Conditions: Non Small Cell Lung Cancer Metastatic
Keywords: NSCLC EGFR TKI EGFRm T790M
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 155
Healthy volunteers: no

Brief summary:
BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation.

Detailed description:
Lung cancer has been the most common carcinoma in the world for several decades. Non-small cell lung carcinoma (NSCLC) represents approximately 80-85% of all lung cancers. At the time of diagnosis approximately 70% of NSCLC patients already have advanced or metastatic disease not amenable to surgical resection. A significant percentage of early stage NSCLC patients who have undergone surgery subsequently develop distant recurrence.

First-generation EGFR tyrosine kinase inhibitors (TKIs) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm) non-small cell lung carcinoma (NSCLC). However, all patients ultimately develop disease progression, driven - as the most prevalent identified biological mechanism - by the acquisition of a second T790M EGFR TKI resistance mutation.

Osimertinib (AZD9291) is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm-sensitizing and T790M resistance mutants. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier first and second generation EGFR TKIs.

Osimertinib is being evaluated in several prospective clinical trials, notably in frontline treatment, in the adjuvant setting, and in combination with later lines in EGFRm positive advanced disease. Combination treatments that target both tumour cells and tumour microenvironment (such as angiogenesis) may be a promising strategy for further improving efficacy outcomes in patients with EGFRm NSCLC following progression on EGFR TKI therapy and other lines of therapy. There is thus a considerable unmet clinical need for novel therapeutic options that can further extend the efficacy of targeted agents such as EGFR TKIs, across all lines of therapy.

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the interaction of VEGF-A to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Neutralising the biological activity of VEGF regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth. Bevacizumab is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC in combination with carboplatin and paclitaxel.

Osimertinib monotherapy, at the dose to be evaluated in this trial, has shown consistent and high objective response rates in the target patient population.

Anti-angiogenic agents targeting the VEGF/VEGFR signalling pathway have been shown to provide additional efficacy when used in combination with first-line platinum-based chemotherapy in several trials in non-squamous NSCLC or in combination with erlotinib as first line therapy in EGFRm positive NSCLC patients. The combination of osimertinib plus an anti-angiogenic agent such as bevacizumab may provide a wider activity against tumours that have developed resistance to EGFR TKI agents by blocking the dual pathways of proliferative signalling and antigenic signalling. Preclinical studies suggested that patients on lower doses of EGFR TKI tend to develop treatment resistance earlier than those who receive higher doses. Therefore the combination may also delay the development of subsequent resistance as the preclinical studies suggested anti-angiogenic agents may increase intratumoural uptake of anti-cancer drugs by changing tumour vessel physiology.

Efficacy and safety data from the osimertinib monotherapy studies have shown promising efficacy and an acceptable safety profile at the recommended dose of 80 mg once daily. The combination of osimertinib with bevacizumab may have the potential to provide additional clinical benefit in terms of increased and/or prolonged disease control and a delay in the emergence of resistance in patients with advanced EGFRm NSCLC who have progressed following a prior EGFR TKI agent, compared against the current standard of care (chemotherapy or another EGFR TKI) or monotherapy of any of the individual agents.

Arms:
arm 1: Patients will receive treatment with osimertinib and bevacizumab until disease progression, lack of tolerability or the patient declines further treatment. Treatment may also continue beyond progression for as long as the patient may still derive benefit. arm 2: Patients will receive treatment with osimertinib until disease progression, lack of tolerability or the patient declines further treatment. Treatment may also continue beyond progression for as long as the patient may still derive benefit.

Interventions: intervention 1: Osimertinib intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Osimertinib is administered orally at 80mg once daily. Doses should be taken approximately 24 hours apart at the same time point each day. The appropriate number of osimertinib tablets will be provided to patients to be self-administered at home. AstraZeneca will supply osimertinib as tablets for oral administration.

AstraZeneca will supply osimertinib as tablets for oral administration. intervention 2: Bevacizumab is administered at 15mg/kg intravenously on day 1 of every 3-week cycle. Bevacizumab for intravenous administration will be supplied by Roche.

Protocol document:
Prot_000.pdf: 
ETOP 10-16 BOOSTER v1.0 20161114 
 
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ETOP 10-16 BOOSTER 
A randomised phase II trial of osimertinib and bevacizumab versus 
osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC 
with confirmed EGFRm and T790M 
 
BOOSTER: Osimertinib and Bevacizumab versus Osimertinib alOne as 
Second-line Treatment in stage IIIb-IVb NSCLC with confirmed EGFRm 
and T790M 
 
 
Sponsor: European Thoracic Oncology Platform (ETOP) 
 
 
 
 
EudraCT number: 2016-002029-12 
 
 
AstraZeneca Number: ESR-15-11666 
Roche Number: MO39447 
 
 
ETOP c/o IBCSG Coordinating Centre, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 511 94 00 
Fax: +41 31 511 94 01 
 
Version 1.0 
14 November 2016 
 


ETOP 10-16 BOOSTER v1.0 20161114 
 
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Contacts 
 
Trial Chair 
Solange Peters, MD-
PhD 
 
 
 
 
Address 
 
 
Tel:  
Fax: 
Email: 
Département d'Oncologie 
Centre Hospitalier Universitaire Vaudois  
1011 Lausanne, Switzerland 
+41 79 556 01 92 
+41 21 314 07 37 
solange.peters@chuv.ch 
Trial Chair and ETOP 
Chairman 
Rolf Stahel, MD 
Address 
 
 
 
Tel: 
Fax: 
Email:  
Clinic of Oncology 
University Hospital Zuerich  
Raemistrasse 91 
CH-8091 Zürich, Switzerland  
+41 44 255 22 19 
+41 44 255 9780 
rolf.stahel@usz.ch 
Trial Co-Chair 
Ross Soo 
Address 
 
 
Tel: 
Fax: 
Email: 
National University Hospital 
1E Lower Kent Ridge Road 
Singapore 
+6567724140 
+6567775545 
ross_soo@nuhs.edu.sg 
Trial Co-Chair 
Ji-Youn Han 
Address 
 
 
Tel: 
Fax: 
Email: 
National Cancer Center 
323 Ilsan-ro, Ilsan-dong-gu 
Goyang, Korea 
82-31-920-1154 
82-31-920-2587 
jymama@ncc.re.kr 
Translational Research 
Coordinator 
Rosita Kammler 
Address 
 
 
 
Tel: 
Fax: 
Email:  
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 28 
+41 31 511 94 01 
rosita.kammler@ibcsg.org 
Central Laboratory 
 
Address 
CHUV - Department of oncology 
Center for Experimental Therapeutics (CTE) 
Hôpital Orthopédique 
HO 05/1552 
Av. Pierre-Decker 4 
CH-1011 Lausanne, Switzerland 
Statistics 
Urania Dafni, ScD 
 
 
 
 
 
Zoi Tsourti, PhD 
Address 
 
 
Tel:  
Fax: 
Email: 
Email: 
Frontier Science Foundation – Hellas 
116 Papadiamantopoulou Str. 
15773, Zografou, Athens, Greece 
+302107710902 
+302107710903 
udafni@frontier-science.gr 
ztsourti@frontier-science.gr 
Project Manager 
 
 
 
 
 
 
 
Data Management 
Mark Finlayson, PhD 
 
 
 
 
 
 
Anne-Christine 
Piguet, PhD 
Address 
 
 
 
Tel: 
Fax: 
Email: 
 
Tel: 
Fax: 
Email: 
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 34 
+41 31 511 94 01 
BOOSTER@etop-eu.org 
 
+41 31 511 94 21 
+41 31 511 94 01 
ETOPDataManagement@etop-eu.org 


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Drug supply 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Drug Supply Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 16 
+41 31 389 92 29 
drugsupply@etop-eu.org 
Safety and Regulatory 
Affairs 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email: 
ETOP Safety and Regulatory Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 16 
+41 31 389 92 29 
regulatoryoffice@etop-eu.org 
ETOP Medical Affairs 
 
 
 
 
 
Manuela Rabaglio, 
MD 
Address 
 
 
 
Tel. 
Fax : 
Email : 
ETOP Medical Affairs 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 20 
+41 31 511 94 01 
medical.affairs@ibcsg.org 
ETOP Coordinating 
Office 
Anita Hiltbrunner 
 
 
 
 
 
 
Heidi Roschitzki, 
PhD 
 
Address 
 
 
Tel:  
Fax: 
Email: 
 
Tel: 
Fax: 
Email: 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 42 
+41 31 511 94 01 
anita.hiltbrunner@etop-eu.org 
 
+41 31 511 94 18 
+41 31 511 94 01 
heidi.roschitzki@etop-eu.org 
Remote Data Entry 
system 
Anne-Christine 
Piguet, PhD 
 
Technical assistance 
 
ETOPDataManagement@etop-eu.org 
 
 
richard.king@etop-eu.org 
 
In collaboration with AstraZeneca (supply of osimertinib and trial support) and Roche (supply 
of bevacizumab). 
 
 


ETOP 10-16 BOOSTER v1.0 20161114 
 
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Protocol Signature Page 
 
 
ETOP 10-16 BOOSTER 
 
A randomised phase II trial of osimertinib and bevacizumab versus 
osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC with 
confirmed EGFRm and T790M 
 
Approved by: 
 
Solange Peters 
Trial Chair 
 
 
 
 
 
Date 
 
Rolf Stahel 
Trial Chair and 
ETOP Chairman 
 
 
 
 
 
 
Date 
 
Urania Dafni 
Biostatistician 
 
 
 
 
 
Date 
 
Anita Hiltbrunner 
ETOP Director 
 
 
 
 
 
Date 
 
 


ETOP 10-16 BOOSTER v1.0 20161114 
 
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Principal Investigator Protocol Signature Page 
 
 
ETOP 10-16 BOOSTER 
 
A randomised phase II trial of osimertinib and bevacizumab versus 
osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC with 
confirmed EGFRm and T790M 
 
I have read the protocol and agree that it contains all necessary details for conducting this 
trial. I will conduct the trial as outlined in the following protocol and in compliance with 
GCP, and will apply due diligence to avoid protocol deviations. I will provide copies of the 
protocol and all drug information relating to pre-clinical and prior clinical experience 
furnished to me by ETOP, to all physicians responsible to me who participate in this trial. I 
will discuss this material with them to assure that they are fully informed regarding the drug 
and the conduct of the trial. I agree to keep accurate records on all patient information 
including patient's informed consent statement, drug shipment and return forms, and all 
other information collected during the trial for a minimum period of 15 years. 
 
 
Name of Principal Investigator:  
 
 
 
Institution’s name and place: 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 


ETOP 10-16 BOOSTER v1.0 20161114 
 
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TABLE OF CONTENTS  
Section 
Page 
1. 
Protocol summary ...................................................................................................... 9 
2. 
List of abbreviations ................................................................................................ 13 
3. 
Trial schedule ........................................................................................................... 16 
4. 
Background and rationale ........................................................................................ 19 
4.1. 
Disease background ............................................................................................. 19 
4.2. 
Treatment background ......................................................................................... 21 
4.3. 
Overall risk / benefit assessment ......................................................................... 22 
4.4. 
Rationale for trial design, doses and control groups ........................................... 23 
5. 
Objectives and endpoints ......................................................................................... 24 
5.1. 
Primary objective ................................................................................................. 24 
5.2. 
Secondary objectives ........................................................................................... 24 
5.3. 
Primary endpoint ................................................................................................. 24 
5.4. 
Secondary endpoints ............................................................................................ 25 
5.5. 
Correlative studies ............................................................................................... 25 
6. 
Trial design, duration and termination ..................................................................... 25 
6.1. 
Trial design .......................................................................................................... 25 
6.2. 
Sample size and trial duration ............................................................................. 26 
7. 
Patient selection ....................................................................................................... 26 
7.1. 
Inclusion criteria .................................................................................................. 26 
7.2. 
Exclusion criteria ................................................................................................. 28 
8. 
Patient screening and randomisation ....................................................................... 29 
8.1. 
Screening ............................................................................................................. 29 
8.2. 
Randomisation and stratification ......................................................................... 29 
9. 
Investigational medicinal products .......................................................................... 30 
9.1. 
Osimertinib .......................................................................................................... 30 
9.2. 
Bevacizumab ....................................................................................................... 30 
9.3. 
Packaging and labeling ........................................................................................ 31 
9.4. 
Clinical supplies disclosure ................................................................................. 31 
9.5. 
Storage and handling ........................................................................................... 31 
10. 
Trial treatments ........................................................................................................ 32 
10.1. 
Overview trial treatment ...................................................................................... 32 
10.2. 
Osimertinib .......................................................................................................... 32 
10.3. 
Treatment compliance ......................................................................................... 32 
10.4. 
Prohibited and restricted concomitant therapies during treatment with 
osimertinib .......................................................................................................... 33 
10.5. 
Management of osimertinib related toxicities ..................................................... 34 
10.6. 
Bevacizumab ....................................................................................................... 38 
10.7. 
Contraception, nursing, pregnancy ...................................................................... 42 
10.8. 
Treatment duration .............................................................................................. 43 
11. 
Safety of trial treatments .......................................................................................... 43 
11.1. 
Safety profile of osimertinib ................................................................................ 43 
11.2. 
Safety profile of bevacizumab ............................................................................. 46 
12. 
Adverse event and serious adverse event reporting ................................................. 53 
12.1. 
Adverse event (AE) ............................................................................................. 53 
12.2. 
Adverse reaction (AR) ......................................................................................... 53 
12.3. 
Unexpected adverse reaction (UAR) ................................................................... 53 


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12.4. 
Serious adverse events (SAE) .............................................................................. 54 
12.5. 
Serious adverse reaction (SAR) ........................................................................... 56 
12.6. 
Suspected unexpected serious adverse reaction (SUSAR) .................................. 56 
12.7. 
Severity / intensity of (serious) adverse events ................................................... 56 
12.8. 
Causality of adverse events ................................................................................. 57 
12.9. 
Duration of adverse events .................................................................................. 57 
12.10. Action taken ......................................................................................................... 57 
12.11. Reporting SAEs ................................................................................................... 57 
12.12. Pregnancy ............................................................................................................ 59 
12.13. Reference safety information............................................................................... 59 
13. 
Response evaluation ................................................................................................ 60 
13.1. 
CT schedule for response evaluation ................................................................... 60 
13.2. 
Response evaluation criteria in solid tumours (RECIST version 1.1) ................. 60 
14. 
Endpoints definition ................................................................................................. 66 
14.1. 
Progression-free survival ..................................................................................... 66 
14.2. 
Objective response ............................................................................................... 66 
14.3. 
Disease control .................................................................................................... 66 
14.4. 
Toxicity ................................................................................................................ 66 
14.5. 
Overall survival ................................................................................................... 66 
15. 
Biological material and translational research ......................................................... 67 
15.1. 
Central Histology Review, Biomarker Testing and Biobanking ......................... 67 
15.2. 
Required biomaterial ........................................................................................... 67 
15.3. 
Biomaterial at disease progression on trial treatment .......................................... 68 
15.4. 
Submission of biomaterial ................................................................................... 68 
16. 
Trial procedures ....................................................................................................... 70 
16.1. 
Safety assessments ............................................................................................... 70 
16.2. 
Tumour assessment.............................................................................................. 71 
16.3. 
Baseline evaluations before randomisation ......................................................... 71 
16.4. 
Evaluations in the experimental arm ................................................................... 72 
16.5. 
Evaluations in the control arm ............................................................................. 73 
16.6. 
Evaluations at disease progression ...................................................................... 74 
16.7. 
Evaluation under treatment beyond progression ................................................. 75 
16.8. 
Evaluations at the end of treatment visit ............................................................. 76 
16.9. 
Evaluations in the follow-up phase (post treatment) before progression ............ 76 
16.10. Evaluations in the follow-up phase beyond progression of disease .................... 77 
17. 
Case report forms and documentation ..................................................................... 77 
17.1. 
Case report forms schedule .................................................................................. 77 
18. 
Statistical considerations ......................................................................................... 80 
18.1. 
Primary objective ................................................................................................. 80 
18.2. 
Sample size determination ................................................................................... 80 
18.3. 
Trial duration ....................................................................................................... 80 
18.4. 
Analysis populations............................................................................................ 81 
18.5. 
Evaluation of primary and secondary objectives ................................................. 81 
18.6. 
Early safety analysis ............................................................................................ 82 
18.7. 
Interim efficacy analysis ...................................................................................... 82 
19. 
Criteria for termination of the trial .......................................................................... 82 
19.1. 
General criteria for termination of the trial ......................................................... 82 
19.2. 
Discontinuation of protocol treatment for individual patients ............................. 82 
19.3. 
Withdrawal of consent ......................................................................................... 83 
20. 
Ethics aspects, regulatory approval, and patient informed consent ......................... 84 


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20.1. 
Ethical Review Board/Ethics Committee ............................................................ 84 
20.2. 
Regulatory approval procedures .......................................................................... 84 
20.3. 
Informed consent ................................................................................................. 84 
21. 
Governance and administrative issues ..................................................................... 85 
21.1. 
Final report .......................................................................................................... 85 
21.2. 
Steering Committee ............................................................................................. 85 
21.3. 
Independent Data Monitoring Committee ........................................................... 85 
21.4. 
Publication ........................................................................................................... 86 
21.5. 
Clinical trial insurance ......................................................................................... 86 
21.6. 
Quality assurance ................................................................................................. 86 
21.7. 
Protocol adherence .............................................................................................. 86 
21.8. 
Data protection .................................................................................................... 87 
21.9. 
Record retention .................................................................................................. 87 
22. 
References ................................................................................................................ 88 
 
Appendices: 
1. Template for patient information and informed consent form 
2. Guidance for the management of adverse events in studies of osimertinib 
3. ETOP publication guidelines  
 
Index of tables 
Table 1: Drugs prolonging QT interval ................................................................................. 33 
Table 2: Osimertinib dose adjustment information for adverse reactions ............................. 35 
Table 3: Osimertinib dose interventions ................................................................................ 35 
Table 4: Management of bevacizumab-related hypertension ................................................ 39 
Table 5: Management of Proteinuria ..................................................................................... 40 
Table 6: Measurable Disease - Overall Response.................................................................. 65 
Table 7: Non-measurable Disease - Overall Response .......................................................... 65 
Table 8: Case report forms: .................................................................................................... 77 
 
 


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1. 
Protocol summary  
 
ETOP 10-16 BOOSTER 
 
A randomised phase II trial of osimertinib and bevacizumab versus 
osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC 
with confirmed EGFRm and T790M 
 
BOOSTER: Osimertinib and Bevacizumab versus Osimertinib alOne as 
Second-line Treatment in stage IIIb-IVb NSCLC with confirmed EGFRm and 
T790M 
 
Sponsor:  
European Thoracic Oncology Platform (ETOP) 
Pharma Partner: 
AstraZeneca 
Population:  
Patients with locally advanced or metastatic (stage IIIb-IVb) 
 
EGFRm (exon 19 deletion or exon 21 L858R) NSCLC with T790M 
 
resistance mutation at progression on prior EGFR TKI therapy 
Design: 
Open label randomised phase II  
 
Sample size: 
154 patients 
Randomisation: 
Block stratified randomisation balanced by institution. 
Stratification factors: Ethnicity (Asian, Non-asian) and material used for T790M testing 
(tumour vs circulating DNA) 
Stage IIIb-IVb NSCLC
- confirmed EGFRm
- confirmed T790M
- PD on/after previous EGFR TKI
1 : 1
∙∙∙
∙∙∙
until PD*, lack of tolerability 
or refusal
until PD*, lack of tolerability 
or refusal
R
* Trial treatment may continue beyond PD 
if patient shows clinical benefit
CT
CT
3
Weeks
6
9
18
27
0

Blood
FFPE
Blood
Blood
CT
CT
CT
(FFPE)
at PD
Biomaterial
collection:
Osimertinib 80mg p.o. daily
Bevacizumab 15mg/kg i.v.
day 1 of each 3-week cycle 
Osimertinib 80mg p.o. daily


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Rationale: 
First-generation EGFR tyrosine kinase inhibitors provide significant clinical benefit in 
patients with advanced EGFR-mutant (EGFRm) non–small cell lung carcinoma (NSCLC). 
However, all patients ultimately develop disease progression, driven – as the most prevalent 
identified biological mechanism – by the acquisition of a second T790M EGFR TKI 
resistance mutation. 
Osimertinib (AZD9291) is a novel oral, potent, and selective third-generation irreversible 
inhibitor of both EGFRm-sensitizing and T790M resistance mutants. This mono–anilino–
pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and 
offers a pharmacologically differentiated profile from earlier first and second generation 
EGFR TKIs. 
Preclinically, the drug potently inhibits signaling pathways and cellular growth in both 
EGFRm and EGFRm plus T790M cell line in vitro, with lower activity against wild-type 
EGFR lines. 
In the recently published osimertinib phase I trial, a total of 253 patients were treated. 
Among 31 patients enroled in the dose-escalation cohorts, no dose-limiting toxic effects 
occurred at the doses evaluated. An additional 222 patients were treated in five expansion 
cohorts. The most common all-cause adverse events were diarrhoea, rash, nausea, and 
decreased appetite, however were significantly reduced in occurrence and severity as 
compared to first/second EGFR TKIs. 
The overall objective tumour response rate of osimertinib was 51% (95% CI, 45 - 58). 
Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for 
response, the response rate was 61% (95% CI, 52 - 70). In contrast, among 61 patients 
without centrally detectable EGFR T790M who could be evaluated for response, the 
response rate was 21% (95% CI, 12 - 34). The median progression-free survival was 
9.6 months (95% CI, 8.3 to not yet reached) in patients with EGFR T790M and 2.8 months 
(95% CI, 2.1 - 4.3) in patients without EGFR T790M. Osimertinib is being evaluated in 
several prospective clinical trials, notably in frontline treatment, in the adjuvant setting, and 
in combination with later lines in EGFRm positive advanced disease. 
Objectives and endpoints:  
Primary objective: 
To assess the efficacy of the combination of osimertinib and bevacizumab versus 
osimertinib alone in terms of progression-free survival (PFS) assessed by RECIST 1.1. 
Secondary objectives:  
To compare short and long term clinical efficacy outcomes as well as tolerability of the two 
treatments. 
 
 


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Primary endpoint: 
 Progression-free survival (PFS) based on RECIST 1.1 criteria  
 
Secondary endpoints: 
 Objective response, based on RECIST 1.1 criteria 
 Disease control, defined as complete or partial response, or disease stabilisation, 
confirmed at subsequent radiological assessment 
 Adverse events graded by CTCAE V4.0 
 Overall survival 
 
Correlative studies: 
 T790M evolution in tissue and plasma/serum (between baseline and relapse) 
 Monitoring of mutation burden and specific EGFR mutations (del19, L858R, T790M) in 
sequential plasma/serum samples 
 Analysis of bevacizumab/osimertinib resistance mechanism in relapse biopsy samples 
(Next Generation Sequencing) 
 
Most important eligibility criteria (see Section 7 for complete list):  
Inclusion criteria 
 NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to 
8th TNM classification, after progression following prior EGFR TKI (erlotinib, gefitinib, 
dacomitinib or afatinib) therapy as the most recent treatment regimen. 
 Pathological diagnosis of predominantly non-squamous NSCLC. 
 Maximum of one line of previous platinum based chemotherapy. 
 Histological or cytological confirmation of EGFRm (exon19 deletion or exon 21 L858R). 
 Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating 
tumour DNA, documented in tissue, plasma or serum after disease progression on the 
most recent EGFR TKI regimen. 
 Plasma, serum, and tumour (preferred) tissue or cytology (if biopsy was taken and FFPE 
tumor material is not yet fully depleted) after disease progression on the most recent 
EGFR TKI treatment available for central confirmation of T790M. 
 Measurable or evaluable disease 
 Adequate haematological, renal and liver function 
 Performance status 0-2 
 
 


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Exclusion criteria 
 Patients with mixed NSCLC with predominantly squamous cell cancer, or with any small 
cell lung cancer (SCLC) component. 
 Symptomatic or active central nervous system metastases, as indicated by clinical 
symptoms, cerebral edema, and/or progressive growth. 
 Previous treatment with osimertinib and/or bevacizumab 
 Patients currently receiving medications or herbal supplements known to be potent 
CYP3A4 inducers 
 Any unresolved toxicities from prior therapy greater than CTCAE V 4.0 grade 1 
 
Treatment arms: 
Experimental arm: Osimertinib, 80 mg p.o., once daily plus bevacizumab 15 mg/kg i.v. on 
day 1 of every 3-week cycle. 
Control arm: Osimertinib, 80 mg p.o., once daily 
Patients will receive the treatment until progression, lack of tolerability, or patient declines 
further protocol treatment. Trial treatment may also continue beyond progression for as long 
as the patient may still derive benefit as per investigator decision. 
 
Statistical considerations: 
This superiority, multicentre trial compares PFS between the two randomised arms, and 
includes an interim analysis for the primary endpoint. A treatment effect on PFS, leading to 
a 36% reduction in HR is assumed under the alternative (HR=0.64). This improvement 
corresponds to an increase for the median PFS to 17.2 months under the combination 
treatment vs 11 months for the osimertinib treatment. A sample size of 154 patients (with 
126 PFS events) is required for the trial to achieve 80% power to show a statistically 
significant difference in PFS for the assumed treatment effect at the 5% one-sided 
significance level. 
Total trial duration: 5 years from enrolment of the first patient 
 
 


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2. 
List of abbreviations  
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Transaminase 
AT 
Aminotransferase or Transaminase 
AUC 
Area Under the Curve 
BID 
Bis In Die (lat.), twice-daily  
BOR 
Best Overall Response 
BORR 
Best Overall Response Rate 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
Central Nervous System 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Target Volume 
CVA 
Cerebrovascular Accident 
DCR 
Disease Control Rate 
DLCO 
Diffusing Capacity for Carbon Monoxide 
DVH 
Dose Volume Histogramm 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ED 
Extensive Stage Disease 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EGFR 
Epidermal Growth Factor Receptor 
ERB 
Ethical Review Board 
FVC 
Forced Vital Capacity 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FFPE 
Formalin Fixed, Paraffin Embedded 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
GTV 
Gross Tumour Volume  
Hb 
Hemoglobin 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
IA 
Iterim Analysis 
IASLC 
International Association for the Study of Lung Cancer 
IB 
Investigator's Brochure 


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IC 
Informed Consent 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
ILD 
Interstitial Lung Disease 
INR 
International Normalised Ratio 
IMP 
Investigational Medicinal Product 
irAE 
Immune-related Adverse Events 
irBORR 
Best Overall Response Rate by irRC 
irPFS 
Immune-related Progression Free Survival 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
KDR 
Kinase inert domain-containing receptor 
LF 
Lost to Follow-up 
LFT  
Liver Function Test  
LLN 
Lower Limit of Normal Lab Value 
LVEF 
Left Ventricular Ejection Fraction 
MI 
Myocardial Infarction 
MIP 
Maximum Intensity Projection  
MLD 
Mean Lung Dose 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multigated Acquisition Scan 
NE 
Not Evaluable 
NCCN 
National Comprehensive Cancer Network 
NGS 
Next Generation Sequencing 
NSCC 
Nonsquamous-Cell Carcinoma 
NSCLC 
Non-Small Cell Lung Carcinoma 
OAR 
Organs at Risk 
ONJ 
Osteonecrosis of the Jaw 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Cell Death Ligand 1 
PFS 
Progression Free Survival 
PlGF  
Placental Growth Factor  
PIS 
Patient Information Sheet 
PK 
Pharmacokinetics 
PPK 
Population Pharmacokinetic 
PR 
Partial Response 
PRES 
Posterior Reversible Encephalopathy Syndrome 


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PS 
Performance Status 
QD 
Quaque Die, once daily 
PTV  
Planning Target Volume 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SADR 
Serious Adverse Drug Reaction 
SBRT 
Stereotactic Body Radiation Therapy 
SCC 
Squamous-Cell Carcinoma 
SCLC 
Small-Cell Lung Carcinoma 
SD 
Stable Disease 
SIAD 
Syndrome of Inappropriate Diuresis 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standard Uptake Volume 
Tc99mDTPA 
Technetium-99m Diethyl Triamine Penta-Acetic Acid 
TdP 
Torsades de Pointes 
TE 
Ttracheoesophageal 
TIA 
Transient Ischaemic Attack 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal Lab Value 
VALG 
Veterans Administration Lung Study Group 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell Count 
WBRT 
Whole Brain Radiotherapy 
WC 
Withdrawal of Consent 
 
 
 
 


 
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3. 
Trial schedule  
 
 
28 days 
before rando(1) 
Treatment period 
PD(7) 
End of 
treatment 
visit 
Post treatment follow-up 
Control 
Arm(3) 
Experimental 
Arm(4) 
Prior to 
bevacizumab 
cycle 4 / at 
9 weeks 
Beyond 
PD(6) 
Before PD(8) 
After PD 
(every 
12 weeks 
(±2 weeks) 
Written informed consent: before any 
trial specific evaluations and intervention 
within 6 weeks 
before rando 
 
 
 
 
 
 
 
 
Medical history: 
smoking history, comorbidities and 
allergies 
 
 
 
 
 
 
 
 
 
Physical examination(9) 
 
 
 
 
 
 
 
PS, blood 
pressure, weight 
 
Resting 12-lead ECG(10) 
 
 
Every cycle 
 
 
 
 
 
 
LVEF(11) 
 
Every 15 weeks (±1 week) 
 
 
 
 
Ophthalmologic exam(12) 
 
Repeated if patient experiences any visual symptoms 
 
 
 
 
Baseline symptoms 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
Up to 30 days after 
trial treatment stop 
 
 
Concomitant medications(13) 
 
 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
Disease evaluation 
Radiological tumour assessment(14) 
Within 5 weeeks 
before rando 
Every 9 weeks (4 days) until PD 
 
 
 
 
Every 9 weeks 
(4 days) until 
PD 
 
Confirmation of EGFRm(15) 
 
 
 
 
 
 
 
 
 
Confirmation of T790M(16) 
 
 
 
 
 
 
 
 
 
Biological material 
Tumour material 
(17) 
 
 
 
 
Optional 
 
 
 
Whole blood, serum and plasma samples 
(17) 
 
 
(5) 
 
 
 
 
 
 
 


 
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Laboratory tests 
Pregnancy test for women of child 
bearing potential(18) 
 
 
 
 
 
 
 
 
 
Chemistry: serum albumin, glucose, 
potassium, sodium, calcium, amylase, 
lipase and LDH 
(2) 
 
Every cycle 
 
 
 
 
 
 
Haematology: haemoglobin, platelet 
count, white blood cell count including 
differential (absolute neutrophil count) 
(2) 
 
Every cycle 
 
 
 
 
 
 
Liver function test: total bilirubin, ALT, 
AST, ALP, GGT 
(2) 
 
Every cycle 
 
 
 
 
 
 
Renal function tests: urea, uric acid, 
serum creatinine, creatinine clearance 
(Cockroft-Gault). 
(2) 
 
Every cycle 
 
 
 
 
 
 
Urine analysis: specific gravity, pH, 
proteins(19) using dipstick, glucose, blood 
using a dipstick; elements and 
microscopic examination if needed 
(2) 
 
Every cycle(19)(19) 
 
 
 
 
 
 
Coagulation profile: international 
normalized ratio 
 
 
 
 
 
 
 
 
 
Treatment 
Osimertinib, daily 80mg p.o., until PD, 
lack of tolerability or refusal(20) (21) 
 
  
 
 
 
 
 
 
 
Bevacizumab, 15 mg/kg i.v. every 
3 weeks (3 days) until PD, lack of 
tolerability or refusal(20) (22) 
 
 
 
 
 
 
 
 
 
Document further anti-cancer therapies 
after PD 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory evaluation / intervention 
 
 
 


 
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(1) Evaluations to be done within 28 days before randomisation. Examinations done prior to 28 days before randomisation have to be repeated. 
(2) These evaluations have to be repeated within 7 days prior to trial treatment start 
(3) Patients in the control arm: assessments have to be done every 3 weeks (3 days). 
(4) Patients in the experimental arm: assessments have to be done every 3 weeks (within 3 days prior to the next bevacizumab dose) 
(5) Blood samples for translational research have to be collected within 3 days prior to cycle 4 (in the experimental arm) or 9 weeks (1 week) after treatment start (in the control arm). 
(6) In case of clinical benefit, with physician and patient agreement, trial treatment can continue beyond confirmed progression. 
(7) Blood samples have to be taken at the time of tumour progression, a re-biopsy is voluntary. 
(8) Patient who discontinues trial treatment before disease progression should be assessed every 9 weeks (1 week) from end of treatment visit until tumour progression. 
(9) Physical examination include: PS, blood pressure, heart rate, temperature, body weight, height (only at baseline), skin, head and neck (including ears, eyes, nose and throat), 
respiratory, cardiovascular, abdomen, lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and neurological systems. 
(10) Patients should be monitored for ECG changes at every cycle. ECGs should be reviewed and any abnormalities noted. 
(11) LVEF should be measured at baseline, then at least every 15 weeks (1 week) from the time of first dose of osimertinib throughout the treatment period and when clinically indicated. 
In the event of an absolute decrease of 10% from baseline or below 50%, withhold osimertinib for up to 4 weeks. If improved to baseline it can be restarted, but if not, then discontinue. 
It is up to the investigators choice to measure LVEF by either echocardiogram or MUGA scan. The same technique must be used for each patient throughout the treatment period. 
(12) Full ophthalmic assessment, including slit lamp examination, should be performed at screening and if a patient experiences any visual symptoms (including blurring of vision), with 
additional tests if clinically indicated. 
(13) Information on any treatment within 28 days prior to starting trial treatment and all concomitant treatments given during the trial, with reasons for the treatment, will be recorded. 
(14) Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax until adrenal glands and full liver and kidney included) at baseline before randomisation 
and then every 9 weeks (63 ±4 days) from randomisation until PD determined according to RECIST v1.1 criteria. 
(15) Histological or cytological confirmation of exon 19 deletion or exon 21 L858R mutation by a certified local laboratory. 
(16) Confirmation of T790M mutation determined from biopsy (preferred) or on serum circulating tumour DNA by a certified local laboratory that performs this test within their routine 
practise. These samples must be taken after disease progression on the most recent EGFR TKI regimen. 
(17) Whole blood, plasma, serum, and – if a biopsy was taken and the FFPE material is not yet fully depleted - tumour tissue/cytology after disease progression on the most recent EGFR 
TKI treatment administered prior to trial entry must be submitted for central confirmation of T790M and translational research studies. Submission of the same type of material as used 
for local identification of T790M is critical for central confirmatory analysis. 
(18) Pregnancy test: Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine beta HCG pregnancy 
test within 7 days before randomisation. The test has to be repeated before treatment start, if treatment does not start within 72 hours of the previous test. 
(19) Proteinuria should be routinely measured before every infusion of bevacizumab using a dipstick. 
(20) Patients are considered to be on trial treatment for as long as they receive either osimertinib and/or bevacizumab 
(21) Osimertinib treatment may continue beyond progression if the patient shows clinical benefit. 
(22) Bevacizumab for patients in the experimental arm may continue beyond progression if the patient shows clinical benefit.


 
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4. 
Background and rationale 
4.1. 
Disease background 
Lung cancer has been the most common carcinoma in the world for several decades. There 
were estimated 1.8 million new cases in 2012 (12.9% of the total). It is also the most 
common cause of death from cancer worldwide, estimated to be responsible for nearly one 
in five (1.59 million, 19.4% of the total deaths [1]). 
Non-small cell lung carcinoma (NSCLC) represents approximately 80% to 85% of all lung 
cancers. Unfortunately, at the time of diagnosis approximately 70% of NSCLC patients 
already have advanced or metastatic disease not amenable to surgical resection. Furthermore, 
a significant percentage of early stage NSCLC patients who have undergone surgery 
subsequently develop distant recurrence and die as a result of their lung cancer [2]. Patients 
presenting with unselected advanced NSCLC have a median overall survival of 10 to 
12 months [3]. 
4.1.1. 
EGFR mutations 
Progress in molecular biology has changed the therapeutic approach to NSCLC, and the 
treatment of advanced NSCLC can now be guided by the presence of certain mutations, eg, 
epidermal growth factor receptor (EGFR), or anaplastic lymphoma kinase (ALK). Since the 
discovery of the common somatic mutations in the kinase domain of EGFR in 2004 [4], it is 
now confirmed that NSCLC patients with activating EGFR mutations in exons 18 - 21 of 
EGFR (including L858R and exon 19 deletions, collectively described as EGFRm) are a 
distinct subset of NSCLC in terms of pathogenesis, prognosis and treatment. 
EGFR tyrosine kinase inhibitors (TKIs) are now the established first line therapy in patients 
with EGFRm NSCLC (NCCN 2012 [5]). Despite achieving very good initial response rates 
and durable benefit following treatment with approved TKI drugs targeting EGFRm, these 
patients will eventually develop treatment-resistant disease after 9-14 months [6-12]. 
Survival rates of patients with advanced NSCLC who progress following treatment with 
EGFR-TKI remain very low, with a median overall survival of 1-2 years [13-15]. Treatment 
following progression on EGFR TKI therapy is guided by patient performance status, 
symptoms, and extent of disease. Patients have traditionally been treated with chemotherapy. 
In patients able to tolerate platinum-containing doublet chemotherapy, this is most often the 
preferred second-line treatment. Second-line platinum-based chemotherapy post EGFR TKI 
for EGFRm NSCLC generally provides response rates in the range of 20 to 30% [7, 14-17]. 
The most robust estimate of ORR with platinum-containing doublet chemotherapy in the 
relevant patient population (ie, patients with EGFRm NSCLC after first-line EGFR TKI) 
comes from the recently reported IMPRESS study (ORR 25% with independent central 
review) [18]. Median PFS with platinum-containing doublet chemotherapy is generally 
reported to be in the range of 3-6 months (second-line), as was seen in the IMPRESS study 
(median 5.4 months). 
Following progression on an EGFR TKI and doublet chemotherapy the only remaining 
options for patients with EGFRm NSCLC are to re-challenge with EGFR TKI, or to receive 


 
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salvage chemotherapy (usually single-agent) or investigational agents through clinical trials 
[19]. In the subset of patients who have failed prior platinum-containing doublet 
chemotherapy, studies in unselected patient populations highlight the low response rates 
(approximately 10%) and short PFS (median PFS approximately 2-3 months) expected with 
single-agent chemotherapy such as docetaxel, or pemetrexed [20-23] (and NCCN guidelines 
[24]). There are no robust data on treatment outcomes in EGFRm patients in this setting. 
A number of mechanisms of resistance that lead to the EGFR TKI failure have been 
postulated, but the most frequently observed resistance mechanism is the emergence of the 
T790M mutation in EGFR, which is detected in the tumours of around 60% of patients after 
EGFR TKI failure [25-27] 
There are currently no approved therapies that effectively address acquired resistance to 
EGFR TKI therapy as a result of the EGFR T790M mutation. However, a number of 
investigational agents that target both the EGFRm and T790M (TKI-resistance confering 
mutation) receptor forms of EGFR are currently under investigation in clinical trials, and 
two of these agents have shown promising efficacy in phase II studies following treatment 
of patients with locally advanced or metastatic EGFR T790M mutation positive NSCLC 
who have progressed on or after EGFR TKI therapy [28, 29].  
4.1.2. 
Tumour angiogenesis 
Vascular endothelial growth factor (VEGF) is a key angiogenic factor regulating 
angiogenesis, the growth of new vessels from pre-existing vessels. This process is 
fundamental to the growth of solid tumours, which rely on the formation of new blood 
vessels, and it plays a significant role in NSCLC; microvessel count is an independent 
predictor of poor prognosis in patients with NSCLC [30]. The VEGF family comprises in 
mammals five members: VEGF-A, VEGF-B, PIGF, VEGF-C and VEGF-D. 
Two high-affinity receptors for VEGF with associated tyrosine kinase activity have been 
identified on human vascular endothelium: VEGFR-1 (Fms-like-tyrosine kinase-1 [Flt-1]) 
and VEGFR-2 (Kinase inert domain-containing receptor [KDR]). A third receptor, VEGFR-
3 (Flt-4), is expressed on lymphatic endothelium. Although their relative contributions in 
mediating tumour progression have not been clearly understood, a number of studies 
suggest KDR performs a predominant role [31]. 
Clinically, the addition of anti-angiogenic agents to chemotherapy in the treatment of 
advanced NSCLC have led to OS benefit, and two such agents are now approved for this 
indication. The anti-angiogenic agent bevacizumab (a monoclonal antibody that inhibits 
VEGF-A), has been shown to provide additional efficacy when used in combination with 
first-line platinum-based chemotherapy in several trials in non-squamous NSCLC [32, 33]. 
Bevacizumab in combination with platinum based chemotherapy followed by maintenance 
bevacizumab is approved for first-line treatment of patients with advanced non-squamous 
NSCLC. 
Increased production of VEGF has been reported to be associated with resistance to EGFR 
inhibition [34]. Pre-clinical studies suggest that erlotinib resistance may be associated with a 
rise in both tumor cell and host stromal VEGF and that combined blockade of the VEGFR 
and EGFR pathways can abrogate primary or acquired resistance to EGFR TKIs [35]. Pre-
clinical studies also indicate that combination with anti-VEGF therapy could enhance 


 
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antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by 
increasing EGFR TKI concentration in specific tumors that express high levels of VEGF 
protein [36]. 
4.2. 
Treatment background 
4.2.1. 
Osimertinib 
Osimertinib (AZD9291) is an oral, potent irreversible inhibitor, selective for the sensitizing 
EGFR mutations (EGFRm) and T790M resistance mutation with a significant selectivity 
margin against wild-type EGFR. This mono–anilino–pyrimidine compound is structurally 
distinct from other third-generation EGFR TKIs and offers a pharmacologically 
differentiated profile from earlier first and second generation EGFR TKIs [37]. 
Preclinically, the drug potently inhibits signaling pathways and cellular growth in both 
EGFRm and EGFRm plus T790M cell line in vitro, with lower activity against wild-type 
EGFR cell lines [38, 39]. 
Osimertinib is currently under investigation as a treatment option in: 1) Patients with 
advanced T790M positive NSCLC who have previously failed an EGFR-TKI; 2) Patients 
with advanced EGFRm NSCLC who are treatment naïve; 3) In combination with novel 
agents for patients with EGFR TKI resistant NSCLC. 
In the phase 1 dose escalation trial of osimertinib (D5160C00001, AURA), no dose-limiting 
toxicities were reported in any of the dose escalation cohorts (20, 40, 80, 160, and 240 mg) 
and a non-tolerated dose has not been defined. Based on all currently available safety, 
pharmacokinetic and preliminary efficacy data, 80 mg once daily was selected as the 
recommended phase II dose. 
Data from the ongoing phase I AURA trial (D5160C00001) in patients with T790M positive 
NSCLC who were previously treated with EGFR TKI, have achieved promising efficacy 
with osimertinib; 54.2%, with 95% CI (40.8% - 67.3%) of subjects achieved a response, 
91.5%, with 95% CI (81.3% - 97.2%) achieved disease control, medium duration of 
response of 12.4 months 95%, with 95% CI (8.3 - NC) and median PFS based on 38% 
maturity of data was 13.5 months, with 95% CI (8.3 - NC), as assessed by blinded 
independent central review [28]. Promising evidence of efficacy has also observed in 
patients with EGFRm treatment naïve NSCLC treated with osimertinib as first line EGFR 
TKI (Abstract ASCO 2015 [40]). 
Across the clinical development programme, osimertinib has demonstrated a manageable 
safety profile [28]. 
4.2.2. 
Bevacizumab 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and 
inhibits the interaction of VEGF-A to its receptors (Flt-1 and KDR) on the surface of 
endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell 
proliferation and new blood vessel formation in in vitro models of angiogenesis. 
Neutralising the biological activity of VEGF regresses the vascularisation of tumours, 
normalises remaining tumour vasculature, and inhibits the formation of new tumour 


 
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vasculature, thereby inhibiting tumour growth. Administration of bevacizumab to 
xenotransplant models of colon cancer in nude mice caused reduction of microvascular 
growth and inhibition of metastatic disease progression [41, 42]. 
Bevacizumab is indicated for the first-line treatment of unresectable, locally advanced, 
recurrent or metastatic non–squamous NSCLC in combination with carboplatin and 
paclitaxel. The recommended dose of bevacizumab in this indication is 15 mg/kg by i.v. 
infusion once every 3 weeks (Bevacizumab Investigator’s Brochure (IB). 
4.3. 
Overall risk / benefit assessment 
4.3.1. 
Potential benefits 
Osimertinib monotherapy, at the dose to be evaluated in this trial, has shown consistent and 
high objective response rates in the target patient population (see Section 4.2.1). 
Anti-angiogenic agents targeting the VEGF/VEGFR signaling pathway have been shown to 
provide additional efficacy when used in combination with first-line platinum-based 
chemotherapy in several trials in non-squamous NSCLC or in combination with erlotinib as 
first line therapy in EGFRm positive NSCLC patients (see Section 4.2.2). 
The combination of osimertinib plus an anti-angiogenic agent such as bevacizumab may 
provide a wider activity against tumours that have developed resistance to EGFR TKI 
agents by blocking the dual pathways of proliferative signaling and angiogenic signaling. 
Preclinical studies suggested that patients on lower doses of EGFR TKI tend to develop 
treatment resistance earlier than those who receive higher doses [43]. Therefore the 
combination may also delay the development of subsequent resistance as the preclinical 
studies suggested anti-angiogenic agents may increase intratumoural uptake of anti-cancer 
drugs by changing tumour vessel physiology [44]. 
Efficacy and safety data from the osimertinib monotherapy studies have shown promising 
efficacy and an acceptable safety profile (Section 11.1) at the recommended dose of 80 mg 
once daily. The combination of osimertinib with bevacizumab may have the potential to 
provide additional clinical benefit in terms of increased and/or prolonged disease control 
and a delay in the emergence of resistance in patients with advanced EGFRm NSCLC who 
have progressed following a prior EGFR TKI agent, compared against the current standard 
of care (chemotherapy or another EGFR TKI) or monotherapy of any of the individual 
agents. 
4.3.2. 
Potential risks  
Section 10.7 of this protocol summarizes potential risks based upon non-clinical toxicity and 
clinical patient studies with osimertinib or bevacizumab with further detailed information 
available in the respective IBs for osimertinib and bevacizumab. As these agents have not 
previously been administered in combination, although the chances are low based upon the 
associated preclinical and clinical evidence, there is a theoretical potential for synergistic 
toxicity to occur, beyond that described for monotherapy administration. 


 
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4.4. 
Rationale for trial design, doses and control groups 
A combination strategy for the angiogenesis inhibitor bevacizumab has been explored in a 
randomised, open-label phase II trial of erlotinib in combination with bevacizumab versus 
erlotinib alone as first-line therapy in patients with EGFRm NSCLC [45]. The results 
yielded a significantly extended progression-free survival (PFS); median PFS in the 
combination therapy group was 16 months, vs. 9.7 months in the erlotinib alone group, for a 
hazard ratio of 0.54 (95% CI 0.36 - 0.79; P = .0015). Those with exon 19 deletion had a 
median PFS of 18 months with the combination therapy compared with 10.3 months with 
erlotinib alone (HR = 0.41; 95% CI, 0.24 - 0.72). Those with exon 21 L858R mutation, 
however, had a median PFS of 13.9 months with bevacizumab and 7.1 months without it 
(HR = 0.67; 95% CI, 0.38 - 1.18). The overall survival data is still immature, but the 
magnitude of PFS benefit suggests it may translate into an overall survival benefit. Fewer 
patients progressed after response with the combination, suggesting that bevacizumab may 
act to enhance the durability of response and cause sustained tumor shrinkage. 
More recently, the ETOP 2-11 BELIEF trial examined the same combination in patients 
with advanced NSCLC and activating EGFR mutations [46]. In this open-label, phase II 
trial, the combination of bevacizumab and erlotinib was explored in 109 patients with 
metastatic or locally advanced, non-squamous NSCLC who were not candidates for radical 
surgery or radiotherapy.  
Patients had measurable disease and centrally confirmed activating EGFR mutations (exon 
19 deletion or L858R mutations). All patients were treated with intravenous bevacizumab at 
15 mg/kg on day 1 of each 3-week cycle, and oral erlotinib at 150 mg daily. 
Pre-treatment T790M mutations were centrally identified based on laser micro-dissection 
and TaqMan assays in the presence of a specific peptide–nucleic acid to inhibit the 
amplification of the wild-type allele. DNA from PC9 cells containing an ultra-low allele 
frequency (0.004%) of T790M mutation were used as negative and NCI-H1975 (T790M) 
cells as positive controls. With this sensitive PC9 cutoff method, the presence of T790M at 
diagnosis was documented in 37 (34%) of the 109 recruited patients with classical activating 
EGFR mutations. The median age of patients with T790M-mutated NSCLC was 70 years, 
68% were female, 73% were never smokers, and 95% had ECOG PS 0-1. Patients without 
the alteration were at median age of 63 years, 58% were female, 63% never smokers, and 
94% had ECOG PS 0-1.  
At a median follow-up of 17.5 months, 36 patients remained on treatment (17 with a T790M 
mutation and 19 without). 
The combination of erlotinib and bevacizumab resulted in an overall 1-year PFS of 56.7% 
(95% CI, 46.0 - 66.0) and a median PFS of 13.8 months (95% CI, 10.3 - 21.3). In patients 
that did not have the T790M alteration at diagnosis, the 1-year PFS was 49.4% (95% CI, 
36.6 - 61.0) and the median PFS 10.5 (95% CI, 9.2 - 16.2),, while the 1-year PFS was 72.4% 
(95% CI, 53.4 - 84.7) and the median PFS 16.0 months (95% CI: 13.1 - NE) in patients with 
documented T790M mutation at diagnosis [46]. 
The safety profile of the combination was consistent with that of each agent and no 
unexpected toxicities were identified.  


 
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The results from these two studies suggest that combination treatments that target both 
tumour cells and tumour microenviroment (such as angiogensis) may be a promising 
strategy for further improving efficacy outcomes in patients with EGFRm NSCLC 
following progression on EGFR TKI therapy and other lines of therapy. 
First-generation EGFR TKI provide significant clinical benefit in patients with advanced 
EGFRm NSCLC [10, 12, 47]. However, all patients ultimately develop disease progression, 
driven – as the most prevalent identified biological mechanism – by the acquisition of a 
second T790M EGFR TKI resistance mutation [48-50]. 
There is thus a considerable unmet clinical need for novel therapeutic options that can 
further extend the efficacy of targeted agents such as EGFR TKIs, across all lines of therapy. 
4.4.1. 
Rationale for patient selection 
To ensure an appropriate and standardised patient population, all patients must have 
documented radiological progression on EGFR-TKI treatment and on the last treatment 
administered prior to enrolling in the trial. A biopsy (preferred) or blood sample will be 
needed for central testing of T790M mutation status following confirmed disease 
progression on the most recent treatment regimen. 
4.4.2. 
Rationale for osimertinib dose 
In the phase I dose escalation trial of osimertinib (D5160C00001, AURA), once daily doses 
of 20, 40, 80, 160, and 240 mg osimertinib were evaluated. Based on the total, current, 
safety, pharmacokinetic and preliminary efficacy data, 80 mg once daily was selected as the 
recommended phase II dose. The dose of 80 mg osimertinib daily can be reduced to 40 mg 
osimertinib once daily under circumstances described in Section 10.5. Further dose 
reductions are not possible. Please refer to the Osimertinib IB for additional details. No 
dosage adjustment is required due to patient age, body weight, gender, ethnicity and 
smoking status.  
5. 
Objectives and endpoints 
5.1. 
Primary objective 
To assess the efficacy of the combination of osimertinib and bevacizumab versus 
osimertinib alone in terms of progression-free survival (PFS) assessed by RECIST 1.1. 
5.2. 
Secondary objectives 
To compare short and long term clinical efficacy outcomes as well as tolerability of the two 
treatments. 
5.3. 
Primary endpoint 
5.3.1. 
Progression-free survival (PFS) based on RECIST 1.1 criteria 


 
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5.4. 
Secondary endpoints 
5.4.1. 
Objective response, based on RECIST 1.1 criteria 
5.4.2. 
Disease control, defined as complete or partial response, or disease stabilisation, 
confirmed at subsequent radiological assessment 
5.4.3. 
Adverse events graded by CTCAE V4.0 
5.4.4. 
Overall survival 
5.5. 
Correlative studies 
5.5.1. 
T790M evolution in tissue and plasma/serum (between baseline and relapse) 
5.5.2. 
Monitoring of mutation burden and specific EGFR mutations (del19, L858R, 
T790M) in sequential plasma/serum samples 
5.5.3. 
Analysis of bevacizumab/osimertinib resistance mechanism in relapse biopsy 
samples (NGS) 
6. 
Trial design, duration and termination  
This is a randomised controlled phase II multinational, multi-center trial of osimertinib and 
bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-
IVb NSCLC harbouring activating EGFR (exon 19 deletion or L858R) and T790M 
resistance mutation.  
6.1. 
Trial design 
This is a randomised phase II trial, with block stratified randomisation balanced by 
institution with a total of 154 patients randomised 1:1 to the experimental and control arm. 
Stratification factors: 
Ethnicity (Asian, Non-asian) and material used for T790M (tumour vs circulating DNA) 
 


 
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6.2. 
Sample size and trial duration 
The total sample size of 154 randomised patients is needed in order to observe the 
126 events required to detect a 36% improvement in PFS under the combination of 
osimertinib and bevacizumab with 80% power at the 5% one-sided significance level. Thus, 
in this phase II trial, 77 patients will be randomised into each of the two treatment arms. 
The recruitment is assumed to be non-linear with recruitment rate increasing to 6 per month, 
after the first 6 months. The required total trial follow-up duration is expected to be 
48 months with an interim efficacy analysis based on O’Brien-Fleming boundary at 
26 months. Estimating a run-in period of 6 months, and a 6-month preparation of the report, 
the total trial duration is expected to be 5 years. 
The 154 patients will be recruited from 25 centres in 6 different countries in Europe and 
Asia. 
7. 
Patient selection 
Written informed consent (IC) must be signed and dated by the patient and the investigator 
prior to any trial-related intervention and biomaterial submission for central review and 
testing. 
7.1. 
Inclusion criteria 
7.1.1. 
Patients (male/female) must be 18 years of age. 
7.1.2. 
NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to 
8th TNM classification, after progression following prior EGFR TKI therapy 
(erlotinib, gefitinib, dacomitinib or afatinib) as the most recent treatment regimen. 
7.1.3. 
Pathological diagnosis of predominantly non-squamous NSCLC.  
7.1.4. 
Maximum one line of previous platinum based chemotherapy. 
Stage IIIb-IVb NSCLC
- confirmed EGFRm
- confirmed T790M
- PD on/after previous EGFR TKI
1 : 1
∙∙∙
∙∙∙
until PD*, lack of tolerability 
or refusal
until PD*, lack of tolerability 
or refusal
R
* Trial treatment may continue beyond PD 
if patient shows clinical benefit
CT
CT
3
Weeks
6
9
18
27
0

Blood
FFPE
Blood
Blood
CT
CT
CT
(FFPE)
at PD
Biomaterial
collection:
Osimertinib 80mg p.o. daily
Bevacizumab 15mg/kg i.v.
day 1 of each 3-week cycle 
Osimertinib 80mg p.o. daily


 
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7.1.5. 
Histological or cytological confirmation of EGFRm (exon 19 deletion or exon 21 
L858R). 
7.1.6. 
Locally confirmed T790M mutation determined from biopsy (preferred) or on 
circulating tumour DNA, documented in tissue, plasma or serum after disease 
progression on the most recent treatment regimen. 
7.1.7. 
Plasma, serum, and tumour (preferred) tissue or cytology (if biopsy was taken and 
FFPE tumor material is not yet fully depleted) after disease progression on the most 
recent EGFR TKI treatment available for central confirmation of T790M. 
7.1.8. 
Measurable or evaluable disease according to RECIST 1.1 
7.1.9. 
Adequate haematological function: 
- 
Haemoglobin 90 g/L 
- 
Absolute neutrophil count (ANC) 1.5 × 109/L 
- 
Platelet count 100 × 109/L 
7.1.10. Adequate renal function: 
- 
Creatinine 1.5 × ULN OR 
- 
Creatinine clearance 30 mL/min (using the Cockroft-Gault formula below).  
Cockroft-Gault formula 
mL
min =
(140-age[years])×actual body weight [kg]
72×Creatinineserum (mg
dL)
(×0.85 if female) 
- 
Proteinuria <2+ (dipstick) 
7.1.11. Adequate liver function: 
- 
ALT and AST 2.5 × ULN. If the patient has liver metastases, ALT and AST 
must be ≤5 × ULN  
- 
Total bilirubin 1.5 x ULN. If the patient has liver metastases or documented 
Gilbert’s syndrome (unconjugated hyperbilirubinaemia) 3 x ULN. 
7.1.12. World Health Organization (WHO) performance status 0-2 
7.1.13. Life expectancy 12 weeks 
7.1.14. Women of childbearing potential, including women who had their last menstrual 
period in the last 2 years, must have a negative serum or urine pregnancy test 
within 7 days before randomisation. 
7.1.15. Patient is willing and able to comply with the protocol for the duration of the trial 
including undergoing treatment and scheduled visits and examinations including 
follow up. 


 
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7.1.16. Written Informed Consent (IC) for trial treatment must be signed and dated by the 
patient and the investigator prior to any trial-related evaluation and/or intervention 
and biomaterial submission for central review. 
7.2. 
Exclusion criteria 
7.2.1. 
Patients with mixed NSCLC with predominantly squamous cell cancer, or with any 
small cell lung cancer (SCLC) component. 
7.2.2. 
Symptomatic or active central nervous system metastases, as indicated by 
progressive growth or increasing need of steroids. Patients with history of CNS 
metastases or spinal cord compression are eligible if they are clinically and 
radiologically stable for at least 4 weeks before first dose of investigational product 
and have not required high-dose steroid treatment (>20mg prednisone or 
equivalent) in the last 4 weeks. 
7.2.3. 
Patients currently receiving (or unable to stop within 3 weeks before receiving the 
first dose of trial treatment) medications or herbal supplements known to be potent 
inducers of CYP3A4 (see section 10.4.1). Patients currently receiving 
phenobarbitone must stop this treatment within 5 weeks before receiving the first 
dose of trial treatment). All patients must try to avoid concomitant use of any 
medications, herbal supplements and/or ingestion of foods with known 
inducer/inhibitory effects on CYP3A4 during trial treatment. 
7.2.4. 
Any unresolved toxicities from prior therapy greater than CTCAE V 4.0 grade 1 at 
the time of starting trial treatment with the exception of alopecia and grade 2, prior 
platinum-therapy related neuropathy. 
7.2.5. 
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 
jeopardise compliance with the protocol, or active infection including hepatitis B, 
hepatitis C and HIV. Screening for chronic conditions/infections is not required. 
7.2.6. 
Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation 
pneumonitis requiring steroid treatment, or any evidence of clinically active ILD. 
7.2.7. 
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to 
swallow the formulated product or previous significant bowel resection that would 
preclude adequate absorption of osimertinib. 
7.2.8. 
Any of the following cardiac criteria: 
- 
Mean resting corrected QT interval (QTc using Fredericia’s formula) >470 
msec, obtained from 3 ECGs, using the screening clinic ECG machine derived 
QTc value. 
- 
Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block 
or second degree heart block). 


 
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- 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as heart failure, hypokalemia, congenital long QT syndrome, 
family history of long QT syndrome or unexplained sudden death under 40 
years of age in first degree relatives or any concomitant medication known to 
prolong the QT interval. 
7.2.9. 
Previous history of significant hemoptysis (defined as at least 2.5mL emission of 
red blood) in the 3 months prior to inclusion. 
7.2.10. Recent surgery:  
- 
Major surgery or significant traumatic injury within 28 days prior to inclusion 
- 
Minor surgical procedure within 7 days, or placement of a vascular access 
device within 2 days of study enrolment. 
7.2.11. Previous treatment with bevacizumab. 
7.2.12. Previous treatment with osimertinib. 
7.2.13. Women who are pregnant or in the period of lactation. 
7.2.14. Sexually active men and women of childbearing potential who are not willing to 
use an effective contraceptive method during the trial and up to 6 months after 
discontinuing trial treatment (see Section 10.7.1). 
8. 
Patient screening and randomisation 
8.1. 
Screening 
Complete the following steps to screen and include a patient into this trial. Please consult 
the BOOSTER procedures manual for detailed instructions. 
Note that written informed consent has to be obtained from the patient prior to any trial-
specific intervention or submission of biomaterial for central review. 
Verify eligibility and randomise the patient in the EDC system ETOPdata according to the 
information in the BOOSTER procedures manual. The dates the patient signed informed 
consent to enter the trial and to pathology material submission as well as the dates the 
investigator signed those forms are all required to complete the eligibility checklist. 
8.2. 
Randomisation and stratification 
Patients will be randomly assigned (1:1) to receive either osimertinib plus bevacizumab or 
osimertinib alone. 
Block stratified randomisation [51] balanced by institution will be performed centrally, 
stratified by ethnicity (Asian vs non-Asian) and material used for T790M testing (tumour, 
circulating DNA) (tumour vs circulating DNA). Blocks will be multiples of two (block size 
either 4 or 6), randomly generated. 


 
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All patients and investigators will be unmasked to the trial treatment. 
9. 
Investigational medicinal products 
Osimertinib and bevacizumab are the investigational medicinal products (IMPs) in this trial. 
Complete details of the IMP logistics, distribution, packaging, labeling and handling as well 
as accountability are described in the BOOSTER drug supply manual. 
9.1. 
Osimertinib 
Osimertinib is an oral, potent irreversible inhibitor, selective for sensitizing (EGFRm) and 
T790M resistance mutation with a significant selectivity margin against wild-type EGFR. 
As a result, osimertinib can effectively block EGFR signaling both in EGFR single mutant 
cells with activating EGFR mutations and in double mutant cells bearing the T790M 
resistance mutation. Osimertinib is currently under investigation as a treatment option in:  
1) Patients with advanced T790M positive NSCLC who have previously failed an EGFR-
TKI;  
2) Patients with advanced EGFRm NSCLC who are treatment naïve, and,  
3) In combination with novel agents for patients with EGFR TKI resistant NSCLC. 
Please refer to the Osimertinib IB for details of the clinical programme for osimertinib. 
9.1.1. 
Formulation 
Investigational product 
Dosage form and strength 
Manufacturer 
Osimertinib 
40 mg tablets 
80 mg tablet 
AstraZeneca 
 
AstraZeneca will supply osimertinib as tablets for oral administration. Osimertinib will be 
supplied in bottles with 25 tablets per bottle. Additional information about pharmaceutical 
formulation may be found in the current version of the Osimertinib IB. 
9.2. 
Bevacizumab 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and 
inhibits the interaction of VEGF-A to its receptors (Flt-1 and KDR) on the surface of 
endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell 
proliferation and new blood vessel formation in in vitro models of angiogenesis. 
Neutralising the biological activity of VEGF regresses the vascularisation of tumours, 
normalises remaining tumour vasculature, and inhibits the formation of new tumour 
vasculature, thereby inhibiting tumour growth. Please refer to the current Avastin IB for 
details. Bevacizumab will be supplied by Roche. 
 
 


 
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9.2.1. 
Formulation 
Clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate for solution 
for intravenous (i.v.) infusion 
9.3. 
Packaging and labeling 
Clinical supplies will be affixed with a clinical trial label in accordance with regulatory 
requirements. 
9.4. 
Clinical supplies disclosure 
This trial is open-label; therefore, the patient, the trial site personnel, ETOP and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text. 
9.5. 
Storage and handling 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. The investigator shall take responsibility for and shall take 
all steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations. 
The investigational product label on the bottle and concentrate and the Investigator 
Brochures (IBs) specify the appropriate storage. 
 
 


 
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10. 
Trial treatments 
10.1. 
Overview trial treatment 
Experimental arm: Osimertinib, 80 mg p.o., once daily plus bevacizumab 15 mg/kg i.v. on 
day 1 of every 3-week cycle. 
Control arm: Osimertinib, 80 mg p.o., once daily 
Patients will receive the trial treatment until progression, lack of tolerability to osimertinib 
and bevacizumab, or patient declines further protocol treatment. Trial treatment may also 
continue beyond progression for as long as the patient may still derive benefit as per 
investigator decision. 
10.2. 
Osimertinib 
Osimertinib is administered as 80 mg once daily. Osimertinib can be taken without regard to 
food. 
Doses should be taken approximately 24 hours apart at the same time point each day with 
water. Doses should not be missed. If a patient misses taking a scheduled dose, within a 
window of 12 hours, it is acceptable to take the dose. If it is more than 12 hours after the 
scheduled dose, the missed dose should not be taken, and patients should be instructed to 
take the next dose at the next scheduled time. If a patient vomits after taking their 
osimertinib, they should not make up for this dose, but should take the next scheduled dose. 
The dose of 80 mg osimertinib daily can be reduced to 40 mg osimertinib once daily under 
circumstances described in Section 10.5. Further dose reductions are not possible. Once a 
dose has been reduced, it should not be re-escalated at future cycles. Any change from 
dosing schedule, dose interruptions, or dose reductions should be recorded. 
10.3. 
Treatment compliance 
Osimertinib will be given in accordance with the protocol and the instructions of a site 
investigator or pharmacist.  
The appropriate number of osimertinib tablets will be provided to patients to be self-
administered at home. Patients should be instructed to use the patient diary to record every 
self-administration as well as any symptoms and to bring the patient diary to every visit at 
the clinic. 
Patients will be asked to bring the remaining trial medication at the end of each cycle to the 
investigator site for a compliance check. The remaining film-coated tablets will be counted 
by the investigator/site staff and recorded at the investigator site. Discrepancies between the 
number of tablets remaining and the calculated number of tablets the patients should have 
taken as well as the information recorded in the patient diary must be documented and 
explained. 
The investigator and/or ETOP can withdraw a patient from the trial in the event of serious 
and persistent non-compliance which jeopardizes the patient’s safety or render trial results 
for this patient unacceptable. Patients who do not attend a minimum of 75% of scheduled 


 
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trial visits, unless due to exceptional circumstances, should be discussed with ETOP and be 
evaluated for compliance. 
10.4. 
Prohibited and restricted concomitant therapies during treatment with 
osimertinib 
Information on any treatment within 28 days prior to starting trial treatment and all 
concomitant treatments given during the trial (and up to 30 days after end of trial treatment), 
with reasons for the treatment, will be recorded. If medically feasible, patients taking regular 
medication, with the exception of potent inducers of CYP3A4 (see below), should be 
maintained on it throughout the study period. Guidance on medicines to avoid, medications 
that require close monitoring and on washout periods while the patient is receiving 
osimertinib is provided below. 
10.4.1. Strong CYP3A inhibitors/inducers 
Based on in vitro data and predicted clinical exposure data, osimertinib is considered 
unlikely to cause clinically significant drug interactions through inhibition or induction of 
cytochrome P450 enzyme activity. In vitro data have shown that the principal CYP enzymes 
responsible for the phase I metabolism of osimertinib are CYP2C8 and CYP3A4. 
The contribution of phase I metabolism to the total clearance of osimertinib is currently 
unknown but, to ensure patient safety, the following potent inhibitors and inducers of 
CYP2C8 and CYP3A4 must not be used during this trial for any patient receiving 
osimertinib. 
CYP3A inducers: 
The concurrent use of CYP3A inducers, including carbamazepine, phenobarbital, 
phenobarbitone, phenytoin, rifabutin, rifampicin, rifapentin, and St. John’s wort, are not 
allowed in the trial and withdrawal period prior to osimertinib start is 3 weeks for all the 
above except phenobartitone, the withdrawal period prior to starting osimertinib treatment is 
5 weeks). 
 
10.4.2. Drugs known to prolong QT interval 
The following drugs are known to prolong QT interval or induce Torsades de Pointes and 
should not be combined with osimertinib. Recommended withdrawal periods prior to 
osimertinib start with these agents are provided in the Table 1. 
Table 1: Drugs prolonging QT interval 
Contraindicated drug 
Withdrawal period 
Clarithromycin, droperidol, erythromycin, procainamide 
2 days 
Cisapride, disopyramide, dofetilide, domperidone, ibutilide, quinidine, 
sotalol, sparfloxacin, thioridazine 
7 days 
Bepridil, chlorpromazine, halofantrine, haloperidol, mesoridazine 
14 days 
Levomethadyl, methadone, pimozide 
4 weeks 


 
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Arsenic trioxide 
6 weeks* 
Pentamidine 
8 weeks 
Amiodarone, chloroquine 
1 year 
* Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
10.4.3. Other concomitant medications 
 Statins: Up to 1.5-fold increase in statin exposure may occur when coadministered with 
osimertinib. It is recommended that the starting and maintenance dose of statins should 
be as low as possible and should be guided by the statin prescribing information. 
Monitoring of low density lipoprotein (LDL) cholesterol levels is advised. If the patient 
experiences any potentially relevant adverse events suggestive of muscle toxicity 
including unexplained muscle pain, tenderness, or weakness, particularly if 
accompanied by malaise or fever, the statin should be stopped, creatine kinase (CK) 
levels should be checked, and any appropriate further management should be taken.  
 Patients taking warfarin should be monitored regularly for changes in prothrombin time 
or international normalized ratio (INR). 
 Patients who wear contact lenses must discontinue wearing their lenses if they have any 
mild to moderate eye symptoms (CTCAE V 4.0 grade ≤2) while receiving treatment 
with osimertinib until at least one week after symptoms have resolved. If a patient has a 
recurrence of eye symptoms or experiences any severe (CTCAE V 4.0 grade ≥3) ocular 
events, they must discontinue wearing their contact lenses until at least one week after 
treatment with osimertinib is permanently discontinued. Patients must not use any eye 
drops or ointment for treatment of eye symptoms, unless agreed to by the investigator, 
at any time during the access program until 1 week after osimertinib has been 
permanently discontinued. Patients should consult their clinician promptly if they have 
any concerns. 
10.5. 
Management of osimertinib related toxicities 
If a patient experiences a grade 3 or higher and/or unacceptable toxicity (any grade), where 
the clinician considers the event of concern to be specifically associated with osimertinib 
(and not attributable to the disease or disease-related processes for which patient is being 
treated), dosing will be interrupted and supportive therapy administered as required in 
accordance with local practice/guidelines. Detailed information on the clinical management 
of events may be found in the appendix 2 (Guidance for the management of adverse events 
in studies of osimertinib). 
If the toxicity resolves or reverts to grade ≤2 within 3 weeks of onset, trial treatment may be 
restarted at the same dose (starting dose) or at a reduced dose of 40 mg osimertinib at the 
investigator’s discretion and with discussion and agreement with ETOP medical review if 
needed. 
 
If the toxicity does not resolve to grade ≤2 after 3 weeks, then the patient will be 
permanently withdrawn from the study treatment after discussion and agreement with ETOP 
medical review and observed until resolution of the toxicity. There will be no individual 


 
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modifications to the treatment schedule in response to toxicity, only potential dose reduction 
or dose interruption. 
 
Dose adjustments and interventions for adverse events should be in accordance with Table 2 
and Table 3. 
Table 2: Osimertinib dose adjustment information for adverse reactions 
Target Organ 
Adverse reaction(*) 
Dose modification  
Pulmonary  
ILD/Pneumonitis (grade 3) 
Permanently discontinue osimertinib  
Cardiac 
QTc interval greater than 500 msec on 
at least 2 separate ECGs 
 
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, then 
restart at a reduced dose (40 mg). 
QTc interval prolongation with 
signs/symptoms of serious arrhythmia 
Permanently discontinue osimertinib 
 
Other  
Grade 3 or higher adverse reaction 
Withhold osimertinib for up to 
3 weeks  
If grade 3 or higher adverse reaction 
improves to grade 0-2 after 
withholding of osimertinib for up to 
3 weeks  
osimertinib may be restarted at the 
same dose (80 mg) or a lower dose 
(40 mg) 
Grade 3 or higher adverse reaction that 
does not improve to grade 0-2 after 
withholding for up to 3 weeks  
Permanently discontinue 
osimertinib 
(*) Graded by CTCAE V 4.0. 
Table 3: Osimertinib dose interventions 
 
osimertinib dose 
Starting Dose 
80 mg daily 
Reduced Dose 
40 mg daily 
If an event subsequently requires dose interruption, osimertinib may restart at the same dose 
or the reduced dose, on resolution/improvement of the event at the discretion of the clinician. 
Once a dose has been reduced, it should not be re-escalated at future cycles. 
 
10.5.1. Interstitial lung disease/pneumonitis 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality 
suggestive of interstitial lung disease is observed, an interruption in osimertinib dosing is 
recommended, and ETOP medical review (Medical.Affairs@ibcsg.org) should be informed. 
It is strongly recommended to perform a full diagnostic workup, to exclude alternative 


 
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causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or 
pulmonary hemorrhage. 
Where ILD is suspected, administer corticosteroids at a dose of 1 – 2 mg/kg/day prednisone 
equivalents for grade 2 or greater pneumonitis, followed by corticosteroid taper.  
In the absence of a diagnosis of ILD osimertinib may be restarted. 
A diagnostic workup (including high-resolution computed tomography (HRCT), blood and 
sputum culture, laboratory parameters) should be performed, to exclude conditions such as 
lymphangitic carcinomatosis, infection, allergy or pulmonary haemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms 
have been excluded a diagnosis of interstitial lung disease should be considered and trial 
treatment permanently discontinued.  
10.5.2. Left ventricular ejection fraction (LVEF) 
Osimertinib and its active metabolite may also inhibit HER2. For this reason: 
 Measurement of LVEF should be performed if the investigator has clinical suspicion of 
new onset impaired cardiac function 
 Consult cardiologist for abnormal LVEF results, at the investigator’s discretion  
 Patients are to be managed clinically according to standard of care 
10.5.3. QTc Prolongation 
Patients with QTc prolongation (i.e., confirmed QTc prolongation to >500 msec absolute or 
a > 60 msec increase from baseline) should have osimertinib treatment interrupted and 
regular ECGs performed until resolution to baseline. 
If the toxicity resolves or reverts to grade ≤2 within 3 weeks of onset, treatment with 
osimertinib may be restarted at the same dose (80 mg, daily) or a lower dose (40 mg, daily) 
using the rules for dose modifications (see also appendix 2, “Guidance for the management 
of adverse events in studies of osimertinib”). 
If the toxicity does not resolve to grade ≤2 after 3 weeks, then the patient should be 
withdrawn from the trial and observed until resolution of the toxicity. 
10.5.4. Ophtalmic adverse events 
There is a known association between the use of EGFR TKIs and the occurrence of 
ophthalmic adverse events. 
Patients on EGFR TKIs, including osimertinib, should be  
 Fully informed that ophthalmic events may occur during treatment with osimertinib 
 Monitored periodically for these events 
 Osimertinib should not be administered on the first scheduled day if the patient has any 
clinically significant eye symptoms. 


 
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 Patients should be encouraged to report any instances of ophthalmic symptoms and/or 
vision changes to allow the appropriate treatment to be initiated. Symptoms may 
include: 
- 
Burning / itching / irritation / smarting 
- 
Redness with / without discharge 
- 
Blurred vision 
- 
Light sensitivity 
Patients who wear contact lenses must discontinue wearing them if: 
 They have any mild to moderate eye symptoms (CTCAE V 4.0 grade ≤2) until at least 
one week after symptoms have resolved. 
 They have a recurrence of eye symptoms or experience any severe (CTCAE V 4.0 
grade ≥3) ocular events until at least one week after treatment with osimertinib is 
permanently discontinued. 
Patients must not use any eye drops or ointment for treatment of eye symptoms, unless 
agreed by treating physician, at any time during the trial until one week after osimertinib has 
been permanently discontinued. 
10.5.5. Corneal Ulceration 
Patients experiencing corneal ulceration will not be permitted to restart osimertinib 
treatment. 
10.5.6. Skin reactions 
Skin effects may occur at any time, but are most likely to start within 2 weeks of 
commencing treatment. 
 Patients may consider applying over-the-counter moisturising cream to face, hands and 
feet twice daily from the start of treatment with osimertinib. 
 Physicians may consider issuing a prescription to patients for topical treatment. 
However, topical steroids and topical or oral antibiotics should not be implemented 
prophylactically and treatment should only be started when confirmed by the treating 
physician. 
 As soon as an acneiform / papulopustular rash occurs, treatment with moderate strength 
topical steroids and antibiotics should be implemented.  
 The occurrence of non-papulopustular skin reactions should be treated appropriately, as 
defined by the treating physician, and in consultation with a dermatologist where 
necessary. 
 Use of topical benzoyl peroxides and other irritating anti-acne agents should be avoided. 
 Patients should be fully informed regarding skin reactions: 
- 
may occur during treatment with osimertinib 


 
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o skin reactions are not contagious, and  
o do not result from allergy to treatment  
- 
may consider applying over-the-counter moisturising cream to face, hands and feet 
bid from the start of treatment 
- 
to contact the site to report any instances of skin reaction as soon as they arise so that 
appropriate treatment can be promptly initiated 
o and, especially if the skin reaction changes (e.g. if it spreads or becomes 
painful) 
- 
It may be beneficial to avoid irritating skin products (e.g. irritating soaps, products 
containing retinol or retinoic acid) 
- 
Camouflage make-up (non-comedogenic or non-pore blocking) can be used during 
treatment. 
10.5.7. Diarrhea 
Patients should be fully informed that diarrhea may occur during treatment with osimertinib 
and that diarrhea is not contagious, and does not result from allergy to treatment. Patient 
should contact the site to report any instances of diarrhea as soon as they arise so that 
appropriate treatment can be promptly initiated. 
Recommendations for appropriate management of diarrhea, including dose-adjustments for 
adverse events of diarrhea that are of grade ≥3 or that are clinically significant and/or 
intolerable and considered by the clinician to be causally related to osimertinib, is provided 
in Appendix 2, “Guidance for the Management of Adverse Events in Studies with 
osimertinib”. 
10.6. 
Bevacizumab 
The dose of bevacizumab is calculated based on the body weight of the patient [kg]. If the 
body weight changes by 10% or more in the course of the treatment, dose adjustment is 
recommended for further infusions. If the body weight changes by less than 10%, no dose 
adjustment is needed. 
 Blood pressure should be routinely measured before every infusion and after a resting 
period of 10 min.  
 Proteinuria should be routinely measured before every infusion of bevacizumab using 
dipstick.  
 No routine premedication (e.g. to prevent infusion reaction) is recommended for 
bevacizumab. 
The initial infusion of bevacizumab should be given over 90 minutes. If the initial infusion 
is well tolerated, the second infusion can be given over 60 minutes. If the second infusion is 
again well tolerated, all subsequent infusions can be given over 30 minutes. 
In case of relevant toxicity, bevacizumab should be paused or discontinued. Dose reductions 
are not recommended. 


 
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Bevacizumab should be given every 3 weeks 3 days. If the administration was pre- or 
postponed up to 3 days the patient should (if possible) return to schedule and the next dose 
should be given 21 days after the last administration. 
10.6.1. Management of bevacizumab related toxicities 
Treatment with bevacizumab should be temporarily interrupted if one of the following 
adverse events occurs despite optimal supportive care, when not attributable to the disease 
under investigation, where the investigator considers the AE of concern to be specifically 
associated with bevacizumab:  
 Any intolerable adverse event regardless of grade 
 Any adverse events CTCAE V 4.0 grade 3 (despite optimal supportive care) 
If toxicity resolves or reverts to CTCAE V4.0 grade ≤1 within 21 days of onset and the 
patient is showing clinical benefit, treatment with bevacizumab may be restarted using the 
rules below for dose modifications and with discussion and agreement with ETOP medical 
review (Medical.Affairs@ibcsg.org) as needed. 
If toxicity does not resolve to CTCAE V 4.0 grade ≤1 after 21 days, then the patient should 
be withdrawn from the trial and observed until resolution of the toxicity. 
There are no recommended dose reductions. Bevacizumab should be discontinued in the 
event of GI perforation, fistula, reversible posterior leukoencephalophathy syndrome (RPLS) 
and wound healing complications.   
The bevacizumab-related AEs hypertension, proteinuria, thromboembolism and hemorrhage 
indlucing any CNS bleeding, as well as any grade 3 or 4 bevacizumab related AEs, should 
be managed as described below. 
 
Hypertension 
Table 4: Management of bevacizumab-related hypertension 
 
 
Description 
Actions 
Grade 1 
Prehypertension (systolic BP 120 to 
139 mmHg or diastolic BP 80 to 89 mmHg) 
No bevacizumab dose 
modification 
Grade 2 
Stage 1 hypertension (systolic BP 140 to 
159 mmHg or diastolic BP 90 to 99 mmHg); 
recurrent or persistent (≥24 hours); 
symptomatic diastolic BP increase by 
>20 mmHg; monotherapy indicated 
Start anti-hypertensive therapy. 
Once blood pressure is <150/100 
mmHg, patients may continue 
bevacizumab therapy 
Grade 3 
Stage 2 hypertension (systolic BP 
≥160 mmHg or diastolic BP ≥100 mmHg); 
more than one drug or more intensive therapy 
than previously used indicated 
Hold bevacizumab for persistent 
or symptomatic hypertension and 
discontinue permanently if 
hypertension is not controlled 
Grade 4 
Life-threatening consequences (eg, malignant 
hypertension, transient or permanent 
neurologic deficit, hypertensive crisis); 
urgent intervention indicated 
Permanently discontinue 
bevacizumab 


 
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Proteinuria 
Table 5: Management of Proteinuria 
 
Description 
Action 
Grade 1 
Urine dipstick 1+ or urine protein 
level 0.15 - 1.0 g/24 hrs 
No bevacizumab dose modification 
Grade 2 
Urine dipstick 2+ to 3+ or urine 
protein level >1 - 3.5 g/24 hrs 
Suspend bevacizumab for ≥2 g/24 hrs and 
resume when proteinuria is <2 g/24 hrs 
For 2+ dipstick: May administer 
bevacizumab, obtain 24 hour urine prior to 
the following dose of bevacizumab 
For 3+ dipstick: Obtain 24 hour urine prior to 
administration 
Grade 3 
Urine dipstick 4+ or urine protein 
level >3.5 g/24 hrs 
Suspend bevacizumab. Resume when 
proteinuria is <2 g/24 hrs, as determined by 
24-hrs urine collection <2 grams. 
Grade 4 
Nephrotic syndrome 
Permanently discontinue bevacizumab 
 
Thrombosis/Embolism 
 Arterial thromboembolism (ATE, including pulmonary embolism):  
Permanently discontinue bevacizumab for any grade ATE; 
 Venous thromboembolism (grade 3) 
- 
First occurrence: discontinue bevacizumab, until toxicity has improved to grade1 
within 21 days; 
- 
Second occurrence: permanently discontinue bevacizumab. 
 
Hemorrhage 
 Any grade of CNS bleeding: permanently discontinue bevacizumab.  Patients should be 
monitored for signs and symptoms of CNS bleeding, and bevacizumab treatment 
discontinued in case of intracranial bleeding of any grade. 
 Grade >=2 hemoptysis: permanently discontinue bevacizumab. 
 Grade 3 or 4 bleeding of any other kind: permanently discontinue bevacizumab. 
 
Surgery and wound healing complications 
Bevacizumab may adversely affect the wound healing process. Bevacizumab therapy should 
not be initiated for at least 28 days following major surgery or until the surgical wound is 
fully healed. In patients who experience wound healing complications during bevacizumab 
treatment, bevacizumab should be withheld until the wound is fully healed. Bevacizumab 
therapy should be withheld 4 weeks prior to elective surgery.  


 
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Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with 
bevacizumab. This condition is usually secondary to wound healing complications, 
gastrointestinal perforation or fistula formation. Bevacizumab therapy should be 
discontinued in patients who develop necrotising fasciitis, and appropriate treatment should 
be promptly initiated.  
Temporarily suspend bevacizumab for: 
 At least 4 weeks prior to elective surgery  
 First venous thromboembolic event grade 3 or 4 requiring full anticoagulation; 
bevacizumab may be resumed after initiation of therapeutic-dose anticoagulant therapy 
if the patient is on a stable dose of anticoagulant 
 Severe hypertension not controlled with medical management. Blood pressure should 
be less than 150 mmHg systolic and 100 mmHg diastolic before bevacizumab is given. 
If blood pressure is higher, measurement should be repeated and if hypertension is 
confirmed, antihypertensive medication should be started and bevacizumab should be 
delayed until blood pressure drops below 150/100 mmHg.  
 Proteinuria grade 3; resume bevacizumab once grade 2 or less has been attained. 
 Grade 3 or 4 bevacizumab-related events (except grad 3 hypertension) occurring for the 
first time: bevacizumab should be discontinued until toxicity improves to grade 1. 
When a grade 3 o 4 occurs for second time, bevacizumab should be discontinued 
permanently 
 
Discontinue bevacizumab for: 
 Arterial thromboembolism (any grade) 
 Febrile grade 4 neutropenia and/or grade 4 thrombocytopenia regardless of the 
relationship to treatment 
 Grade ≥3 venous thrombosis/embolism (including pulmonary embolism) and recurrent 
venous thromboembolic event requiring full anticoagulation 
 Gastrointestinal perforations (gastric ulcer, fistula formation in the gastrointestinal tract, 
intra-abdominal abscess) 
 Grade ≥2 fistula formation involving an internal organ  
 Cerebral or cardiac ischemic events 
 Grade ≥3 left ventricular dysfunction (CHF) 
 Wound dehiscence and wound healing complications requiring medical intervention  
 Nephrotic syndrome. 
 CNS bleeding (any grade) or grade ≥3 bleeding of any kind  
 Grade >=2 hemoptysis 


 
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 Medically significant hypertension not controlled with antihypertensive therapy, 
hypertensive crisis or hypertensive encephalopathy 
 Posterior reversible encephalopathy syndrome (PRES) 
 Severe infusion reactions  
 Recurring grade 3 or 4 bevacizumab-related event  
 A treatment delay of more than 6 weeks 
10.7. 
Contraception, nursing, pregnancy 
10.7.1. Contraception 
Female patients who are not of childbearing potential due to being postmenopausal (2 year 
without menstruations) or surgically sterilised (oophorectomy, hysterectomy and/or tubal 
ligation) do not need to use contraception to be eligible for the trial. All other female 
patients are considered to be of childbearing potential. 
Women of childbearing potential and sexually active men must use highly effective contra-
ception from the start of treatment with osimertinib and bevacizumab and until 6 months 
after the last dose. The following contraception methods are considered highly effective: 
 Hormonal 
(estrogen 
and 
progesterone) 
contraception 
(oral, 
intravaginal, 
transdermal) associated with inhibition of ovulation 
 Progesterone-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation 
 Intrauterine deviced (IUD) or intrauterine hormone releasing systems (IUS) 
 Bilateral tubal occlusion 
 Vasectomy 
Women who become pregnant while participating in the trial must discontinue trial medica-
tion immediately. The pregnancy must be reported following procedures detailed in 
Section 12.12. Also any pregnancy that occurs in a female partner of a male trial participant 
must be reported. 
Patients should be informed that taking the trial medication may involve unknown risks to 
the fetus if pregnancy were to occur during the trial. In order to participate in the trial they 
must adhere to the contraception requirement (described above) for the duration of the trial 
up to 6 months after the last dose of any trial treatment. If there is any doubt whether a 
patient will reliably comply with the requirements for contraception, that patient should not 
be entered into the trial. 
10.7.2. Use in pregnancy 
If a patient inadvertently becomes pregnant while on trial treatment, trial treatment will be 
stopped immediately for the patient and the event reported immediately, see Section 12.12. 
The site will contact the patient at least monthly and document the patient’s status until the 
pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to ETOP without delay and within 24 hours if the outcome is a serious adverse 


 
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experience (e.g. death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The trial investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to ETOP.  
10.7.3. Use in nursing women 
It is unknown whether osimertinib or bevacizumab is excreted in human milk. Since 
maternal IgGs and many drugs are excreted in milk and because of the potential for serious 
adverse reactions in the nursing infant, patients who are breast-feeding are not eligible for 
randomisation. 
10.8. 
Treatment duration 
Patients remain on treatment until one of the following events, whichever occurs first: 
 Documented progression according to RECIST v1.1, except if the patient may still 
derive benefit as per investigator’s decision. 
 Unacceptable toxicity to either osimertinib or bevacizumab 
 Medical condition that prevents further treatment 
 Patient withdraws consent 
 Patient becomes pregnant 
 Trial termination (e.g. approximately 18 months after randomisation of the last 
patient).  
 
11. 
Safety of trial treatments 
Clinical experience with osimertinib is described in the current version of the Osimertinib 
Investigator’s Brochure. 
11.1. 
Safety profile of osimertinib 
11.1.1. Potential risks with osimertinib 
Important treatment emergent adverse events associated with the monotherapy 
administration of osimertinib include diarrhoea, rash/acne and dry skin. Other potential 
EGFR-TKI class-related effects include corneal ulceration, liver transaminases increases 
and ILD, although none of these events are currently considered to be associated with 
administration of osimertinib. As of the cut-off of 19 November 2013 there have been 5 
reports of unconfirmed ILD-like events identified in the ongoing study. Assessment of 
causality is complicated by the diagnosis of advanced NSCLC, including prior treatments, 
which are known to pre-dispose patients to occurrence of ILD. 
Based on the identified and potential risks associated with osimertinib treatment, this trial 
protocol incorporates mandatory safety monitoring procedures and guidance to assist with 


 
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early diagnosis and rapid management of potential osimertinib drug-related symptoms. Dose 
modification algorithms are also included in this protocol. 
11.1.2. Known adverse reaction 
The following CTC v 4.0 grade 3 - 5 adverse reactions have been reported: 
Very common (≥10%): diarrhoea, rash and acne, dry skin, stomatitis, nail effects, 
leucopenia, thrombocytopenia, neutropenia 
Common (1 – <10%): rash and acne, dry skin, stomatitis, ILD, nail effects 
Uncommon (0.1% - <1%): QTc prolongation (grade 3; >500 ms QTcF) 
11.1.3. Contraindications 
Osimertinib is contraindicated in individuals who are hypersensitive to any component of 
the finished dosage forms. 
11.1.4. Gastrointestinal tract effects including stomatitis 
Diarrhoea is the most commonly reported AE with osimertinib, reported at a frequency of 
very common (>10%). The majority of reported AEs of diarrhoea were considered mild or 
moderate in severity. AEs of diarrhoea were rarely reported as grade 3 and did not 
generally lead to discontinuation of osimertinib. 
There were no reports of haemorrhagic diarrhoea or GI perforation in phase I or II studies. 
Stomatitis has been reported by NSCLC patients in clinical trials with osimertinib during the 
reporting period, at a frequency between 5.5% and 13.7% across dose levels, with most 
events mild in severity and a small number of moderate cases. Only 1 patient experienced a 
grade 3 event. There is an upward inflection in the incidence of stomatitis between 80 mg 
and 160 mg. The impact of stomatitis on patients receiving osimertinib, as measured by 
numbers of SAEs (including hospitalisations) and dose modifications or discontinuations is 
low. 
Patients with refractory nausea, vomiting and chronic gastrointestinal diseases are excluded 
from participating in studies. Detailed information on the treatment of gastrointestinal 
adverse events are described in section 10.5 and are included in the “guidance for the 
management of adverse events in studies of osimertinib” (appendix 2). 
11.1.5. Dermatological events and nail disorders 
Dermatological events such as rash, acne and dry skin have occurred in the osimertinib 
clinical studies at a frequency of common (>1% and <10%) to very common (>10%) across 
dose levels. Most events were CTCAE V 4.0 grade 1. Nail effects have previously been 
identified as a potential risk of treatment with osimertinib as a known class effect for EGFR 
inhibitors. Nail effects is a group term of closely related events, which includes changes to 
the nail and nail bed which have been reported at all doses of osimertinib in clinical trials. 
The highest incidence has been seen at the highest doses of osimertinib and the incidence 
ranges from 25.1% for the 80 mg dose to 50.0% for the 240 mg dose. Nail effects have been 


 
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mostly mild (grade 1) or moderate (grade 2) in severity. There has been one severe event 
(paronychia, grade 3) for which dosing was interrupted. 
There are no specific dermatological exclusion criteria. However, patients with any 
unresolved adverse event from prior therapy greater than grade 1 will be excluded from 
participating in studies. Dermatological treatment should be instituted for patients with any 
skin reactions, considered by the investigator to be causally related to osimertinib. Detailed 
information on the treatment of dermatological adverse events is included in the “guidance 
for the management of adverse events in studies of osimertinib” (appendix 2). 
11.1.6. Ocular surface effects 
There is no evidence of a causal relationship between osimertinib and ocular surface effects.  
Full ophthalmic assessment, including slit lamp examination, will be performed at screening 
and should be repeated if a patient experiences any visual symptoms (including blurring of 
vision), with additional tests if clinically indicated. Any clinically significant findings, 
including those confirmed by the ophthalmologist must be reported as an AE.  
Any patient developing corneal ulceration will be permanently discontinued from trial 
treatment and should be followed regularly until resolution of the event. 
Patients who wear contact lenses should discontinue wearing lenses if they have any mild to 
moderate eye symptoms (grade 2) while receiving treatment with osimertinib until at least 
one week after symptoms have resolved. If a patient has a recurrence of eye symptoms or 
experiences any severe (grade 3) ocular events they should discontinue wearing their 
contact lenses until at least one week after treatment with osimertinib is permanently 
discontinued. Patients should not use any eye drops or ointment for treatment of eye 
symptoms, unless agreed by the investigator, at any time during the trial until 1 week after 
osimertinib has been permanently discontinued. Patient will be advised to consult the clinic 
promptly if they have any concerns. 
11.1.7. Cardiac Contractility 
There is no evidence of a causal relationship between osimertinib and decrease in cardiac 
function or cardiac contractility. In the phase II pooled population, of 375 patients who had 
post-baseline echocardiography assessment, an LVEF decrease from baseline of 
10 percentage points to an LVEF value <50% occurred in 2.4% (9/375) of patients. 
Additionally, an LVEF increase from baseline of ≥10 percentage points occurred in 9.9% 
(37/375) of patients. Evaluation of LVEF measurement during the treatment period did not 
identify any clinically significant change in median values over time, and there is no 
suggestion that osimertinib causes an adverse reaction on cardiac contractility. 
11.1.8. QTc 
Across AURA phase I and II; and AURA2, an increase in QTcF interval compared with 
baseline was observed, with a median increase of approximately 15 msec, at steady state on 
day 1 of cycle 3 but with no evidence that this is associated with an increased risk of cardiac 
arrhythmias or TdP. 


 
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In AURA2 an intensive assessment of ECG parameter was performed addressing key 
aspects of a conventional thorough QT/QTc study, including time-matched ECG 
assessments, to enable evaluation of any pro-arrhythmic risk of osimertinib. 
The mean time-matched change from baseline in QTcF at week 6 across all time points was 
14.5 ms (90% CI 14.0 - 15.0), with the maximum upper 90% CI limit at any time point 
being 17.5 ms. 
In AURA2, based on the time-matched pre-dose baseline and post-dose ECG samples with 
post-dose PK sampling at the same time points, the mean (90% CI) increase in ΔQTcF 
interval was estimated to be 0.271 (90% CI: 0.241 - 0.301) msec per 10 nM-increase in 
osimertinib plasma levels, based on a linear mixed effects model, with gender not having a 
significant effect in the model. Based on this concentration QTc analysis, the predicted drug 
related QTc interval prolongation at the proposed osimertinib therapeutic dose (80 mg) is 
14.2 msec (upper bound of 90% CI: 15.8 msec). 
This magnitude of effect exerted by osimertinib is considered to be of limited clinical 
significance as evidenced by the low number of AEs reported under the QT prolongation 
SMQ in the phase II studies - 17 (4.1%) patients with ECG QT prolonged: 9 (2.2%) patients 
had AEs that were maximum grade 1, 3 (0.7%) patients had AEs that were maximum 
grade 2, and 5 (1.2%) patients had AEs that were maximum grade 3. 
11.1.9. Respiratory effects, including ILD 
Like many EGFR inhibitors, osimertinib is associated with ILD. In the phase II studies 
(AURA extension and AURA2), at the DCO date of 01 May 2015 ILD (grouped terms) was 
reported in 2.7% (11/411) of patients during treatment with osimertinib 80 mg in the 
phase II studies. The median time to onset for ILD grouped term events in the phase II 
studies was 83 days (range 17 to 230 days). 
Considering the importance of ILD as an event, an additional analysis has been conducted, 
which includes other ongoing studies with osimertinib, at a DCO date of 01 June 2015. At 
this date, osimertinib had been dosed to 1221 patients across the clinical development 
programme. A total of 2.9% (35/1221) patients have reported ILD or suspected ILD-like 
events. 
11.2. 
Safety profile of bevacizumab 
11.2.1. Potential risks with bevacizumab 
Warnings and precautious for bevacizumab include perforation or fistula; surgery and 
wound healing complications; hemorrhage; arterial thrombembolic events; venous 
thromboembolic events; hypertension; posterior reversible encephalopathy syndrome 
(PRES); proteinuria; infusion reactions; ovarian failure. The most common adverse 
reactions observed in bevacizumab patients at a rate >10% and at least twice the control arm 
rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, 
rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis (see SPC for 
details). 


 
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In a phase II study of erlotinib in combination with bevacizumab as first line therapy for 
EGFRm NSCLC patients, no new safety signals were identified between erlotinib plus 
bevacizumab group and erlotinib alone group, with hypertension (60% vs 10%) and 
proteinuria (8% vs 0%) being the more frequently observed grade 3 AEs in the combination 
group compared against erlotinib alone group [45]. 
Based on the identified and potential risks associated with bevacizumab, this trial protocol 
incorporates mandatory safety monitoring procedures and guidance to assist with early 
diagnosis and rapid management of potential drug-related symptoms. 
11.2.2. Known adverse reactions 
The following NCI CTC grade 3 - 5 adverse reactions have been reported: 
Very common (≥10%): Febrile neutropenia, leucopenia, thrombocytopenia, neutropenia, 
anorexia, peripheral sensory neuropathy, dysarthria, headache, dysguesia, eye disorder, 
lacrimeation icreased, hypertension, thromboembolism, dyspnoea, rhinitis, rectal 
haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, absominal pain, wound 
healing complications, exfoliative dermatitis, dry skin, skin discoloration, arthralgia, 
proteinuria, ovarian failure, asthenia, fatigue, pyrexia, pain, mucosal inflammation, weight 
decreased. 
Common (1 – <10%): Sepsis, abscess, cellulitis, infection, urinary tract infection, anaemia, 
lymphopenia, hypersensitivity, infusion reaction, dehydration, cerebrovascular accident, 
syncope, somnolence, headache, congestive heard failure, supraventricular tachycardia, 
arterial thromboembolism, deep vein thrombosis, haemorrhage, pulmonary haemorrhage, 
haemoptysis, pulmonary embolism, dysphonia, hypoxia, epistaxis, gastrointestinal 
perforation, intestinal perforation, ileus, intestinal obstruction, recto-vaginal fistulae, 
gastrointestinal disorder, proctalgia, palmar-plantar erythrodysaesthesia syndrome, fistula, 
muscular weakness, myalgia, back pain, pelvic pain, lethargy. 
11.2.3. Contraindications  
Bevacizumab is contraindicated in patients with known hypersensitivity to any components 
of the product, and to Chinese hamster ovary (CHO) cell products or other recombinant 
human or humanised antibodies. 
11.2.4. Special warnings and precautions for use 
Gastrointestinal (GI) perforations and fistulae 
Patients may be at an increased risk for the development of gastrointestinal perforation and 
gall bladder perforation when treated with bevacizumab. Intra-abdominal inflammatory 
process may be a risk factor for gastrointestinal perforations in patients with metastatic 
carcinoma of the colon or rectum, therefore, caution should be exercised when treating these 
patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, 
recurrent or metastatic cervical cancer with bevacizumab and all patients with GI 
perforation had a history of prior radiation. Therapy should be permanently discontinued in 
patients who develop gastrointestinal perforation. 
 
 


 
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GI-vaginal fistulae 
Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are 
at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-
vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal 
fistulae and all patients with GI-vaginal fistulae had a history of prior radiation. Recurrence 
of cancer within the field of prior radiation is an additional important risk factor for the 
development of GI-vaginal fistulae.  
 
Non-GI fistulae 
Patients may be at increased risk for the development of fistulae when treated with 
bevacizumab. Permanently discontinue bevacizumab in patients with tracheoesophageal 
fistula or any grade 4 fistula. Limited information is available on the continued use of 
bevacizumab in patients with other fistulae. 
In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of 
bevacizumab should be considered. 
 
Wound healing complications 
Bevacizumab may adversely affect the wound healing process. Serious wound healing 
complications, including anastomotic complications, with a fatal outcome have been 
reported. Therapy should not be initiated for at least 28 days following major surgery or 
until the surgical wound is fully healed. In patients who experienced wound healing 
complications during therapy, treatment should be withheld until the wound is fully healed. 
Therapy should be withheld for elective surgery. 
 
Necrotising fasciitis 
Necrotising fasciitis including fatal cases, has rarely been reported in patients treated with 
bevacizumab. This condition is usually secondary to wound healing complications, 
gastrointestinal perforation or fistula formation. Bevacizumab therapy should be 
discontinued in patients who develop necrotising fasciitis, and appropriate treatment should 
be promptly initiated. 
 
Hypertension 
An increased incidence of hypertension was observed in bevacizumab-treated patients. 
Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. 
Pre-existing hypertension should be adequately controlled before starting bevacizumab 
treatment. There is no information on the effect of bevacizumab in patients with 
uncontrolled hypertension at the time of initiating therapy. Monitoring of blood pressure is 
generally recommended during therapy. 
In most cases hypertension was controlled adequately using standard antihypertensive 
treatment appropriate for the individual situation of the affected patient. The use of diuretics 


 
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to manage hypertension is not advised in patients who receive a cisplatin-based 
chemotherapy regimen. Bevacizumab should be permanently discontinued if medically 
significant hypertension cannot be adequately controlled with antihypertensive therapy, or if 
the patient develops hypertensive crisis or hypertensive encephalopathy. 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been rare reports of bevacizumab-treated patients developing signs and 
symptoms that are consistent with PRES, a rare neurologic disorder, which can present with 
the following signs and symptoms among others: seizures, headache, altered mental status, 
visual disturbance, or cortical blindness, with or without associated hypertension. A 
diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance 
imaging (MRI). In patients developing PRES, treatment of specific symptoms including 
control of hypertension is recommended along with discontinuation of bevacizumab. The 
safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not 
known. 
 
Proteinuria 
Patients with a history of hypertension may be at increased risk for the development of 
proteinuria when treated with bevacizumab. There is evidence suggesting that all grade 
proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is 
recommended prior to starting and during therapy. Grade 4 proteinuria (nephrotic syndrome) 
was seen in up to 1.4% of patients treated with bevacizumab. Therapy should be 
permanently discontinued in patients who develop nephrotic syndrome. 
 
Arterial thromboembolism 
In clinical trials, the incidence of arterial thromboembolic reactions including 
cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial 
infarctions (MIs) was higher in patients receiving bevacizumab in combination with 
chemotherapy compared to those who received chemotherapy alone. 
Patients receiving bevacizumab plus chemotherapy, with a history of arterial 
thromboembolism, diabetes or age greater than 65 years have an increased risk of 
developing arterial thromboembolic reactions during therapy. Caution should be taken when 
treating these patients with bevacizumab. 
Therapy should be permanently discontinued in patients who develop arterial 
thromboembolic reactions. 
 
Venous thromboembolism 
Patients may be at risk of developing venous thromboembolic reactions, including 
pulmonary embolism under bevacizumab treatment. 


 
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Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab in 
combination with paclitaxel and cisplatin may be at increased risk of venous 
thromboembolic events. 
Bevacizumab should be discontinued in patients with life-threatening (grade 4) 
thromboembolic reactions, including pulmonary embolism. Patients with thromboembolic 
reactions ≤ grade 3 need to be closely monitored. 
 
Haemorrhage 
Patients treated with bevacizumab have an increased risk of haemorrhage, especially 
tumour-associated haemorrhage. Bevacizumab should be discontinued permanently in 
patients who experience brade 3 or 4 bleeding during bevacizumab therapy. 
Patients with untreated CNS metastases were routinely excluded from clinical trials with 
bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of 
CNS haemorrhage in such patients has not been prospectively evaluated in randomised 
clinical trials. Patients should be monitored for signs and symptoms of CNS bleeding, and 
bevacizumab treatment discontinued in cases of intracranial bleeding. 
There is no information on the safety profile of bevacizumab in patients with congenital 
bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants 
for the treatment of thromboembolism prior to starting bevacizumab treatment, as such 
patients were excluded from clinical trials. Therefore, caution should be exercised before 
initiating therapy in these patients. However, patients who developed venous thrombosis 
while receiving therapy did not appear to have an increased rate of grade 3 or above 
bleeding when treated with a full dose of warfarin and bevacizumab concomitantly. 
 
Pulmonary haemorrhage/haemoptysis 
Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, 
and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent 
pulmonary haemorrhage/haemoptysis (> 2.5 ml of red blood) should not be treated with 
bevacizumab. 
 
Congestive heart failure (CHF) 
Reactions consistent with CHF were reported in clinical trials. The findings ranged from 
asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring 
treatment or hospitalisation. Caution should be exercised when treating patients with 
clinically significant cardiovascular disease such as pre-existing coronary artery disease, or 
congestive heart failure with bevacizumab. 
Most of the patients who experienced CHF had metastatic breast cancer and had received 
previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk 
factors for CHF were present. 
In patients in AVF3694g who received treatment with anthracyclines and who had not 
received anthracyclines before, no increased incidence of all grade CHF was observed in the 


 
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anthracycline + bevacizumab group compared to the treatment with anthracyclines only. 
CHF grade 3 or higher reactions were somewhat more frequent among patients receiving 
bevacizumab in combination with chemotherapy than in patients receiving chemotherapy 
alone. This is consistent with results in patients in other studies of metastatic breast cancer 
who did not receive concurrent anthracycline treatment. 
 
Neutropenia and infections 
Increased rates of severe neutropenia, febrile neutropenia, or infection with or without 
severe neutropenia (including some fatalities) have been observed in patients treated with 
some myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy 
alone. This has mainly been seen in combination with platinum- or taxane-based therapies in 
the treatment of NSCLC, metastatic breast cancer, and in combination with paclitaxel and 
topotecan in persistent, recurrent, or metastatic cervical cancer.  
 
Hypersensitivity reactions/infusion reactions 
Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation 
of the patient during and following the administration of bevacizumab is recommended as 
expected for any infusion of a therapeutic humanised monoclonal antibody. If a reaction 
occurs, the infusion should be discontinued and appropriate medical therapies should be 
administered. A systematic premedication is not warranted. 
 
Osteonecrosis of the jaw (ONJ) 
Cases of ONJ have been reported in cancer patients treated with bevacizumab, the majority 
of whom had received prior or concomitant treatment with intravenous bisphosphonates, for 
which ONJ is an identified risk. Caution should be exercised when bevacizumab and 
intravenous bisphosphonates are administered simultaneously or sequentially. 
Invasive dental procedures are also an identified risk factor. A dental examination and 
appropriate preventive dentistry should be considered prior to starting the treatment with 
bevacizumab. In patients who have previously received or are receiving intravenous 
bisphosphonates invasive dental procedures should be avoided, if possible. 
 
Intravitreal use 
Bevacizumab is not formulated for intravitreal use.  
 
Eye disorders 
Individual cases and clusters of serious ocular adverse reactions have been reported 
following unapproved intravitreal use of bevacizumab compounded from vials approved for 
intravenous administration in cancer patients. These reactions included infectious 
endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and 
vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, 


 
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intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and 
conjunctival haemorrhage. Some of these reactions have resulted in various degrees of 
visual loss, including permanent blindness. 
Systemic effects following intravitreal use 
A reduction of circulating VEGF concentration has been demonstrated following intravitreal 
anti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and 
arterial thromboembolic reactions have been reported following intravitreal injection of 
VEGF inhibitors. 
 
Ovarian failure/fertility 
Bevacizumab may impair female fertility. Therefore fertility preservation strategies should 
be discussed with women of child-bearing potential prior to starting treatment with 
bevacizumab. 
 
11.2.5. Elderly Patients 
In randomised clinical trials, age >65 years was associated with an increased risk of 
developing arterial thromboembolic events including cerebrovascular accidents, transient 
ischemic attacks and myocardial infarction as compared to those aged ≤65 years when 
treated with bevacizumab. Other reactions with a higher frequency seen in patients over 65 
were grade 3 - 4 leucopenia, thrombocytopenia; and all grade neutropenia, diarrhoea, nausea, 
headache and fatigue. 
No increase in the incidences of other reactions, including gastrointestinal perforation, 
wound healing complications, hypertension, proteinuria, congestive heart failure and 
haemorrhage, was observed in elderly patients (>65 years) receiving bevacizumab as 
compared to those aged ≤65 years treated with bevacizumab. 
 
 


 
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12. 
Adverse event and serious adverse event reporting 
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. 
 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the CTCAE version 4.0. The CTCAE is 
available for downloading on the internet at http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
An interactive version can be found at https://safetyprofiler-ctep.nci.nih.gov/. 
12.1. 
Adverse event (AE) 
An adverse event (AE) is defined as any untoward medical occurrence that occurs from the 
date of signature of informed consent until 30 days after all trial treatment discontinuation, 
regardless of whether it is considered related to a medication. 
Any grade of any observed AE should be reported on the AE eCRFs. 
12.2. 
Adverse reaction (AR) 
An adverse reaction (AR) is defined as “any noxious and unintended response to an IMP 
related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship (see Section 12.8) to an IMP qualify as adverse reactions. The 
expression suspected/related means to convey in general that there is evidence or argument 
to suggest a causal relationship to the trial treatment. 
12.3. 
Unexpected adverse reaction (UAR) 
An unexpected adverse reaction (UAR) is any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information. 
When the outcome of the adverse reaction is not consistent with the IB or summary of 
product characteristics (SPC) this adverse reaction should be considered as unexpected. 
 
 


 
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12.4. 
Serious adverse events (SAE) 
A serious adverse event (SAE) is defined as any undesirable medical occurrence/adverse 
drug experience that at any dose: 
 results in death (any cause, except progression of cancer under study) 
 is life-threatening 
 requires or prolongs inpatient hospitalisation 
 results in persistent or significant disability/incapacity 
 constitutes an important medical event 
 is a congenital anomaly or birth defect (including neonatal deaths) 
 is a secondary malignancy (see 0) 
 is an event of clinical interest (see 12.4.4) 
12.4.1. Inpatient hospitalisation 
A hospital stay equal to, or greater than, 24 hours. Hospitalisations occurring under the 
following circumstances are not considered to be SAEs:  
 elective surgery, for pre-existing conditions and planned prior to trial entry 
 occur on an outpatient basis and do not result in admission (hospitalisation <24h) 
 are part of the normal treatment or monitoring of the studied treatment 
12.4.2. Important medical events 
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalisation, or disability, but may jeopardise the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
12.4.3. Secondary malignancies 
Primary malignancy 
A second primary malignancy is one that is unrelated to the treatment of a previous 
malignancy (and is NOT a metastasis from the previous malignancy). 
Secondary malignancy 
A 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. 
12.4.4. Events of clinical interest (ECI) 
The following events of clinical interest (ECIs) are not necessarily SAEs, but should be 
reported as such on the SAE eCRFs (SAE Initial Reports) by indicating that this is an 
“event of special interest”. 


 
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 Drug induced liver injury (DILI): AST or ALT elevations ≥3x ULN with 
concurrent elevation of total bilirubin ≥2× ULN and, at the same time, alkaline 
phosphatase (AP) <2 × ULN. 
 Overdose: All overdose with and without an AE must be reported by the 
investigator to ETOP safety office within 24 hours. 
12.4.5. Osimertinib overdose  
Osimertinib overdose is defined as any dose received above the protocol-mandated dose of 
80 mg once daily. 
There is no known antidote to osimertinib and there are no definitions regarding what 
constitutes an overdose. Investigators will be advised that any patient who inadvertently 
receives a higher dose than stated in the protocols should be treated with appropriate 
supportive care until recovery and followed up carefully. 
12.4.6. Bevacizumab overdose 
The highest dose tested in humans (20 mg/kg of body weight every 2 weeks i.v.) was 
associated with severe migraine in several patients. In the event of overdose, bevacizumab 
should be discontinued and the patient should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
12.4.7. Exceptions to the SAE definition  
The following situations do not need to be reported as SAEs:  
 Elective hospitalisation for pre-existing conditions that have not been exacerbated by 
trial treatment.  
 A hospitalisation which was planned before the patient consented for trial 
participation and where admission did not take longer than anticipated (see also 
12.4.1). 
 A hospitalisation 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 (serious) AE.  
 Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the trial that do not worsen significantly. 
 Progression of cancer under study: 
By 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. 


 
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12.5. 
Serious adverse reaction (SAR) 
A serious adverse reaction (SAR) is defined as any SAE which is considered related to the 
protocol treatment. 
12.6. 
Suspected unexpected serious adverse reaction (SUSAR) 
Suspected unexpected serious adverse reactions (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 
12.7. 
Severity / intensity of (serious) adverse events 
The (serious) AE severity grade provides a qualitative assessment of the extent or intensity 
of a specific event, as determined by the investigator or as reported by the patient. The 
severity grade does not reflect the clinical seriousness of the event, only the degree or extent 
of the affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the 
relationship to trial drug. A severe event may be of relatively minor medical significance 
(such as severe headache). The term “severe” is not the same as “serious”, which is based 
on patient/event outcome or action criteria associated with events that pose a threat to a 
patient’s life or functioning. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
 Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
 Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may 
be needed; no or minimal medical intervention/therapy required 
 Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalisation is possible 
 Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalisation or 
hospice care probable 
 Grade 5 = Death – the event results in death 
 
 


 
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12.8. 
Causality of adverse events 
The investigator must determine the relationship between the administration of trial drug(s) 
and the occurrence of an AE/SAE following the definitions indicated below: 
Not suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship unlikely or remote, 
or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event. 
Suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event. 
Relationship to the protocol treatment 
Not suspected  
Suspected / related to trial treatment 
- 
unrelated 
- 
unlikely 
- 
possible 
- 
probable 
- 
definite 
12.9. 
Duration of adverse events 
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of 
the event. 
12.10. Action taken 
The investigator will report the action taken with trial drug(s) because of an AE or SAE, as 
applicable (e.g. discontinuation of trial drug(s), medication needed for the treatment of an 
AE) and in case of an SAE report if concomitant and/or additional treatments were given for 
the event. 
12.11. Reporting SAEs 
Any SAE, whether related to trial drug or not, occurring in a patient after providing written 
informed consent (IC) must be reported, which occurs within 30 days following cessation of 
treatment or until the initiation of a new anticancer therapy, whichever is earlier. 
Information about all such events will be collected and recorded on the SAE eCRFs (SAE 
Initial Reports). 
After completion of trial treatments, report all SAEs beyond 30 days that are considered at 
least possibly related to previous trial treatment. Cases of secondary malignancies and 
congenital abnormalities and neonatal deaths are to be considered as SAEs, regardless of 
whether they occur during or after trial treatment. These events should be reported during 
the whole trial duration on the serious adverse event eCRFs (SAE Initial Reports) 


 
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To ensure patient safety, ETOP must be informed of each SAE using the procedures 
described below: 
 Any SAE must be reported by submitting the completed SAE Initial Reports eCRF 
in English within 24 hours of awareness in the EDC system ETOPdata. 
 Queries may be issued by the ETOP safety office; a timely response by the 
investigator to all SAE-related queries is crucial. 
 The SAE outcome must be reported within 15 days after initial reporting by online 
submitting the SAE Follow-up Report eCRF. In case the SAE is reported as ongoing 
after 15 days, a second follow-up report has to be submitted with the final outcome. 
Submission of SAE is done via the EDC system, or in case of unavailability, by sending the 
SAE form by fax to the ETOP safety office: 
+41 31 389 92 29 
As soon as the EDC system is available again, the SAE eCRF has to be completed and 
submitted by the site. 
The ETOP safety office will inform AstraZeneca and Roche safety and other appropriate 
persons about all SAEs within 24 hours of receipt at the ETOP safety office.  
The ETOP safety office will review the SAE and prepare a summary report of all SAEs 
received. Listings of SAEs will be prepared as required. 
 
 
 


 
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12.12. Pregnancy 
Patients who are not of childbearing potential due to being postmenopausal (2 years without 
menstruation) or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) 
do not need to use contraception to be eligible for the trial. All other patients are considered 
to be of childbearing potential and must use adequate contraception throughout the trial. 
Women of childbearing potential and sexually active men must use highly effective 
contraception during trial treatment and until 6 months thereafter. Please refer to 
section 10.6.1 for highly effective contraception methods. 
12.12.1. Maternal exposure 
In the case of pregnancy occurring during the course of the trial or within 6 months after 
treatment discontinuation, the investigator shall immediately (within 24 hours after 
awareness of pregnancy) notify ETOP by completing the pregnancy eCRF in ETOPdata in 
accordance with the SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported (within 
14 days) by submitting a second pregnancy eCRF in ETOPdata. All neonatal deaths that 
occur within 30 days of birth should be reported, irrespective of causality, as SAEs. In 
addition, any infant death after 30 days, irrespective of causality should also be reported 
within 24 hours of the investigator’s knowledge of the event using the SAE forms. 
12.12.2. Paternal exposure 
Pregnancy that occurs in a female partner of a male trial participant is not considered to be 
an adverse event. However, the outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth or congenital abnormality) should be 
reported to during the course of the trial or within 6 month after treatment discontinuation 
by completing the pregnancy eCRF in ETOPdata. 
12.13. Reference safety information 
The osimertinib IB (IB AZD9291 edition 6, January 2016) section 5.4 and Avastin IB 
(IB 24 version November 2016) appendices 11 and 12 served as reference documents for the 
protocol.  
For the determination of the expectedness of the serious adverse events of osimertinib and 
bevacizumab, the current versions of the IBs serve as reference safety information. 
 
 


 
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13. 
Response evaluation 
13.1. 
CT schedule for response evaluation 
Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax 
until adrenal glands and full liver and kidney included) will be done at baseline within 
6 weeks before randomisation. 
CT scans will be repeated every 9 weeks (63 ±4 days) from randomisation until progression 
of disease determined according to RECIST v1.1 criteria. The same imaging technique, 
acquisition, and processing parameters should be used in a patient throughout the trial. 
13.2. 
Response evaluation criteria in solid tumours (RECIST version 1.1) 
13.2.1. Introduction 
All included patients will be evaluated for disease response and progression according to the 
revised response evaluation criteria in solid tumours (RECIST version 1.1) [52]. 
In this trial, patients must have measurable or evaluable disease (see definitions below).  
13.2.2. Methods of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumour effect of a treatment. 
CT scan is the best currently available and reproducible method to measure lesions selected 
for response assessment. CT scan should generally be performed using a ≤ 5 mm contiguous 
reconstruction algorithm. MRI is acceptable for certain situations, e.g. body scans. 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin 
nodules) and ≥10 mm. In the case of skin lesions, documentation by colour photography 
including a ruler to estimate the size of the lesion is recommended. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT scan is preferable. 
Ultrasound is not useful in assessment of lesion size and is not accepted as a method of 
assessment. 
FDG-PET is not foreseen for regular response assessments. It may, however, be used to 
detect or confirm the appearance of new lesions. Attenuation correction CT scans performed 
as part of a PET/CT scan frequently show lower resolution; therefore, dedicated CT scans 
are preferred. However, if the site can demonstrate that the CT scan performed as part of a 
PET/CT is of the same diagnostic quality as a diagnostic CT scan (with i.v. and oral 
contrast), then the CT scan portion of the PET/CT can be used for RECIST measurements. 
 
 


 
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13.2.3. Measurable disease 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions: 
 Tumour lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
- 10 mm by CT scan (CT scan slice thickness no greater than 5mm) 
- 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
- 20 mm by chest X-ray 
Reminder: A lesion in a previously irradiated area is not eligible for measurable 
disease. 
 Malignant lymph nodes: to be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan, assuming the slice thickness is ≤ 5 mm. At baseline and in follow-up, only the 
short axis will be measured. 
13.2.4. Non-measurable disease 
Non-measurable disease is defined as lesions or sites of disease that cannot be measured. 
Non-measurable lesions/sites of disease and special considerations:  
 Small non-nodal lesions (longest diameter < 10 mm in CT scan) 
 Small lymph nodes (short axis ≥ 10 and < 15 mm). Lymph nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or 
followed as measurable or non-measurable disease. 
 Bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable 
soft tissue components, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
 Leptomeningeal disease 
 Ascites 
 Pleural or pericardial effusion 
 Lymphangitic involvement of skin or lung 
 Cystic lesions. Cystic lesions thought to represent cystic metastases may be 
considered as measurable lesions. However, if non-cystic lesions are present, these 
are preferred as target lesions 


 
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 Tumour lesions situated in a previously irradiated area, or subjected to other 
locoregional therapy. Such lesions may be considered measurable if there has been 
demonstrated progression in the lesion 
 Abdominal masses/abdominal organomegaly identified by physical exam that are 
not measurable by reproducible imaging techniques 
13.2.5. Selection of target lesions 
Target lesions should be identified, measured and recorded at baseline. At baseline, there 
can be up to a maximum of 5 lesions representative of all involved organs, and up to 2 per 
organ. Target lesions should be selected on the basis of their size and their suitability for 
accurate repetitive measurements. A sum of diameters for all target lesions will be 
calculated and reported as the baseline sum of diameters. Lymph nodes selected as target 
lesions should always have the short axis recorded. All other lesions should always have 
their longest diameters recorded. The sum of diameters will be used as reference to further 
characterize the objective tumour response of the measurable dimension of the disease. 
13.2.6. Selection of non-target lesions  
All other lesions (or sites of disease) not identified as target lesions should also be recorded 
as non-target lesions at baseline.  
For non-target lesions, measurements are not required, but the presence or absence of each 
should be noted throughout follow-up. It is possible to record multiple non-target lesions as 
a single item on the eCRF. 
13.2.7. Evaluation of target lesions 
All target lesions will be measured at each tumour assessment, and the sum of their 
diameters will be compared to previous assessments in order to assign the response status as 
specified below. 
 Complete Response (CR): Disappearance of all target lesions. Lymph nodes selected 
as target lesions must each have reduction in the short axis to < 10 mm in order for 
the response to be considered complete. In this case, the sum of diameters may be > 
0. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions taking as reference the baseline sum of diameters. 
 Progression (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum recorded on the trial. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of one or more new lesions (see section 13.2.9) denotes disease 
progression. 
 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 recorded 
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Note: All target lesions, including lymph nodes, should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist 
does not feel comfortable assigning an exact measure and reports a lesion as "too small to 
measure", a default value of 5 mm should be recorded. If a target lesion is thought likely to 
have disappeared, use "0 mm." 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. 
13.2.8. Evaluation of non-target lesions  
 Complete Response (CR): Disappearance of all non-target lesions; lymph nodes 
selected as non-target lesions must be non-pathological in size (< 10 mm). 
 Non-CR/non-PD: Persistence of one or more non-target lesions (non-CR). 
 Progression (PD): unequivocal progression of existing non-target lesions. 
Unequivocal means: comparable in magnitude to the increase that would be required 
to declare PD for measurable disease, or an overall substantial increase in tumour 
burden that merits treatment discontinuation. 
When no imaging is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. If only a subset of lesions are evaluated at an assessment, usually the case is 
also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would be most likely to happen in the case of PD. 
13.2.9. Determination of new lesions 
The appearance of any new malignant lesions denotes disease progression. The finding of a 
new lesion should be unequivocal, i.e. not attributable to differences in scanning technique 
or findings thought to represent something other than tumour. If a new lesion is equivocal, 
e.g. because of its small size, the patient will stay on treatment (if the decision on PD is 
based on this lesion only). If the repeat scans confirm there is definitely a new lesion, then 
progression should be declared using the date of the previous scan when the lesion was 
discovered. 
Lesions or sites of disease found in a new location not included in the baseline scan (e.g. 
brain metastases) are considered new lesions. The detection of new lesions is not restricted 
to the examination methods used at baseline. 
Note: the "re-appearance" of a previously "disappeared" target or non-target lesion does not 
in itself necessarily qualify as PD; this is the case only if the overall evaluation meets the 
PD criteria, or if the patient was previously in CR. 
13.2.10. Additional considerations 


 
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In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumour has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an effusion 
may be a side effect of the treatment) and progressive disease. 
13.2.11. When the patient has only non-measurable disease 
This circumstance arises in some phase III trials when it is not a criterion of study entry to 
have measurable disease. The same general concepts apply here as noted above, however, in 
this instance there is no measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden. Worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable). 
A useful test that can be applied when assessing patients for unequivocal progression is to 
consider if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e.an increase in tumour burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ or an 
increase in lymphangitic disease from localised to widespread. Some illustrative examples 
are shown in Figs. 5 and 6 in Appendix II of reference [52]. 
If ‘unequivocal progression’ is seen, the patient should be considered to have had overall 
PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so, therefore 
the increasemust be substantial. 
13.2.12. Determination of time point response 
Based on the responses of target lesions, non-target lesions, and the presence or absence of 
new lesions, the overall response will be determined at each tumour evaluation time point, 
according to the table below. 
 
 


 
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13.2.13. For patients with measurable disease 
Table 6: Measurable Disease - Overall Response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD* 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any  
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes  
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
13.2.14. For patients with non-measurable disease 
Table 7: Non-measurable Disease - Overall Response 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR / non-PD* 
No 
Non-CR / non-PD* 
Not evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any  
Yes 
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
 
13.2.15. Determination of best overall response 
Best overall response is defined as best response recorded from the start of treatment across 
all time points until disease progression. Confirmation of partial or complete response by an 
additional scan is not requested in this trial.  
13.2.16. Storage of images 
All CT images must be stored locally in electronic format for later central review, please 
consult the BOOSTER procedures manual for detail. 
 
 


 
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14. 
Endpoints definition 
14.1. 
Progression-free survival  
PFS, the primary endpoint, is defined as the time from the date of randomisation until 
documented progression (based on RECIST 1.1 criteria) or death, if progression is not 
documented. Censoring (for patients without a PFS/death event) will occur at the last 
tumour assessment if patient is lost to follow-up or refuses further documentation of follow-
up. 
14.2. 
Objective response 
Objective response is defined as best overall response (CR or PR) across all assessment 
time-points according to RECIST criteria v1.1 (see section 13.2.14.), during the period from 
randomisation to termination of trial treatment. 
14.3. 
Disease control 
Disease control is defined as complete or partial response, or disease stabilisation, 
confirmed at subsequent radiological assessment. 
14.4. 
Toxicity 
Adverse events classified according to CTCAE version 4.0. 
14.5. 
Overall survival 
OS is defined as time from the date of randomisation until death from any cause. Censoring 
will occur at the last follow-up date. 
 


 
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15. 
Biological material and translational research 
15.1. 
Central Histology Review, Biomarker Testing and Biobanking 
A biobank for all biological material collected from every patient randomised in this trial 
will be created with centralised samples for translational research, integral to the trial.  The 
required pathological material (described below) is submitted to, catalogued, and maintained 
at the Central Laboratory: Tumour tissue blocks, whole blood, serum and plasma samples 
will be centrally collected and biobanked at the central reference laboratory in Lausanne 
(Center for Experimental Therapeutics CTE, University of Lausanne, Switzerland). The 
material will be centrally archived, and subjected to central histology review and biomarker 
testing. Eventually, the biological material will be made available for translational research, 
following completion of the primary trial translational research objectives. 
Translational research will encompase, but is not limited to, sequencing of most relevant 
oncogenes as well as EGFR/VEGFR pathways components will be retrospectively analysed 
on the tumour samples and compared to circulating surrogates in serum/plasma. Extension 
to a larger panel of genes by NGS (up to whole genome) on the tumour and on the 
serum/plasma might be performed and compared to germline DNA in whole blood. 
Potientially, gene expression analyisis on tumour and circulating RNA might be added to 
this project, depending on current lung cancer biology knowledge at the time of analysis. 
15.2. 
Required biomaterial 
Whole blood, plasma, serum, and – if a biopsy was taken and the FFPE material is not yet 
fully depleted - tumour tissue/cytology after disease progression on the most recent EGFR 
TKI treatment administered prior to trial entry must be submitted for central confirmation of 
T790M and translational research studies. Submission of the same type of material as used 
for local identification of T790M is critical for central confirmatory analysis. 
15.2.1. Tumour tissue (if a biopsy was done after disease progression on the most recent 
treatment regimen) 
Formalin-fixed, paraffin embedded (FFPE) tumour material (tissue or cytology) after 
disease progression on the most recent treatment regimen: 
 FFPE tumour/cytology block (preferred) or 
 alternatively 10 tissue sections of 4 (-5) µm thickness 
 10 slides cut from cytoblocks are acceptable only if tissue is not available and 
rebiopsy is not feasible 
Please note: cytosmears are not sufficient for this trial. 
15.2.2. Whole blood, serum and plasma samples 
 2.5 mL whole blood will be collected in PAXgene DNA tubes (for germline 
mutation assessment as a reference for tumour somatic mutation analysis) at baseline 
(after disease progression on the most recent treatment regimen). 


 
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 2.5 mL whole blood will be collected in PAXgene RNA tubes at baseline (after 
disease progression on the most recent treatment regimen), 9 weeks after treatment 
start and at disease progression. 
 Serum samples from 5 mL blood taken at baseline (after disease progression on the 
most recent treatment regimen), 9 weeks after treatment start and at disease 
progression, should be immediately frozen at -80ºC. 
 Plasma samples from 5 mL blood taken at baseline (after disease progression on the 
most recent treatment regimen), 9 weeks after treatment start and at disease 
progression, should be immediately frozen at -80ºC. 
It is anticipated that targeted NGS will be performed on DNA and RNA at a later time 
point.  Whole genome squencing on tumour with blood as reference for germline DNA 
might also be a possibility. Nanostring expression analysis on blood and tumour could 
also be a priority at a later time point. 
 
 
15.3. 
 Biomaterial at disease progression on trial treatment 
15.3.1. FFPE-material 
 FFPE tumour block (preferred) or alternatively 10 tissue sections of 4 (-5) µm 
thickness, from re-biopsy at disease progression on trial treatment should be 
centrally submitted whenever feasible. 
15.4. 
Submission of biomaterial 
All biological samples collected during the conduct of the trial must be marked with the 
patient identifier issued by the EDC system and registered in the system. FFPE tumour 
tissue and blood samples to the central reference laboratory in Lausanne (Center for 
Experimental Therapeutics CTE, University of Lausanne, Switzerland).  
Stage IIIb-IVb NSCLC
- confirmed EGFRm
- confirmed T790M
- PD on/after previous EGFR TKI
1 : 1
∙∙∙
∙∙∙
until PD*, lack of tolerability 
or refusal
until PD*, lack of tolerability 
or refusal
R
* Trial treatment may continue beyond PD 
if patient shows clinical benefit
CT
CT
3
Weeks
6
9
18
27
0

Blood
FFPE
Blood
Blood
CT
CT
CT
(FFPE)
at PD
Biomaterial
collection:
Osimertinib 80mg p.o. daily
Bevacizumab 15mg/kg i.v.
day 1 of each 3-week cycle 
Osimertinib 80mg p.o. daily


 
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15.4.1. Submission of FFPE material 
 FFPE tumour material as defined in Section 15.2.1. and 15.3.1 
 Pathology report from biopsy after disease progression on the most recent treatment 
regimen (all information allowing identification of the patient, e.g. patient name, day 
and month of birth, must be removed). 
 Pathology report from re-biopsy at progression (all information allowing 
identification of the patient, e.g. patient name, day and month of birth, must be 
removed). 
Tumour material should be submitted as soon as obtained (but not no later than 4 weeks 
after patient randomisation), and documented in the Biological Material Tracking eCRF in 
the database. On request, blocks can be returned to the submitting site within a reasonable 
time frame (est. 3 months) and after slides for the planned analyses have been cut. 
All reports, slides, and blocks must be marked with the patient identification number issued 
by the EDC system. All information allowing identification of the patient should be 
removed or blackened. 
Please ensure that the blocks and/or slides are carefully packaged according to the 
BOOSTER procedures manual, as otherwise they could easily get damaged during 
transport. 
Samples have to be sent to: 
 
Center for Experimental Therapeutics CTE 
University of Lausanne 
(Exact address to follow) 
 
CH-1011 Lausanne, Switzerland 
 
Anonymised pathology reports should be uploaded via the EDC system. Please consult the 
BOOSTER procedures manual for specific instructions. 
15.4.2. Submission of blood samples 
For blood collection and serum preparation see BOOSTER procedures manual. 
Blood samples as defined in Sections 15.2.2. 
Blood samples must be stored locally at -80ºC and will be kept at the participating site until 
shipment. Shipments will be arranged centrally once a site has collected all blood samples 
after the inclusion of the last patient. Samples have to be sent to the same address as 
indicated above. 
 
 


 
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16. 
Trial procedures 
This section gives an overview of procedures, clinical and laboratory evaluations and 
follow-up investigations. 
16.1. 
Safety assessments 
16.1.1. Physical examination 
Physical examination includes: PS, blood pressure, heart rate, temperature, body weight, 
height (only at baseline), general appearance, skin, head and neck (including ears, eyes, nose 
and throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, musculo-skeletal 
(including spine and extremities) and neurological systems. 
16.1.2. Resting 12-lead ECG 
Patients should be monitored for ECG changes at every cycle. ECGs should be reviewed 
and any abnormalities noted. 
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 
10 minutes. All ECGs should be recorded with the patient in the same physical position. For 
each time point three ECG recordings should be taken at 5 minute intervals. A standardised 
ECG machine should be used and the patient should be examined using the same machine 
throughout the trial if possible. 
The investigator or designated physician will review each of the ECGs and may refer to a 
local cardiologist if appropriate. A paper copy should be filed in the patient’s medical 
records. If an abnormal ECG finding at screening or baseline is considered to be clinically 
significant by the investigator, it should be reported as a concurrent condition. For all ECGs 
details of rhythm, ECG intervals and an overall evaluation will be recorded. 
16.1.3. Left ventricular ejection fraction (LVEF) 
Osimertinib and its active metabolite may also inhibit HER2. For this reason LVEF should 
be measured at baseline, then at least every 15 weeks (1 week) from the time of first dose 
throughout the treatment period and when clinically indicated. It is up to the investigators 
choice to measure LVEF by either echocardiogram or MUGA scan. The same technique 
must be used within a patient. 
16.1.4. Ophthalmologic exam 
Full ophthalmic assessment, including slit lamp examination, should be performed at 
screening and if a patient experiences any visual symptoms (including blurring of vision), 
with additional tests if clinically indicated. Ophthalmology examination results should be 
collected and documented in the eCRF. 
Any clinically significant findings, including those confirmed by the ophthalmologist must 
be reported as an AE. Photographs should be performed to record any clinically significant 
findings. These photographs should be available for submission to ETOP medical review if 
necessary. 


 
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16.2. 
Tumour assessment 
Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax 
until adrenal glands and full liver and kidney included) will be done as indicated in section 
13.1 until PD. 
16.3. 
Baseline evaluations before randomisation 
The following examinations should be done within 28 day before randomisation. If 
examinations were done prior to 28 day before randomisation, they have to be repeated 
before treatment start. 
Note: evaluations marked with * have to be repeated within 7 days prior to trial treatment 
start. 
16.3.1. Written informed consent: 
before any trial specific evaluations or interventions (within 6 weeks prior 
randomisation) 
16.3.2. Medical history: 
including baseline symptoms, smoking history, medications, comorbidities and 
allergies 
16.3.3. *Physical examination: 
Including PS, blood pressure, heart rate, temperature, body weight, height, skin, 
head and neck (including ears, eyes, nose and throat), respiratory, cardiovascular, 
abdomen, lymph nodes, thyroid, musculo-skeletal (including spine and extremities) 
and neurological systems. 
16.3.4. Resting 12-Lead ECG 
16.3.5. LVEF 
Echocardiogram or MUGA scan should be measured at baseline. 
16.3.6. *Pregnancy test 
Women of childbearing potential, including women who had their last menstrual 
period in the last 2 years, must have a negative serum or urine beta-HCG 
pregnancy test within 7 days before randomisation. 
Note: Test has to be repeated before treatment start, if treatment does not start 
within 72 hours of the previous test 
16.3.7. *Chemistry 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 
16.3.8. *Haematology 
haemoglobin, platelet count, white blood cell count including differential (absolute 
neutrophil count) 
16.3.9. *Liver function test 


 
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total bilirubin, ALT, AST, ALP, GGT 
16.3.10. *Renal function test 
urea, uric acid, serum creatinine, creatinine clearance (Cockroft-Gault). 
16.3.11. *Urine analysis (using dipstick) 
pH, proteins, glucose, blood 
specific gravity, elements and microscopic examination if needed. 
16.3.12. Coagulation profile 
international normalized ratio 
16.3.13. Ophtalmologic exam 
including slit lamp examination. 
16.3.14. Radiological tumour assessment 
by CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included), performed within 6 weeks before randomisation. 
16.3.15. Confirmation of EGFRm 
Histological or cytological confirmation of exon 19 deletion or exon 21 L858R 
mutation by a certified local laboratory. 
16.3.16. Confirmation of T790M 
Determined from biopsy (preferred) or on serum circulating tumour DNA by a 
certified local laboratory, that perform this within their routine practice. These 
samples must be taken after disease progression on the most recent EGFR TKI 
regimen. 
16.3.17. Biological material 
Tumour tissue and whole blood, serum and plasma samples after disease 
progression on the most recent treatment regimen must be available for central 
confirmation of T790M and further translational research studies. Submission of 
the same type of material as used for local identification of T790M is critical for 
central confirmatory analysis. 
16.4. 
Evaluations in the experimental arm 
At each treatment cycle 
The following evaluations have to be done on day 1 of every treatment cycle (or within 
3 days before these dates): 
16.4.1. Recording of symptoms, adverse events and concomitant medications. 
16.4.2. Physical examination: 
Including PS, blood pressure, heart rate, temperature, body weight, skin, head and 
neck (including ears, eyes, nose and throat), respiratory, cardiovascular, abdomen, 


 
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lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurological systems. 
16.4.3. Resting 12-Lead ECG 
Patients should be monitored for ECG changes at every cycle. ECGs should be 
reviewed and any abnormalities noted. 
16.4.4. LVEF 
Echocardiogram or MUGA scan should be measured at least every 15 weeks 
(1 week) from the time of first dose of osimertinib throughout the treatment 
period and when clinically indicated. In the event of an absolute decrease of 10% 
from baseline and below 50%, withhold osimertinib for up to 4 weeks. If improved 
to baseline it can be restarted, but if not, then discontinue. 
16.4.5. Chemistry 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 
16.4.6. Haematology 
haemoglobin, platelet count, white blood cell count including differential (absolute 
neutrophil count) 
16.4.7. Liver function test 
total bilirubin, ALT, AST, ALP, GGT 
16.4.8. Renal function test 
urea, uric acid, serum creatinine, creatinine clearance (Cockroft-Gault). 
16.4.9. Urine analysis (using dipstick) 
pH, proteins, glucose, blood 
specific gravity, elements and microscopic examination if needed. 
Proteinuria should be routinely measured before every infusion of bevacizumab 
using dipstick. 
 
In addition before bevacizumab cycle 4 
Within 3 days prior to cycle 4: 
16.4.10. Whole blood, serum and plasma samples 
Blood samples for translational research have to be collected within 3 days prior to 
cycle 4. 
16.5. 
Evaluations in the control arm 
The following evaluations have to be done every 3 weeks (3 days): 
16.5.1. Recording of symptoms, adverse events and concomitant medications. 


 
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16.5.2. Physical examination: 
Including PS, blood pressure, heart rate, temperature, body weight, skin, head and 
neck (including ears, eyes, nose and throat), respiratory, cardiovascular, abdomen, 
lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurological systems. 
16.5.3. Resting 12-Lead ECG 
Patients should be monitored for ECG changes at every cycle. ECGs should be 
reviewed and any abnormalities noted. 
16.5.4. LVEF 
Echocardiogram or MUGA scan should be measured at least every 15 weeks (1 
week) from the time of first dose of osimertinib throughout the treatment period 
and when clinically indicated. In the event of an absolute decrease of 10% from 
baseline and below 50%, withhold osimertinib for up to 4 weeks. If improved to 
baseline it can be restarted, but if not, then discontinue. 
16.5.5. Chemistry 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 
16.5.6. Haematology 
haemoglobin, platelet count, white blood cell count including differential (absolute 
neutrophil count) 
16.5.7. Liver function test 
total bilirubin, ALT, AST, ALP, GGT 
16.5.8. Renal function test 
urea, uric acid, serum creatinine, creatinine clearance (Cockroft-Gault). 
16.5.9. Urine analysis (using dipstick) 
pH, proteins, glucose, blood 
specific gravity, elements and microscopic examination if needed. 
 
In addition at 9 weeks 
The following additional evaluations have to be done 9 weeks (1 week) after start of trial 
treatment: 
16.5.10. Whole blood, serum and plasma samples 
Blood samples for translational research have to be collected 9 weeks (1 week) 
after trial treatment start. 
16.6. 
Evaluations at disease progression 
At progression, the following assessments are required: 


 
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16.6.1. Radiological tumour assessment 
by CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included). 
16.6.2. Biological material 
- Tumour tissue from re-biopsy (strongly encouraged)  
- Whole blood, serum and plasma (mandatory)  
for further translational research studies. 
16.7. 
Evaluation under treatment beyond progression 
In case of clinical benefit, with physician and patient agreement, trial treatment can continue 
beyond confirmed progression for as long as the patient may still derive benefit as per 
investigator decision.The following evaluations have to be done on day 1 of every treatment 
cycle or every 3 weeks (or within 3 days before these dates) 
16.7.1. Recording of symptoms, adverse events and concomitant medications. 
16.7.2. Physical examination: 
Including PS, blood pressure, heart rate, temperature, body weight, skin, head and 
neck (including ears, eyes, nose and throat), respiratory, cardiovascular, abdomen, 
lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurological systems. 
16.7.3. Resting 12-Lead ECG 
Patients should be monitored for ECG changes at every cycle. ECGs should be 
reviewed and any abnormalities noted. 
16.7.4. LVEF 
Echocardiogram or MUGA scan should be measured at least every 15 weeks 
(1 week) from the time of first dose of osimertinib throughout the treatment 
period and when clinically indicated. In the event of an absolute decrease of 10% 
from baseline and below 50%, withhold osimertinib for up to 4 weeks. If improved 
to baseline it can be restarted, but if not, then discontinue. 
16.7.5. Chemistry 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 
16.7.6. Haematology 
haemoglobin, platelet count, white blood cell count including differential (absolute 
neutrophil count) 
16.7.7. Liver function test 
total bilirubin, ALT, AST, ALP, GGT 
16.7.8. Renal function test 
urea, uric acid, serum creatinine, creatinine clearance (Cockroft-Gault). 


 
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16.7.9. Urin analysis 
specific gravity, pH, glucose, blood using a dipstick; elements and microscopic 
examination if needed. 
16.8. 
Evaluations at the end of treatment visit 
Patients are considered to be on trial treatment for as long as they receive either osimertinib 
and/or bevacizumab. At the end of all trial treatment and irrespective of the reason for 
stopping treatment, an end of treatment visit at the centre is to be scheduled within 30 days 
following the decision to stop trial treatment or within 30 days after planned treatment start 
if treatment never started. This visit has to be done for all patients, including those who did 
not start trial treatment.  
In case treatment was delayed due to AEs and could not be resumed, the end of treatment 
visit should be performed within 10 weeks after the last dose. The following procedures 
should be performed: 
16.8.1. Recording of symptoms, adverse events and concomitant medications 
16.8.2. Physical examination: 
Including PS, blood pressure, heart rate, temperature, body weight, skin, head and 
neck (including ears, eyes, nose and throat), respiratory, cardiovascular, abdomen, 
lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurological systems. 
16.8.3. Resting 12-Lead ECG 
ECGs should be reviewed and any abnormalities noted. 
16.8.4. Chemistry 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 
16.8.5. Haematology 
haemoglobin, platelet count, white blood cell count including differential (absolute 
neutrophil count) 
16.8.6. Liver function test 
total bilirubin, ALT, AST, ALP, GGT 
16.8.7. Renal function test 
urea, uric acid, serum creatinine, creatinine clearance (Cockroft-Gault). 
16.8.8. Urin analysis 
specific gravity, pH, glucose, blood using a dipstick; elements and microscopic 
examination if needed. 
16.9. 
Evaluations in the follow-up phase (post treatment) before progression 
Patients who discontinue trial treatment before progression should have the following 
examinations documented every 9 weeks (1 week) starting from the end of treatment visit 


 
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until trial end (e.g. approximately 18 months after randomisation of the last patient). The 
following evaluations will be done: 
16.9.1. Physical examination: 
Including PS, blood pressure and body weight. 
16.10. Evaluations in the follow-up phase beyond progression of disease 
Patients with progression that ends trial treatment will be followed up every 12 weeks 
(2 weeks) starting from date of progression until trial end (e.g. up to 2 years after the 
randomisation of the last patient). They should have documented: 
16.10.1. Survival 
16.10.2. Further lines of treatment 
17. 
Case report forms and documentation 
17.1. 
Case report forms schedule 
eCRFs will only be available on-line at the electronic data capture (EDC) facility ETOPdata. 
No paper forms will be used, with the exception of a paper SAE form and pregnancy form 
in case of system unavailability. 
 
Table 8: Case report forms: 
eCRF in ETOPdata 
To be completed 
1 - Eligibility Check and 
Randomisation 
Within 28 days of start of baseline evaluations 
2 - Baseline  
Within 14 days after randomisation 
3 - Tumour Assessments  
Baseline for randomisation: within 14 days after 
randomisation; 
During trial until tumour progression: within 14 days of date 
of each radiological imaging. 
4 - Concomitant 
Medications 
Continously from date of randomisation to 30 days after end 
of trial treatment; 
 
To be updated  
- 
within 14 days after randomisation 
- 
within 14 days of start of each Experimental Arm / 
Control Arm cycle 
- 
within 14 days of End of Treatment  visit 
or within 14 days of Follow-up visits. 


 
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eCRF in ETOPdata 
To be completed 
5 - Experimental Arm /  
Control Arm  
Within 14 days of start of each Experimental Arm cycle; 
Within 14 days of each Control Arm visit. 
6 - Adverse Events  
Continuously from date of Informed Consent signature to 
30 days after all treatments discontinuation; 
 
To be updated  
- 
within 14 days of randomisation (baseline symptoms) 
- 
within 14 days of start of each Experimental Arm / 
Control Arm cycle 
- 
within 14 days after End of Treatment visit 
or within 14 days of Follow-up visits. 
7 - Serious Adverse Event 
Initial Reports 
Within 24h of awareness of SAE; 
Must be submitted via ETOPDdata, submission via fax to 
ETOP safety office only in case of unavailability of 
ETOPdata. 
8 - Serious Adverse Event 
Follow-up Reports 
Within 15 days of completion of initial report. 
If event was not resolved after 15 days, submit an additional 
report within 7 days of resolution of event.  
9 - End of Treatment  
Within 14 days after End of Treatment visit (which is to take 
place within 30 days following the decision to stop trial 
treatment). 
10 - Follow-up 
Follow-up before progression: 
Within 14 days of clinical follow-up visits (which will take 
place every 9 weeks (+/-1 week) until tumour progression); 
 
Follow-up after progression: 
Within 14 days of clinical follow-up visits (which will take 
place every 12 weeks (+/-2 weeks) from date of progression; 
 
Follow-up on death:  
Within 14 days upon awareness of death. 
11 - Pregnancy  
Within 24h of first documentation of pregnancy; 
Within 14 days of end of pregnancy. 


 
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eCRF in ETOPdata 
To be completed 
12 - Biological Material 
Tracking  
This eCRF is to be completed incrementally. 
Entries are to be made: 
- within 4 weeks of randomisation: for information 
pertaining to “Tumour material at enrollment” (after disease 
progression on the most recent treatment); 
- immediately after local storage of blood samples (on same 
day): for information pertaining to “Date of blood draw”; 
- immediately (on same day) after submission of material 
(FFPE and blood) for central biobanking: for “Date Sent to 
Central Biobank”; 
- within 4 weeks of progression: for information pertaining 
to “Tumour material from re-biopsy at progression” (after 
trial treatment, optional). 
13 - WC/LFU 
Within 14 days of awareness of withdrawal of consent or 
loss to follow-up. 
 
 


 
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18. 
Statistical considerations 
18.1. 
Primary objective 
The primary objective of this randomised phase II trial is to assess the efficacy of the 
combination of osimertinib and bevacizumab versus osimertinib alone in terms of PFS, 
assessed by RECIST 1.1, for patients with locally advanced or metastatic (stage IIIb-IVb) 
EGFRm (exon 19 deletion or exon 21 L858R) NSCLC with T790M resistance mutation at 
progression on prior EGFR TKI therapy. 
18.2. 
Sample size determination 
The current randomised phase II trial is a superiority trial aiming to compare PFS between 
the two randomised arms (combination of osimertinib and bevacizumab versus osimertinib 
alone). An interim efficacy analysis for the primary endpoint (PFS) is also included. 
Our target population includes patients with locally advanced or metastatic (stage IIIb-IVb) 
NSCLC with EGFR mutation (exon 19 deletion or exon 21 L858R) and T790M resistance 
mutation at progression on prior EGFR TKI therapy. 
The median PFS for the target population under osimertinib alone is assumed to be 
11 months [53]. 
Patient accrual is assumed to be non-linear with increasing rate to 6 per month, after the first 
6 months. 
In order to detect a 36% improvement in PFS under the combination of osimertinib and 
bevacizumab with 80% power at the 5% one-sided significance level, a total number of 
126 events is required. For the targeted HR=0.64, corresponding to an increase for the 
median PFS from 11 to 17.2 months, a total of 154 randomized patients need to be 
followed for an expected duration of 48 months, assuming an accrual period of 29 months. 
A cumulative loss to follow-up rate of 5% by 30 months is assumed. 
Thus, in this phase II trial, 77 patients will be randomised 1:1 into each arm. PFS is 
measured, according to RECIST v1.1, from randomisation and compared between treatment 
arms in the ITT cohort. 
18.3. 
Trial duration 
Total follow-up to observe the required events is expected to be 48 months. Taking into 
account a run-in period of 6 months and an additional 6 months for the final analysis report, 
the study duration is 5 years.  
End of trial occurs when both of the following criteria have been satisfied: 
 The trial is mature for the analysis of the primary endpoints as defined in the 
protocol 
 The database has been fully cleaned and frozen for this analysis. 


 
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18.4. 
Analysis populations 
18.4.1. Efficacy Cohort 
The primary statistical analysis of the efficacy data will include all randomised subjects and 
will compare the treatment groups on the basis of randomised treatment, regardless of the 
treatment actually received. Patients who were randomised but did not receive trial 
treatment will be included in the ITT population. 
18.4.2. Safety Cohort 
The safety analysis population consists of all subjects who received at least one dose of trial 
treatment according to the treatment they actually received, regardless of their allocated 
treatment at randomisation. 
18.5. 
Evaluation of primary and secondary objectives 
Primary analysis on PFS will be performed overall and stratified by the randomisation 
stratification factors. An intent to treat primary efficacy analysis will be performed, 
including all randomised patients (= efficacy cohort). 
PFS, OS as well as all time-to-event endpoints will be presented and evaluated from date of 
randomisation. The primary endpoint of PFS will be estimated by the Kaplan Meier method 
and compared between treatment groups. Similar analysis will be performed for OS and the 
other time-to-event time-points. Comparisons between the two treatment arms will be based 
on stratified logrank tests. In addition, stratified (by the randomisation stratification factors) 
and multivariate Cox models will be used for exploring the association of PFS (and the 
other time-to-event endpoints) with treatment in the presence of prognostic factors. 
The two treatment groups will also be compared with respect to secondary efficacy and 
tolerability endpoints. No multiplicity adjustment will be performed for these analyses. 
Clinical efficacy will be further described by objective response rate (ORR, defined as 
percentage of patients reaching a complete or partial response) based on RECIST 1.1 
response criteria and disease control rate (DCR) along with 95% exact confidence intervals, 
overall and by treatment arm. ORR and DCR will be compared between the two treatment 
groups using Fisher’s exact tests and Cochran-Mantel-Haenszel test stratified by the 
stratification factors of the trial (odds ratio will also be provided). Logistic regression 
models will be further applied to investigate the treatment effect, adjusting for stratification 
factors and variables of clinical interest. Duration of response and clinical benefit (including 
patients with at least stable disease as described in section 14.3) will also be compared 
between the two treatment groups, using Kaplan-Meier method.  
Safety and tolerability of the trial treatment will be described by tabulation of the CTCAE 
V4 grade (by treatment arm). The safety cohort will encompass all patients who have 
received at least one dose of trial treatment. 
The correlation of biological markers with PFS will be evaluated by univariate and 
multivariate Cox proportional hazards regression. 
Statistical analysis for the primary, secondary endpoints and translational research will be 
described in detail in the Statistical Analysis Plan (SAP) document. 


 
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18.6. 
Early safety analysis 
This phase II trial will evaluate the combination of osimertinib (80 mg, orally, once daily) 
with bevacizumab (15 mg/kg as i.v. infusion every 3 weeks). This allows a direct 
comparison for early safety signals. There will be a safety interim evaluation after the first 
10 patients have been randomised to the experimental arm (total of 20 patients, 10 in the 
experimental and 10 in the control arm) and have received trial treatment for 30 days. This 
first safety evaluation will be submitted to the ETOP Independent Data Monitoring 
Committee (IDMC) for advice. The recruitment into the trial will continue while safety is 
evaluated. 
Safety evaluations will be performed twice a year and submitted to the ETOP IDMC at their 
regular meeting. 
18.7. 
Interim efficacy analysis 
The interim efficacy analysis will be carried out when 63 (out of the 126) events are 
available. This is expected to occur approximately 26 months after the randomisation of the 
first patient. 
According to O' Brien-Fleming approach, the treatment effect on PFS will be tested at type I 
error rate of 0.6%. If the boundary is crossed in favour of the alternative, the recruitment 
will stop early and a significant PFS benefit will be claimed for the combination. 
19. 
Criteria for termination of the trial 
19.1. 
General criteria for termination of the trial 
The trial may be discontinued early in parts or completely if the information on the IMPs 
leads to doubt as to the benefit/risk ratio, by decision of ETOP Foundation Council upon 
recommendation of the ETOP 10-16 BOOSTER Steering Committee and IDMC. Specific 
considerations will be based on the interim safety and efficacy evaluations. 
The trial can be terminated at any time if the authorization and approval to conduct the trial 
is withdrawn by ethics committee or regulatory authority decision, insufficient accrual, 
emerging new data impacting the scientific value of the trial or ethical grounds. 
19.2. 
Discontinuation of protocol treatment for individual patients  
Protocol treatment should be stopped in the following situations: 
 Disease progression according to RECIST criteria 1.1, except if the patient may still 
derive benefit as per investigator decision. 
 Occurrence of unacceptable toxicities. Stopping protocol treatment is determined by 
medical judgment of the treating physician. 
 Patients experiencing corneal ulceration or ILD will not be permitted to restart trial 
treatment. 
 Inter-current severe illnesses which would in the judgment of the investigator affect 
assessments of the clinical status to a significant degree and require discontinuation 


 
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of protocol therapy. Note: Diagnosis of another neoplastic disease (second malignant 
tumour) does not mandate a stop of trial therapy, patients may continue to receive 
protocol treatment after appearance of a second primary tumour, stopping protocol 
treatment is determined by the medical judgment of the treating physician. 
 Request by the patient. Patients have the right to refuse further trial treatment at any 
time during the trial. Such patients will remain in the trial and will be transferred to 
the follow-up phase. 
 If a patient refuses to have the treatments or follow-up examinations and tests 
needed to determine whether the treatment is safe and effective. 
The decision for discontinuation of protocol treatment of individual patients is taken by the 
treating physician based on his medical evaluation and taking into account the patient’s 
individual situation. 
19.3. 
Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the time point of withdrawal will 
continue to be evaluated in the trial. The investigator should ask the patient for consent to 
continue to collect information on her/his disease and survival status. 
It should be documented in both the medical records and in the eCRF, according to the 
instructions in the BOOSTER CRF completion guidelines, if the patient accepts to be 
contacted for survival status despite withdrawing the trial consent. For the patient’s safety, 
an end of treatment visit should be performed and documented in the eCRF if the patient 
agrees to this. 
 
 


 
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20. 
Ethics aspects, regulatory approval, and patient informed consent 
The investigator will ensure that this trial is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. 
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice (GCP)” ICH Tripartite Guideline (January 1997) or with local law if it affords 
greater protection to the patient. For studies conducted in the EU/EEA countries, the 
investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC). 
20.1. 
Ethical Review Board/Ethics Committee 
All protocols and the patient informed consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The ERB/IRB 
decision must contain approval of the designated investigator, the protocol (identifying 
protocol title and version number), and of the patient informed consent. 
The Ethical Review Board/Institutional Review Board (ERB/IRB) written, signed approval 
letter/form must contain approval of the designated investigator, the protocol (identifying 
protocol title and version number), and of the patient informed consent. Documentation of 
Ethics Committee approval must be sent to the ETOP coordinating office prior to 
randomisation of the first patient. 
Any modifications made to the protocol must be submitted to the appropriate ERB/IRB for 
information or approval in accordance with local procedures and regulatory requirements 
and to health authorities if required. 
Once approved or acknowledged by the appropriate ERB/IRB and by the health authorities 
(if required), the investigator shall implement the protocol modifications. Protocol 
modifications for urgent safety matters may be directly implemented following the 
instructions of ETOP. 
20.2. 
Regulatory approval procedures 
If applicable, in addition to the approval of the ethics committee according to national 
legislation, the protocol, protocol related documents including patient information and 
informed consent and other documents as required locally must be submitted to and be 
approved by the health authority. Documentation of health authority approval must be sent 
to the ETOP coordinating office prior to participating centre activation. 
20.3. 
Informed consent 
Informed consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “patient information and informed consent" (see Appendix 1). One 
signed and dated, a copy of the informed consent must be given to each patient and the 
original copy must be retained in the investigator’s trial records. The informed consent form 
must be available in the case of data audits. Verification of signed informed consent and the 
date signed are required for randomisation into this trial. 
The “Declaration of Helsinki” recommends that consent be obtained from each potential 
patient in biomedical research trials after the aims, methods, anticipated benefits, and 


 
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potential hazards of the trial, and discomfort it may entail, are explained to the individual by 
the physician. The potential patient should also be informed of her/his right to not 
participate or to withdraw from the trial at any time. The patient should be told that material 
from her/his tumour and blood and serum samples will be stored and potentially used for 
additional studies not described in this protocol. 
If the patient is in a dependent relationship to the physician or gives consent under duress, 
the informed consent should be obtained by an independent physician. If the patient is 
legally incompetent (i.e. a minor, or mentally incompetent), informed consent must be 
obtained from the parent, legal guardian, or legal representative in accordance with the law 
of the country in which the trial is to take place. By signing this protocol, the investigator 
agrees to conduct the trial in accordance with GCP and the "Declaration of Helsinki". 
ETOP recognises that each institution has its own local, national, and international 
guidelines to follow with regard to informed consent. Therefore, we provide a template 
information sheet and informed consent form (appendix 1), which can be edited to 
incorporate information specific to your institution. The template patient information sheet 
and informed consent has been written according to ICH guidelines which state the 
informed consent should adhere to GCP and to the ethical principles that have origin in the 
“Declaration of Helsinki”. The final version should receive the IRB / local EC approval in 
advance of its use. Centres should send their locally modified PIS/IC to ETOP for review 
and approval before submitting to their ethics committee. 
21. 
Governance and administrative issues 
21.1. 
Final report 
A final clinical trial report will be written and distributed to health authorities as required by 
applicable regulatory requirements 
21.2. 
Steering Committee 
A Steering Committee will be constituted for this trial. The Steering Committee is 
responsible for maintaining the scientific integrity of the trial, for example, by 
recommending changes to the protocol in light of emerging clinical or scientific data from 
other trials. Membership will include the trial chairs and co-chairs, trial statisticians, ETOP 
officials, representatives from participating institutions and a representative from Astra 
Zeneca and Roche. 
21.3. 
Independent Data Monitoring Committee 
The ETOP IDMC is a standing committee of independent experts. Its role is the systematic 
review of the accumulating data from all ongoing ETOP sponsored trials including accrual, 
safety and efficacy. The primary mandate of the IDMC is to safegueard the interest and 
safety of the patients in the trial and to ensure the scientific integrity of the trial. Details of 
the particular responsibilities and procedures within the ETOP 10-16 BOOSTER trial are 
summarised in the ETOP IDMC Guidelines and the trial-specific IDMC charter. 


 
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The trial will be presented for review to the ETOP IDMC at each of their bi-annual meetings. 
Based on this review, the IDMC recommends to the trial Steering Committee whether to 
continue, modify or stop the trial. 
21.4. 
Publication 
The results of the trial will be published according to the ETOP publication guidelines 
(appendix 2). 
21.5. 
Clinical trial insurance 
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer 
injuries due to the trial should report them immediately to their physician. The local 
group/institution should report all alleged claims immediately to the ETOP coordinating 
office. 
21.6. 
Quality assurance 
ETOP conducts trials according to the ICH GCP guidelines. The Trial data manager reviews 
each eCRF as it is received. In addition, the ETOP medical reviewer reviews each case at 
specific time points. ETOP conducts periodic audit visits to ensure proper trial conduct, 
verify compliance with GCP, and perform source data verification. 
The investigator should ensure that source documents are made available to appropriately 
qualified personnel from ETOP or its designees, or to ethics committee and health authority 
inspectors after appropriate notification. 
At regular intervals during the clinical trial, the centre will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the monitoring team to review trial 
progress, investigator and patient compliance with clinical trial protocol requirements and 
any emergent problems. These monitoring visits will include but not be limited to review of 
the following aspects: patient informed consent, patient recruitment and follow-up, SAE 
documentation and reporting, AEs with pre-specified monitoring documentation and 
reporting, AE documentation, dispensing IMP, compliance with protocol, drug 
accountability, concomitant therapy use, quality of data and storage of blood and serum 
samples. 
21.7. 
Protocol adherence 
Investigators ascertain that they will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact ETOP or personnel monitoring the trial to 
request approval of a protocol deviation, as no deviations are permitted. The investigator 
should document and explain any deviations from the approved protocol. The investigator 
should promptly report any deviations to the sponsor and to the EC concerned in accordance 
with the applicable EC policies and procedures. If the investigator feels a protocol deviation 
would improve the conduct of the trial this must be considered a protocol amendment, and 
unless such an amendment is developed and activated by the sponsor and approved by the 
IRB/IEC/ERB it cannot be implemented. All protocol deviations will be recorded. 


 
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21.8. 
Data protection 
The samples and data collected will be coded to protect patient confidentiality. Each patient 
will have a unique identifier assigned by the EDC facility ETOPdata. Sites are responsible 
to keep a patient log locally in order to be able to link the unique identifier to the record of 
the patient.  
Biological material will be assigned the same unique identifier. No identifiable / personal 
data will be stored in the trial database or the tissue repositories in the central labs. 
Biological material will be transferred outside the treating institution for central screening 
and review. Results of the assays will be coded only by the patient identifier. 
Regulatory authorities and pertinent ethics committees (IRB/ERB) may have access to 
patient data on-site. ETOP audit or monitoring personnel will also have access to such data 
on-site. 
21.9. 
Record retention 
The centre must retain all essential documents according to ICH GCP. This includes copies 
of the patient trial records, which are considered as source data, patient informed consent 
statement, laboratory printouts, drug inventory and destruction logs, and all other 
information collected during the trial. These documents are to be stored until at least 
15 years after the termination of the trial. ETOP guarantees access and availability of the 
data entered into ETOPdata for at least 15 years after the termination of the trial. 
Longer retention may be required for participating centres according to national regulations. 
In the event that the principal investigator retires or changes employment, custody of the 
records may be transferred to another competent person who will accept responsibility for 
those records. Written notice of such transfer has to be given to ETOP and the local ethics 
committee at least one month in advance. 
 
 


 
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22. 
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SAP_001.pdf: 
 
 
 
 
ETOP 10-16 BOOSTER 
 
 
A randomised phase II trial of osimertinib and bevacizumab versus 
osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC with 
confirmed EGFRm and T790M 
 
 
 
Statistical Analysis Plan (SAP)  
Final efficacy analysis 
 
 
 
 
A clinical trial of ETOP 
 
 
SAP VERSION 
2.1 
SAP DATE 
23.12.2020 
 
 
 


BOOSTER SAP – Final analysis  
2 
 
Contents 
 
INTRODUCTION ..................................................................................................................................................... 4 
1 
Trial oversight ............................................................................................................................................... 5 
1.1 
Objectives.............................................................................................................................................. 5 
1.2 
Endpoints .............................................................................................................................................. 6 
1.3 
Most important eligibility criteria ......................................................................................................... 6 
1.4 
Trial treatment ...................................................................................................................................... 7 
1.5 
Statistical design, sample size & power ................................................................................................ 7 
1.6 
Total trial duration ................................................................................................................................ 8 
2 
Statistical considerations for final analysis ................................................................................................... 9 
2.1 
Analysis timing ...................................................................................................................................... 9 
2.2 
Study’s endpoints .................................................................................................................................. 9 
2.2.1 
Primary endpoint .......................................................................................................................... 9 
2.2.2 
Secondary endpoints .................................................................................................................... 9 
2.2.3 
Exploratory endpoints ................................................................................................................... 9 
2.2.4 
Correlative endpoints.................................................................................................................. 10 
2.3 
(Serious) Adverse Events ..................................................................................................................... 11 
2.4 
Analysis populations ........................................................................................................................... 12 
3 
Primary efficacy analysis of progression-free survival (PFS) ....................................................................... 14 
4 
Additional secondary analysis ..................................................................................................................... 16 
4.1 
Patient accrual, balance of stratification factors and baseline characteristics .................................. 16 
4.2 
Follow-up information and treatment administration ....................................................................... 16 
4.3 
Secondary (efficacy) and exploratory endpoints ................................................................................ 17 
4.3.1 
Overall survival ............................................................................................................................ 17 
4.3.2 
Objective response rate & disease control rate ......................................................................... 18 
4.3.3 
Duration of response and duration of clinical benefit ................................................................ 18 
4.3.4 
Subgroup analysis ....................................................................................................................... 18 
4.4 
Sensitivity efficacy analysis ................................................................................................................. 19 
4.5 
Safety analysis ..................................................................................................................................... 19 


BOOSTER SAP – Final analysis  
3 
 
5 
Technical details .......................................................................................................................................... 21 
5.1 
Data Retrieval Information ................................................................................................................. 21 
5.2 
Missing Data ........................................................................................................................................ 21 
5.3 
Reporting conventions ........................................................................................................................ 22 
5.4 
Multiple recordings of an event for the same patient ........................................................................ 22 
5.5 
Presentation of results ........................................................................................................................ 22 
 
 
 


BOOSTER SAP – Final analysis  
4 
 
INTRODUCTION 
The aim of this Statistical Analysis Plan (SAP) is to describe an analytic and solid framework that will 
be followed in order the final efficacy analysis of the BOOSTER trial to be implemented. A short 
description of the contents of this statistical analysis plan is provided below: 
1. Trial oversight: trial’s schema, objectives and trial endpoints, eligibility criteria, study 
treatment, statistical design (sample size and power), trial duration  
2. Statistical considerations for final analysis: analysis timing, definition of primary and 
secondary endpoints, (serious) adverse events definition, analysis populations 
3. Primary efficacy analysis of progression-free survival (PFS) 
4. Additional secondary analysis: accrual and baseline characteristics, follow-up and 
treatment administration, secondary and exploratory analysis 
5. Technical issues: data retrieval, testing, handling of missing data, reporting conventions. 
 


BOOSTER SAP – Final analysis  
5 
 
1 Trial oversight  
This is a randomized controlled phase II multinational, multi-center trial of osimertinib and 
bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb NSCLC 
harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation.  
 
SCHEMA 1. Trial design  
BOOSTER is a trial with block stratified randomization balanced by institution and patients 
randomized 1:1 to the experimental and control arm. The two stratifications factors are: ethnicity 
(Asian, Non-Asian) and material used for T790M testing (tumor vs circulating DNA). 
 
1.1 Objectives  
Primary objective 
The primary objective of the study is to assess the efficacy of the combination of osimertinib and 
bevacizumab versus osimertinib alone in terms of progression-free survival (PFS) assessed by 
RECIST 1.1 criteria.  
Secondary objectives  
The secondary objectives of the study include: 
• 
To compare short and long-term clinical efficacy outcomes 
• 
To assess the tolerability of the two treatment 
 


BOOSTER SAP – Final analysis  
6 
 
1.2 Endpoints  
Primary endpoint:  
• 
Progression-free survival (PFS) based on RECIST 1.1 criteria 
Secondary endpoints:  
• 
Objective response (OR) based on RECIST 1.1 criteria 
• 
Disease control defined as complete or partial response, or disease stabilization confirmed at 
subsequent radiological assessment 
• 
Adverse events graded according to CTCAE v4.0 
• 
Overall survival (OS) 
Correlative endpoints: 
• 
T790M evolution in tissue and plasma/serum (between baseline and relapse). 
• 
Monitoring of mutation burden and specific EGFR mutations (del19, L858R, T790M) in 
sequential plasma/serum samples 
• 
Analysis of bevacizumab/osimertinib resistance mechanism in relapse biopsy samples (NGS) 
 
1.3 Most important eligibility criteria  
Inclusion criteria: 
• 
NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to 8th TNM 
classification, after progression following prior EGFR TKI (erlotinib, gefitinib, dacomitinib or 
afatinib) therapy as the most recent treatment regimen.  
• 
Pathological diagnosis of predominantly non-squamous NSCLC.  
• 
Maximum of one line of previous platinum-based chemotherapy.  
• 
Histological or cytological confirmation of EGFRm (exon19 deletion or exon 21 L858R).  
• 
Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating 
tumor DNA, documented in tissue, plasma or serum after disease progression on the most 
recent EGFR TKI regimen.  
• 
Plasma, serum, and tumor (preferred) tissue or cytology (if biopsy was taken and FFPE 
tumor material is not yet fully depleted) after disease progression on the most recent EGFR 
TKI treatment available for central confirmation of T790M.  
• 
Measurable or evaluable disease  


BOOSTER SAP – Final analysis  
7 
 
• 
Adequate hematological, renal and liver function  
• 
Performance status 0-2  
Exclusion criteria:  
• 
Patients with mixed NSCLC with predominantly squamous cell cancer, or with any small cell 
lung cancer (SCLC) component.  
• 
Symptomatic or active central nervous system metastases, as indicated by clinical 
symptoms, cerebral edema, and/or progressive growth.  
• 
Previous treatment with osimertinib and/or bevacizumab  
• 
Patients currently receiving medications or herbal supplements known to be potent CYP3A4 
inducers  
• 
Any unresolved toxicities from prior therapy greater than CTCAE v4.0 grade 1  
 
1.4 Trial treatment 
Experimental arm: Osimertinib, 80 mg p.o., once daily plus bevacizumab 15 mg/kg i.v. on day 1 of 
every 3-week cycle. 
Control arm: Osimertinib, 80 mg p.o., once daily 
Patients will receive the treatment until progression, lack of tolerability, or patient declines further 
protocol treatment. Trial treatment may also continue beyond progression for as long as the patient 
may still derive benefit as per investigator decision. 
 
1.5 Statistical design, sample size & power 
The current randomized phase II trial (stratification factors: Ethnicity (Asian, Non-Asian) and 
material used for T790M testing (tumor vs circulating DNA)) is a superiority trial aiming to compare 
PFS between the two randomized arms (combination of osimertinib and bevacizumab versus 
osimertinib alone).  
The median PFS for the target population under osimertinib alone is assumed to be 11.0 months. In 
order to detect a 36% improvement in PFS under the combination of osimertinib and bevacizumab 
with 80% power at the 5% one-sided significance level, a total number of 126 PFS events is 
required. For the targeted HR=0.64, corresponding to an increase for the median PFS from 11.0 
to 17.2 months, a total of 154 randomized patients need to be followed for an expected duration 
of 48 months, assuming an accrual period of 29 months (accrual is assumed to be non-linear with 


BOOSTER SAP – Final analysis  
8 
 
increasing rate to 6 patients per month, after the first 6 months).  A cumulative loss to follow-up rate 
of 5% by 30 months is assumed. 
Thus, in this phase II trial, 77 patients will be randomized 1:1 into each arm. PFS is measured, 
according to RECIST 1.1 criteria, from randomization and compared between treatment arms in the 
ITT cohort. 
An interim efficacy analysis for the primary endpoint of PFS is also included in the statistical design, 
which will be carried out when 63 (50%) of the 126 PFS events have been observed (expected to 
occur approximately 26 months after the randomisation of the first patient). According to O' Brien-
Fleming approach, in this interim analysis, the treatment effect on PFS will be tested at one-sided 
type I error rate of 0.6%. If the boundary is crossed in favour of the alternative hypothesis of 
superiority, the recruitment will stop early and a significant PFS benefit will be claimed for the 
combination. Otherwise, the trial will proceed to full accrual and the final analysis (with one-sided 
type I error rate of 4.4%) will be performed when the total number of 126 PFS events has been 
observed. 
 
1.6 Total trial duration 
The total trial follow-up duration to observe the required events is expected to be 48 months with an 
interim efficacy analysis based on O’ Brien-Fleming boundary at 26 months. Taking into account a 
run-in period of 6 months and an additional 6 months for the final analysis report, the total trial 
duration is expected to be 5 years from randomization of first patient. 
End of trial occurs when both of the following criteria have been satisfied: 
a) The trial is mature for the analysis of the primary endpoints as defined in the protocol 
b) The database has been fully cleaned and frozen for this analysis. 
 


BOOSTER SAP – Final analysis  
9 
 
2 Statistical considerations for final analysis 
2.1 Analysis timing 
According to the statistical design, the final analysis will be carried out when the 126 required PFS 
events will be available for the BOOSTER randomized patients. This is expected to occur 
approximately 48 months after the randomization of the first patient, assuming an accrual period of 
29 months. 
 
2.2 Study’s endpoints 
2.2.1 Primary endpoint 
The primary endpoint of the trial is PFS, defined as the time from the date of randomization until 
documented progression (based on RECIST 1.1 criteria) or death, if progression is not documented. 
Censoring for PFS (patients without progression/death) will occur at the last tumor assessment. In 
the frame of a sensitivity analysis, if the last tumor assessment is “Non evaluable” (NE), censoring will 
occur to the most recent tumor assessment where an overall evaluable result is recorded. 
2.2.2 Secondary endpoints  
Secondary endpoints, according to the protocol, include OR, disease control, OS and adverse events 
(AEs). More specifically: 
- 
OR is defined as the best overall response (complete or partial) across all assessment time-
points according to RECIST 1.1 criteria, during the period from randomization to termination 
of trial treatment. In the frame of a sensitivity analysis, all timepoints, until the end of follow-
up for progression, will be taken into account for the determination of best overall response. 
- 
Disease control is defined as complete or partial response, or disease stabilization, confirmed 
at subsequent radiological assessment 
- 
OS is defined as the time from the date of randomization until death from any cause. Censoring 
for OS (patients without death) will occur at the last follow-up date  
- 
Toxicity, defined as AEs graded according to CTCAE v4.0. 
2.2.3 Exploratory endpoints  
- 
Time to treatment failure (TTF) is defined as time from the date of randomization until 
discontinuation of protocol treatment for any reason (including progression of disease, death, 
discontinuation of at least one of the drugs consisting the treatment combination due to any 
reason, such as treatment toxicity or investigator’s decision, withdrawal/lost to follow-up 
(LFU)). Censoring for TTF (patients on treatment) will occur at the last follow-up date. 


BOOSTER SAP – Final analysis  
10 
 
- 
Similar to TTF, time to treatment discontinuation (TTD) for each drug separately (osimertinib 
or bevacizumab) is defined as the time from the date of randomization until discontinuation 
of the specific protocol drug for any reason. 
- 
Duration of response (DoR) is defined as the time from the documentation of tumor response 
(either partial or complete response) to disease progression or death. Censoring will occur at 
the last tumor assessment with response other than progression. 
- 
Duration of clinical benefit (DoCB) is defined as the time from documentation of clinical 
benefit (stable disease, partial or complete response) to disease progression or death. 
Censoring will occur at the last tumor assessment with response other than progression. 
2.2.4 Correlative endpoints  
Correlative endpoints of the study include T790M evolution in tissue and plasma/serum (between 
baseline and relapse), monitoring of mutation burden and specific EGFR mutations (del19, L858R, 
T790M) in sequential plasma/serum samples and analysis of bevacizumab/osimertinib resistance 
mechanism in relapse biopsy samples (NGS). The statistical analysis of these correlative endpoints 
will be specified in a separate SAP document. 
 
 
 


BOOSTER SAP – Final analysis  
11 
 
2.3 (Serious) Adverse Events  
Adverse events (AE) 
The main criterion for treatment tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the NCI CTCAE v4.0. The CTCAE v4.0 is available 
for downloading (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An AE is defined as any untoward medical occurrence that occurs from the date of signature of inform 
consent until 30 days after all trial treatment discontinuation, regardless of whether it is considered 
related to a medication. In addition, any known untoward event that occurs subsequent to the 
adverse event reporting period that the investigator assesses as possibly related to the protocol 
treatment should be considered an adverse event.  
Serious Adverse Events (SAE) 
An SAE is defined in general as any undesirable medical occurrence/adverse drug experience that 
occurs during or within 30 days after stopping study treatment that, at any dose: 
▪ 
results in death (any cause, except progression of cancer under study) 
▪ 
is life-threatening 
▪ 
requires or prolongs inpatient hospitalization 
▪ 
results in persistent or significant disability/incapacity 
▪ 
is a congenital anomaly or birth defect (including neonatal deaths) 
▪ 
is a secondary malignancy 
▪ 
is an event of clinical interest (drug induced liver injury, overdose) 
Other significant/important medical events which may jeopardize the patient are also considered 
serious adverse events. Serious also includes any other event that the investigator or the ETOP Safety 
Office judges to be serious or which is defined as serious by the regulatory agency in the country in 
which the event occurred. 
Severity Grade of (serious) adverse event 
The adverse event severity grade provides a qualitative assessment of the extent or intensity of an 
adverse event, as determined by the investigator or as reported by the subject. The severity grade 
does not reflect the clinical seriousness of the event, only the degree or extent of the affliction or 
occurrence (e.g., severe nausea, mild seizure), and does not reflect the relationship to study drug. A 
severe event may be of relatively minor medical significance (such as severe headache). 


BOOSTER SAP – Final analysis  
12 
 
Severity grade for other adverse events not covered in the toxicity grading scale: 
Grade 1 
Mild- transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Grade 2 
Moderate- mild to tolerate limitation in activity; some assistance may be 
needed; no or minimal medical intervention/therapy required 
Grade 3 
Severe- marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
Grade 4 
Life-threatening- extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice 
care probable 
Grade 5 
Fatal- the event results in death 
Causality of (serious) adverse event 
The investigator must determine the relationship between the administration of trial drug(s) and the 
occurrence of an AE/SAE following the definitions indicated below: 
• 
Not suspected (unrelated/unlikely): The temporal relationship of the adverse event to trial 
drug(s) administration makes a causal relationship unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a sufficient explanation for the 
observed event. 
• 
Suspected (possible/probable/definite): The temporal relationship of the adverse event to 
trial drug(s) administration makes a causal relationship possible, and other medications, 
therapeutic interventions, or underlying conditions do not provide a sufficient explanation for 
the observed event. 
 
2.4 Analysis populations 
Efficacy cohort: The efficacy analysis population includes all randomized subjects. Patients who 
were randomized but did not receive trial treatment will be also included in the efficacy cohort 
(intention-to-treat (ITT) population). 
Safety cohort: The safety analysis population consists of all subjects who have received at least one 
dose of trial treatment according to the treatment they actually received, regardless of their allocated 
treatment at randomization. 
Of note, there will be also an early safety evaluation after the first 10 patients have been randomized 
to the experimental arm (total 20 patients, 10 in the experimental and 10 in the control arm) and 


BOOSTER SAP – Final analysis  
13 
 
have received trial treatment for 30 days. This safety evaluation will be submitted to the ETOP 
Independent Data Monitoring Committee (IDMC) for advice. The recruitment into the trial will 
continue while safety is evaluated. 
 
 


BOOSTER SAP – Final analysis  
14 
 
3 Primary efficacy analysis of progression-free survival (PFS) 
Primary efficacy analysis of PFS (primary endpoint) will be performed on all randomized patients, 
based on their initial treatment assignment (ITT, efficacy cohort). PFS time is measured from 
randomization. 
Formal hypothesis testing 
The study is designed to test the hypothesis that treatment combination of osimertinib and 
bevacizumab will lead to an increase in median PFS to 17.2 months, from 11.0 months under standard 
treatment with osimertinib alone. According to the study design, this corresponds to a HR of 0.64. 
Using 80% power and a one-sided type I error of 5%, a total of 126 PFS events are needed to be 
observed in order to achieve the trial goal, while an interim analysis is scheduled to be performed 
at 50% of the information time, i.e., when 63 PFS events have been observed.  To keep the overall 
one-sided type I error at 5% according to the O' Brien-Fleming approach (calculated by the Lan-
DeMets spending function), a one-sided alpha 0.6% is assigned to the designed interim efficacy 
analysis, while the exact p-value boundary for the final efficacy analysis is 4.8%. 
In the frame of final efficacy analysis, the formal comparison of the PFS between the two 
treatment arms, will be based on the stratified log-rank test (with ethnicity and material used for 
T790M testing being the stratification factors). Unstratified log-rank test will be also calculated. This 
would be of particular value in the case at least one stratum level has very low number of patients. 
Further PFS analyses 
The following PFS analyses will be also performed and presented 
- 
The total number (%) of PFS events observed, overall and by treatment arm will be presented. 
In addition, 1/2-year PFS estimates, median PFS and respective 95% CIs will be provided. 
Respective results by stratification factors will be also presented. 
- 
Graphical representation of PFS, by treatment arm will be performed via a Kaplan-Meir plot. 
The plot will be also produced separately by stratum.  
- 
Number of PFS events, median PFS and unstratified/unadjusted HRs (along with 95% CIs), 
interaction p-value between treatment and each variable of interest, will be summarised for 
the subgroups defined by treatment and the following variables of interest: stratification 
factors (ethnicity, material for T790M testing), gender, age (appropriately categorized), 
smoking history, ECOG performance status at diagnosis, stage of tumor, EGFR mutation 
subtype and biological markers (if available). This information will be depicted in a tabular 
format in the report and a forest plot will be produced for the publication/presentation. 
- 
A table with information about the sites of progression will be also provided. 


BOOSTER SAP – Final analysis  
15 
 
- 
Furthermore, to assess the effect of trial treatment and other clinicopathological variables on 
PFS, Cox proportional hazards model will be fitted. 
o Initially a univariate (stratified and unstratified) Cox model will be fitted in the 
model and the statistical significance of trial treatment will be tested at the 5% 
significance level. 
o Subsequently, multivariate Cox models (stratified and unstratified) will be estimated, 
adjusted for the clinicopathological variables of interest as defined above (in case of 
unstratified model, the stratification factors will be also included as covariates in the 
model). The backward elimination method, with a removal criterion at 10% will be 
implemented to conclude on the statistically significant variables of the model. The 
HRs along with the corresponding 95% CIs for all significant predictors (in the 
multivariate Cox model) will be summarised in a tabular format in the report and the 
corresponding 
forest 
plot 
will 
be 
subsequently 
produced 
for 
presentation/publication.  
o The proportionality assumption of Cox models will be explored by Schoenfeld’s 
residuals and by testing for time-dependent effect of covariates in extended Cox 
models. In cases that non-proportionality is detected further appropriate measures 
will be used: 
▪ 
Use of variable(s), for which proportionality assumption is violated, as 
stratification factor(s) 
▪ 
Use of weighted tests, alternatives to log-rank for the comparison of survivals, 
such as the Wilcoxon test 
▪ 
Estimation of Restricted Mean Survival Time (RMST) at specific time points 
(close to median follow-up and covering the full follow-up time for the majority 
of patients) 
▪ 
Calculation of HR for separate time intervals 
 
 


BOOSTER SAP – Final analysis  
16 
 
4 Additional secondary analysis 
In this section, detailed information about the additional analysis that will be performed in the frame 
of final efficacy analysis for BOOSTER trial is presented. 
4.1 Patient accrual, balance of stratification factors and baseline characteristics 
- 
Patient accrual by center and country will be presented in tabular format. 
- 
In addition, expected vs. observed accrual will be graphically displayed. 
- 
For patients deemed ineligible (patients registered in the online database but eventually not 
randomized) a table summarizing the reasons for non-randomization will be provided. 
- 
Balance of treatment allocation by center and by stratification factor will be summarised as 
well.  
- 
Patient & tumor baseline characteristics (categorical: ethnicity, gender, smoking history, 
ECOG performance status at diagnosis, tumor stage, material used for T790M testing, EGFR 
mutation subtype and continuous: age at randomization), will be presented overall and 
separately by treatment arm. Frequencies and corresponding percentages will be presented 
for categorical variables (if missing cases exist, a separate category named “Missing” will be 
created), while the following descriptive measures will be considered for the continuous ones: 
n (non-missing sample size), mean, 95% CI for the mean, median, maximum and minimum. 
Balance of baseline characteristics by treatment arm will be assessed via the Fisher’s exact 
test for categorical variables and the Mann-Whitney U test for continuous.  
- 
Also available information on medical history and prior treatment will be summarised, by 
treatment arm. 
4.2 Follow-up information and treatment administration 
Firstly, a consort flow diagram will be created to graphically depict the progress through the phases 
of the trial.  
Median follow-up (FU) of the patients (overall and by treatment arm) along with the respective 
interquartile range (IQR) and the number (%) of patients that are still alive, will be summarised in a 
table. A Kaplan-Meier plot, overall and by treatment arm, will be also provided for a graphical 
representation of the respective information. 
Treatment information will be summarised overall and separately by treatment arm. More 
specifically the following information will be presented: 


BOOSTER SAP – Final analysis  
17 
 
- 
Number of patients that started treatment, information on number of cycles (median, min-
max). For those patients randomized, progressed but with physician’s and their own 
agreement continued receiving treatment, information on treatment cycles as well as 
treatment failure after 1st progression will be additionally provided. 
- 
Number of patients that did not receive any dose of trial treatment, along with reasons for not 
doing so 
- 
Number of treatment failures, 1/2-year TTF estimates and median TTF time along with the 
corresponding 95% CIs and the reasons for treatment failure/discontinuation will be 
presented overall and by treatment arm.  The stratified log-rank test will be used to compare 
TTF between the two treatment arms. 
- 
A Kaplan Meier plot for TTF, by treatment group, will be created.  
- 
For patients with treatment failure, information for further lines of treatment will be also 
provided. 
4.3 Secondary (efficacy) and exploratory endpoints 
4.3.1 Overall survival  
Similar to PFS the following will be presented for OS: 
- 
Total number (%) of OS events, overall and by treatment arm (as well as by stratification 
factor) 
- 
1/2-year OS estimates, median OS and respective 95% CIs (comparison between the arms 
based on stratified and unstratified log-rank test) 
- 
Kaplan- Meier plot by treatment arm and separately for each stratum  
- 
Subgroup analysis (number of deaths, median OS and unstratified/unadjusted HRs (along 
with 95% CIs)) by treatment and variables of interest 
- 
Univariate and multivariate Cox proportional hazards model, adjusted for the stratification 
factors and clinicopathological variables of interest; HRs and corresponding 95% CIs for all 
significant OS predictors  
- 
Summary table of the death causes (e.g., lung cancer, toxicity, other, etc) overall and by 
treatment arm. 
Of note, at the time of final analysis for the primary endpoint (PFS), the OS events are not expected to 
be sufficient to provide enough power for comparison between treatments. In case that the endpoint 
is immature at that timepoint an additional OS analysis with longer follow-up will be performed at a 
later time point.  


BOOSTER SAP – Final analysis  
18 
 
4.3.2 Objective response rate & disease control rate 
- 
Best overall responses (BOR) as well as objective response rate (ORR) and disease control 
rate (DCR) will be presented overall and separately for the two treatment arms, along with a 
95% exact binomial CI.   
- 
ORR and DCR will be compared between the two treatment groups using Fisher’s exact test 
and Cochran-Mantel-Haenszel test stratified by the stratification factors of the trial.  
- 
Logistic regression models will be further applied to investigate the treatment effect, 
adjusting for stratification factors and variables of clinical interest. 
- 
A waterfall plot will be created by treatment arm to present the best percent change in tumor 
size (sum of target lesions diameter) from the baseline tumor assessment before 
randomization  
- 
The percent changes in tumor size (sum of target lesions diameter) from the baseline tumor 
assessment before randomization  over the time will be depicted graphically by a spider plot, 
separately for each treatment arm. 
4.3.3 Duration of response and duration of clinical benefit 
- 
Median DoR and DoCB, along with the corresponding 95% CIs will be presented, for all 
responders and separately for the two treatment groups.  
- 
Duration of response and clinical benefit (including patients with at least stable disease) will 
be compared between the two treatment arms using Kaplan-Meier method.  
- 
Graphical representation of DoR and DoCB will be also performed via swimmer plots, 
separately for each treatment arm. 
4.3.4 Subgroup analysis 
To determine whether the treatment effect is consistent across various subgroups the between-group 
treatment effect for all efficacy endpoints will be estimated within each category of the following pre-
specified variables. 
Main subgroup analyses:  
• 
Ethnicity 
• 
Stage 
• 
Gender 
Other pre-planned subgroup analyses: 
• 
Material used for T790M testing 
• 
EGFR mutation subtype 
• 
Tumor Mutation Burden at baseline (if available) 


BOOSTER SAP – Final analysis  
19 
 
• 
Age group 
Notes:  
1. In case of imbalance in number of patients with the subgroups created by treatment and the 
variables of interest, this subgroup analysis will not count in the multiple comparison adjustment.  
2. The interaction of each subgroup with the treatment effect on PFS and OS will be tested based on 
respective Cox models. 
4.4 Sensitivity efficacy analysis 
In a sensitivity analysis framework, the efficacy analysis will be repeated using the safety cohort. 
4.5 Safety analysis  
The safety analysis will be performed based on the safety cohort (i.e., patients who have received at 
least one dose of trial treatment) and will include the following: 
- 
Overview of the number of patients who experienced an AE/SAE, as well as the number of 
patients in the safety cohort who did not experience an event, along with respective 
percentages will be shown. This information will be presented overall and by treatment arm. 
Also, number of patients that entered the study with baseline symptoms will be reported. 
- 
Number of AEs/SAEs and rate of occurrence per month of follow-up, overall and by treatment 
arm.  
- 
Number of patients experiencing a specific number of AEs/SAEs, overall and by treatment 
arm. 
- 
Distribution of AEs/SAEs by grade and CTCAE category, overall and separately for the two 
treatment arms. Six columns, one for each grade and one for all (any) grades, will be shown 
(for each arm). An additional column (by arm) indicating which events were SAEs -or started 
as AEs and became SAEs later on- will be also available. In this column, the frequency of the 
SAEs and the severity grade will be given. The percentages that will accompany the 
frequencies will be based on the respective frequency of an event over the total number of 
patients in the safety cohort and specific treatment arm. This table will include all AEs/SAEs 
irrespective of their relation to the trial treatment. 
- 
Analogous table focusing only on the treatment related AEs/SAEs. 
- 
Number and corresponding percentages of treatment related AEs/SAEs, leading either to 
treatment discontinuation or death will be summarised for the two treatment arms and 
overall.  
- 
Treatment related AEs/SAEs (of any grade) occurring in more than 10% (or any other 
relevant %) will be presented for the two treatments.  


BOOSTER SAP – Final analysis  
20 
 
- 
The risk difference, along with corresponding 95% CIs for specific AEs/SAEs (for example 
most frequent/related events (i.e., ≥10%) or events of grade ≥3), between the two treatment 
arms will be presented and graphically depicted. 
- 
Maximum severity of AEs/SAEs per patient, overall and by treatment arm.  
- 
Number of SAEs by center. 
- 
For all fatal SAEs, cause of death will be provided. 
 
 
 


BOOSTER SAP – Final analysis  
21 
 
5 Technical details 
Data will be primarily analysed using the SAS software package (version 9.4), while the R statistical 
software will be also used for specific analyses and plots.  
All final analysis and reviews will be performed according to the Standard Operating Procedures 
(SOPs) of the Frontier-Science Foundation Hellas (FSFH) statistical team. A second statistician, the 
reviewing statistician, will independently reproduce all analysis and summary statistics. The 
reviewing statistician will have an overview of the entire analysis and will explicitly check the code 
producing tables and figures, as well as any other pieces of code as desired. 
5.1 Data Retrieval Information 
The final analysis will be based on the database download that will take place, as soon as the total 
number of 126 PFS events required according to the statistical design of the trial are observed. Using 
this database extraction, a set of queries will be produced and forwarded to trial’s data manager with 
the expectation to be answered in a pre-specified time period (approximately four weeks). 
Corrections and responses based on these queries, will be used for correcting the previously 
downloaded database, in order to create the final clean dataset to be used for the analysis. 
5.2 Missing Data 
Baseline characteristics 
For categorical baseline characteristics if missing cases exist, a separate category named ‘Missing’ 
will be created. As far as continuous values, missing cases will not be replaced by any statistics 
calculated over non-missing data. 
Dates 
If the day of the month is missing for any date used in the analysis, the 15th of the month will be used 
to replace the missing date unless the calculation results in a negative time duration (e.g., date of 
onset cannot be prior to day one date). In this case, the date resulting in one day of duration will be 
used. If the day of the month and the month are missing for any date used in a calculation, January 1 
will be used to replace the missing date. Missing dates for adverse events will be imputed based on 
the similar principle. 
Incomplete tumor assessment information 
In patients who have no on-study assessments: 
• 
If death is recorded prior to the first planned tumor assessment, the death date will be 
considered as the date of the PFS event. 


BOOSTER SAP – Final analysis  
22 
 
• 
If clinical progression is recorded prior to the first planned tumor assessment, the date of the 
reported clinical progression will be considered as the date of the PFS event. 
• 
In all other cases, the patient will be censored at the date of randomization plus 1 day. 
5.3 Reporting conventions  
Regarding the estimates presented in the report, the following rules will be adopted: 
• 
P-values ≥0.001 will be reported with three decimal places 
• 
P-values >0.010 will be reported with two significant decimal digits 
• 
P-values less than 0.001 will be reported as ‘<0.001’ 
• 
Means, medians, 95% confidence intervals (CIs), quantiles, and any other statistics, will be 
reported with one decimal digit 
• 
Hazard ratios (HRs) and their 95% CIs will be reported with two decimals 
• 
Estimated parameters, not on the same scale as raw observations (e.g., regression 
coefficients) will be reported with three significant figures 
5.4 Multiple recordings of an event for the same patient  
There are some cases where a patient may experience the same event (AE/SAE) more than one time. 
In such cases, the event will be count only once (with the highest grade) for the calculation of the total 
number of events. 
5.5 Presentation of results 
The results will be presented through tables and figures. A summary of the results will also 
accompany the main report. First, a short synopsis of the results will be presented through bullets, 
where only the most important findings will be shown. Following that, a more detailed description of 
the results will be provided, sectioned in the following order: 
I. Patient accrual and baseline characteristics  
II. Follow-up and treatment administration  
III. Efficacy analysis 
IV. Safety analysis  
All tables and figures will be included in an appendix.