CYP3A4 activity. Appropriate medical judgment is required. Please contact 
 with any queries you have on this issue. 
2. Medicines whose exposures may be affected by osimertinib that 
 considers may be 
allowed with caution 
Osimertinib may increase the concentration of sensitive breast cancer resistance protein (BCRP) 
substrates and Pgp substrates (concentration of the sensitive BCRP substrate, rosuvastatin, and sensitive 
Pgp substrate, fexofenadine, are increased). 
 
 

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Table 2 
Exposure, pharmacological action and toxicity may be increased or 
decreased by osimertinib 
Warning of possible interaction 
Advice 
Rosuvastatin 
Sulfasalazine 
Doxorubicin 
Daunorubicin 
Topotecan 
Aliskiren 
Drugs are permitted but caution should be 
exercised and subjects monitored closely for 
possible drug interactions. Please refer to 
full prescribing information for all drugs 
prior to co-administration with osimertinib 
Dabigatran etexilate 
Digoxin 
 
 
3. Drugs that may prolong QT interval 
The drugs listed in this section are taken from information provided by The Arizona Centre for Education 
and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and Rockville, Maryland. 
Ref: https://crediblemeds.org/ndfa-list/. 
The website categorizes drugs based on the risk of inducing Torsades de Pointes (TdP). 
During screening the drugs that patients are currently prescribed should be checked opposite the 
ArizonaCert website. 
4.1 Drugs with a known risk of Torsades de Pointes  
The following drugs prolong the QT interval and are clearly associated with a known risk of TdP, even 
when taken as recommended. These drugs must have been discontinued prior to the start of 
administration of study treatment in accordance with guidance provided in Table 3 and should not be co-
administered with study treatment (osimertinib) and for a period of two weeks after discontinuing study 
treatment, however if it is considered essential for patient management to co-administer these drugs 
with study treatment (osimertinib) close monitoring of ECGs and electrolytes is recommended. The list of 
drugs may not be exhaustive and is subject to change as new information becomes available. As such 
investigators are recommended to search the website to provide the most up to date information. 
Table 3 
Drugs* with known risk of TdP 
Contraindicated drug 
Withdrawal period prior to osimertinib 
start& 
Anagrelide, aclarubicin, ciprofloxacin, 
clarithromycin, cocaine, droperidol, 
erythromycin, levofloxacine, ondansetron, 
papaverine hydrochloride, procainamide, 
sulpiride, sultopride, terfenadine terlipressin 
2 days 

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Table 3 
Drugs* with known risk of TdP 
Contraindicated drug 
Withdrawal period prior to osimertinib 
start& 
Cilostazol, cisapride, disopyramide, 
dofetilide, domperidone, flecainide, 
gatifloxacin, grepafloxacin, ibutilide, 
moxifloxacin, oxaliplatin, propofol, quinidine, 
roxithromicyn, sevoflurane, sotalol, 
sparfloxacin, thioridazine 
7 days 
Azithromycin, bepridil, citalopram, 
chlorpromazine, dronedarone, escitalopram, 
fluconazole, halofantrine, haloperidol, 
levomepromazine, levosulpride, 
mesoridazine 
14 days 
Donezepil, terodiline 
3 weeks 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide, Ibogaine 
  
6 weeks# 
Pentamidine 
8 weeks 
Astemizole, probucol, vandetanib 
4 months 
Amiodarone, chloroquine 
1 year 
* 
This list should be checked against the full and most current list presented in the CredibleMeds® 
website (https://www.crediblemeds.org/). 
& 
Values determined from comprehensive review (internal to 
) of each compound’s PK 
half-life and determination of the wash-out period. 
# 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied. 
4.2 Other TdP risk categories 
Patients receiving drugs that prolong QT interval or may increase the risk of TdP from other TdP risk 
categories can be enrolled, notwithstanding other exclusions and restrictions, if these drugs are 
considered essential for patient management and the patient has been stable on therapy. Close 
monitoring with ECGs and electrolytes is recommended. 
Patients with congenital long QT syndrome (CLQTS) are excluded from this study. 
4.3 Guidance regardless of TdP risk category 
Following study treatment initiation if it is considered essential for patient management to give drugs 
known to prolong QTc interval, regardless of TdP risk category, close monitoring with ECGs and 
electrolytes is recommended. 

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Appendix F: Specific protocol instructions during the 
COVID-19 crisis 
Note: all instructions listed in this Appendix will be solely applicable during the COVID-19 crisis. 
Furthermore, please ensure that any protocol deviations resulting from COVID-19 are: 
• Adequately documented in the eCRF’s, as well as in the patient’s medical records or in a Note To 
File (NTF) to be stored in your Study binder (ISF). 
• Always begin any deviation text with “COVID-19”. 
1. Introduction 
Current information suggests that cancer patients have a higher risk of infection and serious 
complications from infections including COVID-19, than other patients. 
It is strongly recommended that investigators exercise medical/clinical judgement, and decisions 
regarding each patient should be individualized after considering the overall goals of treatment, the 
patient’s current oncologic status and treatment tolerance as well as their general medical condition.  
In addition, investigators should adhere to local and institutional guidelines for SARS-CoV-2 infection and 
suspected COVID-19 infection. 
2. COVID-19 risk-benefit assessment 
EORTC trial 1613-LCG APPLE is enrolling patients with metastatic non-small cell lung cancer and with 
common EGFR activating mutations (del19 or L858R). The trial aims to evaluate the best strategy for 
delivering osimertinib in this patient population. 
Treatment with EGFR inhibitors, such as osimertinib and gefitinib, represents a standard of care in this 
patient population, although the best sequential treatment strategy, as well as the role of the liquid 
biopsy in guiding the treatment decision are under active investigation. EGFR inhibitors increased 
significantly the patient survival, and the identification of the best treatment strategy is crucial to achieve 
further improvements of survival. In addition, the definition of the role of liquid biopsy might decrease 
the patient exposure to invasive procedures (i.e. tissue biopsy) and be essential to guide the treatment in 
the era of the personalized medicine. We believe that the APPLE trial is innovative with this respect and 
very important for the future lung cancer care. 
There are risks about these treatments, and especially during the COVID19 crisis, these risks are 
significantly increased: 
• The fact that included patients need to come for regular visits to the hospital every 4 weeks, 
significantly increases their exposure risk to persons who are contagious for COVID-19. General rules 
like social distancing (1.5 m) and avoidance of persons with possible signs or confirmed diagnosis 
should be applied. But COVID-19 can also be contagious in persons who don’t have symptoms, so 
every hospital visit increases the risk of getting infected with “SARS-CoV2”. In addition, age and 
comorbidities, in particular cardiovascular and diabetes, are risk factors for severe course of the 
infection. 
• Both osimertinib and gefitinib are known to induce pneumonitis and interstitial lung disease. In 
addition, early reductions in leukocytes, lymphocytes, and neutrophils values have been observed 
with osimertinib, which stabilized over time and then remained above the lower limit of normal. 
These may represent additional risks for the patients. 

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• Osimertinib is also known to induce QT interval prolongation, and therefore, concomitant 
administration of drugs known to prolong QT interval is not allowed. Hydroxychloroquine sulphate 
and azithromycin may be used to treat COVID-19 infection. However, these drugs are known to 
prolong QT interval and cannot be administered with osimertinib. The risk related to drugs interaction 
might limit the treatment choice for the patients and this represents an additional risk. 
3. Proposed measures for patients already enrolled during the COVID-19 crisis 
Based on the above risk-benefit assessment, the study coordinators, in collaboration with EORTC, 
propose the following guidelines as long as the current COVID-19 crisis is ongoing. 
a) Study treatment 
Study drugs (osimertinib and gefitinib) are dispensed according to protocol sections 5.1.3 and 5.2.3. 
However, temperature-controlled shipments of osimertinib and gefitinib from the hospital to the 
patient’s homes with a courier can be organized by the EORTC in the case that patients cannot come to 
the hospital due to the COVID-19 crisis.  
Please refer to the IMP guidelines addendum for more detailed and specific instructions on drug 
shipment and storage conditions. 
The process for shipping directly to subjects from sites must be fully documented and traceable in a note 
to file (NTF, template provided by EORTC). 
The site must inform the EORTC 1613 study team (1613@eortc.org) upfront if a shipment of gefitinib 
and/or osimertinib needs to be organized for a patient. 
Before provision of gefitinib and/or osimertinib bottles to the patient, the investigator must provide 
his/her approval to the patient or the qualified person in charge of patient care. 
In case of any delays, the site needs to report this in the comment fields of the applicable CRFs and in 
the Source Data as well. 
The PI should inform the patients that drug suppliers will be receiving their name and address for delivery 
and that they will not store this information.  
Complement of information to provide to patients in relation to the processing of their personal data: 
• To insure the continuity of the treatment and therefore patient's vital interests, patient's name and 
address will be communicated by the investigator or the staff of the hospital to the organization 
responsible for the drug supply. 
• EORTC and/or the hospital will ensure that patient's name and address are processed in the secure 
way and are not used for any other purpose than for delivering the drugs to the patient. 
• EORTC and/or the hospital will ensure that this additional information is not anymore stored by the 
drug suppliers once these exceptional measures are over and the treatment and/or follow-up are 
back to the normal. 
The safety monitoring evaluations (hematology and biochemistry, ECG, echocardiogram, 
ophthalmological examination) should be performed as much as possible in accordance with the protocol 
chapter 6. If this is not possible, taking into consideration that osimertinib and gefitinib are marketed 
drugs in use since several years, some of the above safety evaluations are not critical. During COVID-19 
crisis, it is very important that patients continue to receive the study treatment with minimal risks of 
infection.  
Therefore, the following measures should be considered: 

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• Perform the safety monitoring evaluation at the center. Once the treating physician has assessed the 
results of the evaluations, organize a visit via a phone call/video call to assess the adverse events and 
patient’s performance, and organize the drug shipment to the patient’s home. 
• Provide standard assessments (e.g. hematology, biochemistry) of the subject either by qualified staff 
of contracted laboratories or contractually secured healthcare providers who employ appropriate 
safety measures and excludes patients who are quarantined or living with or have been quarantined 
with a confirmed coronavirus case. 
• If none of the above is possible, and the safety monitoring evaluations are to be skipped, then the 
treating physician has to evaluate the risk-benefit of the patient before skipping any assessment. 
• If the patient has to switch from the treatment with gefitinib to the treatment with osimertinib, all 
the required evaluations have to be performed before the switch. However, echocardiogram and 
ophthalmological examination might be obtained later, as soon as this becomes possible, provided 
that the treating physician has carefully performed a risk-benefit assessment. 
Patients receiving gefitinib who experience disease progression according to RECIST 1.1 should be 
switched to osimertinib at the next per protocol planned medical visit (4 weeks since previous medical 
visit), as per sections 6.2.3 and 6.3.3. Switch delays should be avoided as much as possible. However, if 
the patient is asymptomatic and is experiencing a clinical benefit and provided that the treating physician 
has carefully reviewed the risk-benefit assessment, switch to osimertinib might be delayed (the patient 
has to switch at the latest at the next per protocol planned visit, 4 weeks since the theoretical date of 
switch). 
b) Study imaging procedures 
For the baseline study imaging procedures, the protocol requirements have to be fully met. 
For on-study imaging procedures, it is preferred that the patient has imaging performed at the 
investigative site as directed in the protocol sections 6.1.2.4, 6.2.2.2, 6.2.3.5, 6.3.2.2 and 6.3.3.5. 
If difficulties are encountered to perform the imaging as per the protocol, there are several possibilities, 
in order of preference: 
• Have the imaging performed offsite, locally according to the protocol-specified timing. Guidance 
should be given by the site to the local imaging facility about conducting scans with requirements 
(modality etc, as per Imaging Guidelines).  
• Have the imaging performed at the site but delayed to a significant extent (with a window of 10 days 
from theoretical planned date per protocol) due to travel restriction / safety of the participant. 
• Have the imaging performed offsite but delayed (with a window of 10 days from theoretical planned 
date per protocol) due to travel restriction / safety of the participant.  
• Skip the imaging only if impossible to perform due to travel restriction / safety.  
Particular attention should be given to the imaging for disease evaluation at 18 months (+/- 14 days) 
which should be done on time as this represents the primary endpoint evaluation of the trial. 
For all above situations, the Site needs to report this in the comment fields of the applicable CRFs and 
in the Source Data as well. 
c) Study physical visits 
Patient Physical Visits can be changed into phone visits or video call visits where needed. 
The site must inform the EORTC 1613 study team (1613@eortc.org) upfront if a physical visit will be 
replaced by a phone/video call visit. 
 

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d) Collection of samples for translational research 
Collecting blood samples for assessing T790M status according to the protocol is a priority in the study, 
especially in arm B as these results influence the treatment decision. 
If this is not possible, the study coordinators propose the following: 
• If the patient is randomized in arm B and receiving gefitinib, continue to collect the blood samples for 
central T790M status according to the protocol section 6.2.2.1. However, if this is not possible, then, 
it might be skipped after prior discussion with EORTC Headquarters. 
• If the patient is randomized in arm A and C, or if the patient already switched to osimertinib, 
collection of blood samples for central T790M status might be skipped, according to local situation. 
e) Covid-19 vaccination during study participation 
As per the European Medicines Agency (EMA): 
• If physicians decide to administer SARS-CoV-2 vaccines in patients enrolled in the study, decisions 
should be individualized based on the risk of SARS-CoV-2 complications and potential benefit from 
the vaccine, general condition of the patient and the severity of COVID-19 outbreak in a given area or 
region and in accordance with the vaccine label. Furthermore the Country guidelines and/or 
institutional guidelines, must be followed. 
• Treatment schedule should not be altered because of the COVID-19 vaccination. 
• The administration of a SARS-CoV-2 vaccine stating the name of the vaccine used ( e.g. Moderna, 
Pfizer BioNTech, AstraZeneca Oxford…) shall be added in the concomitant medication form in the 
eCRF and noted in the patient’s Medical file. Any possible vaccine related AE should be captured in 
the AE forms in the eCRFs, specifying the potential relationship to the vaccine. 
f) Serious adverse events reporting 
• Sites should follow the SAE reporting as described in the protocol, e.g. the sites should continue to 
report SAEs immediately and no later than 24 hours form the time the investigator or site staff 
became aware of the event, as described in the protocol. There is no specific adaptations to the 
protocol defined SAE reporting procedure due to COVID-19.  
• Should sites have any SAE reporting related questions, please contact us at 
pharmacovigilance@eortc.org  
• Should there be a suspected or confirmed serious case of COVID-19 infection, this must be reported 
as SAE: 
• Please remember to provide the mandatory SAE information as per protocol and as per the CRF 
completion guidelines.  
• Please indicate if the COVID-19 infection was confirmed by a test.  
• Please provide as much information as available. 
4. Additional guidance specifically for osimertinib during COVID-19 pandemic 
Risk of ILD associated with the use of osimertinib 
Symptoms of the coronavirus include fever, cough, shortness of breath, difficulty breathing and 
sometimes an abnormal chest scan. Please note that these symptoms are also symptoms of osimertinib-
induced ILD/pneumonitis. 
Physicians should be familiar with the accurate diagnosis of a coronavirus infection versus any other 
bacterial or viral lung infection versus symptoms suggestive of ILD since the management is different for 
each. A thorough evaluation should be performed to accurately identify the underlying pathology should 

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a patient present with these symptoms or an abnormal chest radiograph. From available publications, the 
principle difference in imaging findings (Chest X-ray/CT) between drug-induced ILD and COVID-19 is the 
rate of progression and resolution of abnormalities. Notably, some patients presenting early in their 
course may have no significant radiological changes, and initial imaging findings are unlikely to be able to 
discriminate between drug-induced ILD and COVID-19. Data are too limited to provide clear 
recommendations; however, imaging assessment should be performed as per standard management 
guidelines for drug-induced ILD. Improper management or treatment of either etiology could lead to 
severe pulmonary events or death. 
As per standard management guidelines for drug-induced ILD, before initiation of steroid treatment, 
infectious causes of ILD should be excluded. This includes COVID-19 infection because steroid treatment 
should be avoided in COVID-19 as per available recommendations (e.g., CDC, WHO). However, a case-by-
case assessment of the benefit/risk balance is needed for more severe cases of disease, e.g., ARDS/septic 
shock in COVID-19 patients (with ILD or viral pneumonia). 
Similarly, a case-by-case assessment of the benefit/risk balance for an individual patient should be done 
for decisions on discontinuing or pausing treatment.  
For osimertinib induced-ILD monitoring and management, please refer to the protocol (section 5.6 and 
subsections). 
Patients should be reminded that, if a potential exposure to COVID-19 is suspected, they should notify 
the medical personnel of their participation in this clinical trial and medication they are taking. If a 
patient exhibits symptoms consistent with those of either drug-induced ILD or COVID-19, it is 
recommended that she/he should be advised to contact both the recommended COVID-19 point of 
contact (as per local guidance), as well as her/his investigator/oncologist by phone.  
Risk of drug-drug interactions between osimertinib and empirical therapies used to treat COVID-19  
At present several different drugs are empirically investigated for the treatment of COVID-19. The safety 
profile of these drugs in this unapproved indication is currently not known. Therefore, careful 
consideration should be taken when assessing the tolerability profile for these drugs in combination with 
osimertinib.  
Things to consider with osimertinib regarding drug interactions include potentiation of QT prolongation 
with medications known to prolong the QTc interval, avoiding medications that are strong CYP3A4 
inducers (or dose adjusting if avoidance is not possible), and the potential for increased exposure of BCRP 
or P-gp substrates. 
It is deferred to the medical judgement of the investigator on using osimertinib concomitantly with any 
medication which is anecdotally used for treating COVID 19. Reference to the protocol 
inclusion/exclusion criteria and restrictions (please refer to section 5.7 and subsections, and Appendix E, 
for further information on concomitant medications) should be always be considered to maintain the 
safe use of osimertinib in the clinical trial. Additionally, reference to the respective labels of the 
concomitant medications should be made for additional information. 
Risk of QT prolongation 
Antimalarial hydroxychloroquine sulphate and antibiotic azithromycin are both known to cause QT 
prolongation. When the potential benefit of hydroxychloroquine sulphate and/or azithromycin is being 
considered to treat patients with COVID-19, these are not compatible with osimertinib treatment. 
Therefore, per current protocol (please refer to section 5.7 and subsections, and Appendix E, for further 
information on concomitant medications) osimertinib should not be given concomitantly with these 
drugs. 

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Other drugs with a potential risk of QT prolongation include antiretrovirals such as lopinavir/ritonavir. 
Particular caution must be used when considering concomitant treatment of these drugs with 
osimertinib.  
Treatment for COVID-19 should be assessed on an individual case by case basis by the treating physician 
as well as the decision for discontinuing or pausing treatment with osimertinib.