Clinical trial NCT01562028
Conditions: Lung Cancer
Keywords: non small cell lung cancer advanced non-squamous EGFR mutations
Sponsor: ETOP IBCSG Partners Foundation
Start date: 2012-06-01; Completion date: 2018-10-31
Enrollment: 109 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Rationale:

Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways.

The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

Detailed description:
Objectives:

1. To determine long-term outcome of patients with advanced non-squamous NSCLC harbouring EGFR mutations with or without T790M mutation at diagnosis and treated with the combination of erlotinib and bevacizumab. Primary endpoint: progression-free survival
2. To evaluate the efficacy and tolerability of the combination
3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival
4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally
5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab

Design:

This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. Patients will be stratified into two subgroups, with and without EGFR T790M mutation. The stratification will be done after the inclusion of patients.

Sample size: 102 patients

Arms: arm 1: Patients will be treated with erlotinib and bevacizumab. Bevacizumab: 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days) Erlotinib: 150 mg p.o., daily
Interventions: intervention 1: Erlotinib intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Patients will be treated with erlotinib, 150 mg p.o., daily intervention 2: Patients will be treated with bevacizumab 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days)

Protocol documents:
Prot_001.pdf: 
BELIEF V2.0 Amendment 1,  21 November 2013 
Amendment 1: red text 
 
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BELIEF  
 
ETOP 2-11 
 
 
An open-label phase II trial of erlotinib and bevacizumab in patients with 
advanced non-small cell lung cancer and activating EGFR mutations 
 
Bevacizumab and ErLotinib In EGFR mut+ NSCLC 
 
A clinical trial of ETOP 
 
 
 
Coordinated by Grupo Español de Cancer de Pulmón GECP 
(Spanish Lung Cancer Group) 
 
 
 
EudraCT number: 2011-004481-15 
 
Roche number: MO27911 
 
 
 
 
ETOP c/o IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 389 93 91 
Fax: +41 31 389 93 92 
 
 
 
Version 2.0 
 
 
 


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Contacts 
 
Trial Chair and 
President SLCG 
Rafael Rosell, MD 
Address 
 
 
 
Tel:  
Fax: 
Email: 
Catalan Institute of Oncology 
Hospital Germans Trias i Pujol 
Ctra Canyet, s/n 
08916 Badalona (Barcelona), Spain 
 +34 93 497 89 25 
 +34 93 497 89 50 
rrosell@iconcologia.net 
Trial Co-Chair and 
Chairman ETOP  
Rolf Stahel, MD 
Address 
 
 
 
 
Tel:  
Fax: 
Email:  
Laboratory of Molecular Oncology 
Clinic of Oncology 
University Hospital Zuerich  
Häldeliweg 4 
CH-8044 Zürich, Switzerland  
+41 44 634 28 71 
 +41 44 634 28 72 
rolf.stahel@usz.ch 
Translational research, 
central pathology 
office 
Miguel Angel 
Molina 
Address 
 
 
Tel:  
Fax: 
Email:  
Pangaea Biotech 
Medical Oncology Service and Laboratory 
USP Instituto Universitario Dexeus c/ 
Sabino Arana 5-19 08028 Barcelona, Spain 
+34 93 546 0140/0119 +34 93 546 0172 
mamolina@pangaeabiotech.com 
Trial Coordinator 
SLCG 
Enric Carcereny, MD Address 
 
 
 
Email:  
Medical Oncology Service-ICO 
Hospital Germans Trias i Pujol 
Ctra Canyet s/n. 
08916 Badalona, Spain 
ecarcereny@iconcologia.net 
Trial Coordinator 
ETOP 
Oliver Gautschi, MD Address 
 
 
 
Tel:  
Fax: 
Email:  
Medical Oncology 
Luzerner Kantonsspital  
6000 Luzern 16 
Switzerland 
+41 41 205 58 60 
+41 41 205 58 62 
oliver.gautschi@onkologie.ch 
Statistics 
María Sánchez-
Ronco, PhD 
 
 
 
 
 
 
Urania Dafni, ScD 
Address 
 
 
 
 
Tel:  
Email:  
 
Address 
 
 
Tel:  
Fax: 
Email: 
Departamento de Medicosociales 
Facultad de Medicina de la Universidad de 
Alcalá Campus Universitario, Ctra. Madrid-
Barcelona Km 33,600 
28871 Alcalá de Henares (Madrid), Spain 
+34 629076011 
e-mail: maria.ronco@uah.es 
 
Frontier Science Foundation - Hellas 
118-120 Papadiamantopoulou Str. 
15773, Zografou, Athens, Greece 
+302107710902 
+302107710903 
udafni@frontier-science.gr 
Data Management 
Eva Pereira, CRA 
Address 
 
 
Tel:  
Fax: 
Email:  
SLCG Office 
c/ Villarroel 251 
08036 Barcelona, Spain 
+34 93 430 20 06 
+34.93.419 17 68 
epereira@gecp.org 


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Drug supply 
Barbara Ruepp, MD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Drug Supply Office 
c/o IBCSG Coordinating Center 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 93 91 
+41 31 389 92 29 
drugsupply@etop-eu.org 
Safety and Regulatory 
Affairs 
Barbara Ruepp, MD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Safety and Regulatory Office 
c/o IBCSG Coordinating Center 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 93 91 
+41 31 389 92 29 
regulatoryoffice@etop-eu.org 
SLCG Secretariat 
María Fernández 
 
Address 
 
 
Tel:  
Fax: 
Email: 
Secretaría GECP 
Villarroel, 251 pral 2ª 
08036 Barcelona 
+34 93 430 20 06 
+34 93 419 17 68 
secretaria@gecp.org 
ETOP Coordinating 
Office 
Anita Hiltbrunner 
Rudolf Maibach 
Viktor Zsuffa 
Address 
 
 
Tel:  
Fax: 
Email: 
c/o IBCSG Coordinating Center 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 93 91 
+41 31 389 92 29 
anita.hiltbrunner@etop-eu.org 
rudolf.maibach@etop-eu.org 
BELIEF@etop-eu.org 
Remote Data Entry 
system 
Solange Peters 
 
 
 
 
 
 
 
Technical assistance 
Address 
 
 
Tel:  
 
Fax: 
Email: 
 
Email: 
Centre Pluridisciplinaire d'Oncologie 
Centre Hospitalier Universitaire Vaudois  
1011 Lausanne - Suisse 
+41 79 556 01 92 
+41 21 314 67 89 (assistant) 
+41 21 314 01 67 
solange.peters@etop-eu.org 
 
richard.king@etop-eu.org 
In collaboration with Hoffmann-La Roche 




Protocol Signature Page Amendment 1 
STOP 2-1 1 BELIEF 
Approved by: 
Rafael Resell 
Trial Chair and President of SI,CG 
( 
-u11-6/f 
Date 
Rolf Stahel 
Fria] Co-Chair and Chairman of I 	
)P 
7r-77 1? 
Date 
BELIEF V2.0 Amendment I. 21 November 2013 
Amendment I : red test 	
5/62 


BELIEF V2.0 Amendment 1,  21 November 2013 
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Principal Investigator Protocol Signature Page 
 
BELIEF 
 
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. 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 
 
 


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Principal Investigator Protocol Signature Page for Amendment 1 
 
ETOP 2-11 BELIEF 
 
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 
 


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TABLE OF CONTENTS  
Section 
Page 
 
1. 
Protocol Summary .......................................................................................................... 11 
2. 
Flow charts ..................................................................................................................... 13 
2.1. 
Graphical trial design .............................................................................................. 13 
2.2. 
Trial schedule .......................................................................................................... 14 
3. 
List of abbreviations ....................................................................................................... 15 
4. 
Background and Rationale .............................................................................................. 16 
4.1. 
EGFR mutations in lung cancer .............................................................................. 16 
4.2. 
Mechanisms of tumor resistance to erlotinib: T790M and DNA-repair ................. 17 
4.3. 
Rationale for combination therapy with erlotinib and bevacizumab ...................... 18 
4.4. 
Circulating DNA ..................................................................................................... 19 
4.5. 
Hypothesis ............................................................................................................... 19 
4.6. 
Further plans ............................................................................................................ 19 
5. 
Objectives and endpoints ................................................................................................ 20 
5.1. 
Primary objective .................................................................................................... 20 
5.2. 
Secondary objectives ............................................................................................... 20 
5.3. 
Primary endpoint ..................................................................................................... 20 
5.4. 
Secondary endpoints ............................................................................................... 20 
6. 
Trial design, duration and termination ........................................................................... 21 
7. 
Patient selection .............................................................................................................. 21 
7.1. 
Inclusion criteria ...................................................................................................... 21 
7.2. 
Exclusion criteria..................................................................................................... 23 
8. 
Patient screening and registration ................................................................................... 24 
8.1. 
Enrolment of patient ................................................................................................ 25 
9. 
Central testing of EGFR mutation status ........................................................................ 25 
9.1. 
Location of central reference laboratory ................................................................. 26 
9.2. 
Shipping of samples to central laboratory ............................................................... 26 
9.3. 
Communication of result ......................................................................................... 26 
10. 
Study drug ................................................................................................................... 26 
11. 
Trial treatments ........................................................................................................... 27 
11.1. 
Sequence of treatments ........................................................................................ 27 
11.2. 
Dosage, administration and compliance .............................................................. 27 
11.3. 
Precautions........................................................................................................... 28 
11.4. 
Concomitant treatment ........................................................................................ 28 
11.5. 
Treatment delay and dose modification for toxicity ............................................ 28 
11.6. 
Treatment duration .............................................................................................. 30 
12. 
Safety of investigational products ............................................................................... 31 
12.1. 
Bevacizumab ....................................................................................................... 31 
12.2. 
Erlotinib ............................................................................................................... 37 
13. 
Adverse events and reporting...................................................................................... 39 
13.1. 
Adverse event reporting ....................................................................................... 39 
13.2. 
Definition of Serious Adverse Event (SAE)........................................................ 40 
13.3. 
Definition of Serious Adverse Drug Reaction (SADR) ...................................... 41 
13.4. 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) ........ 41 
13.5. 
Definition of Adverse Events of Special Interest (AESI) for Bevacizumab: ...... 41 
13.6. 
Reporting SAEs/AESIs........................................................................................ 42 
14. 
Endpoints definition .................................................................................................... 43 


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14.1. 
Progression-free survival ..................................................................................... 43 
14.2. 
Time to treatment failure ..................................................................................... 43 
14.3. 
Overall survival ................................................................................................... 43 
14.4. 
Objective response ............................................................................................... 43 
14.5. 
Disease control .................................................................................................... 43 
14.6. 
Duration of response ............................................................................................ 43 
14.7. 
Toxicity ................................................................................................................ 43 
15. 
Biological material and translational research ............................................................ 44 
15.1. 
Mandatory evaluations ........................................................................................ 44 
15.2. 
Optional evaluations ............................................................................................ 45 
15.3. 
Submission of material ........................................................................................ 45 
15.4. 
Banking of biological material ............................................................................ 46 
16. 
Trial procedures .......................................................................................................... 46 
16.2. 
Baseline evaluations (within 28 days prior to registration) ................................. 47 
16.3. 
Before enrolment ................................................................................................. 48 
16.4. 
Before start of treatment ...................................................................................... 48 
16.5. 
Routine evaluations before and during trial treatment ........................................ 48 
16.6. 
Trial-specific evaluations during treatment ......................................................... 48 
16.7. 
Evaluations in the follow-up phase before progression ....................................... 48 
16.8. 
Evaluations at progression ................................................................................... 49 
16.9. 
End of treatment visit .......................................................................................... 49 
16.10. 
Evaluations after progression .............................................................................. 49 
17. 
Case report forms and documentation ........................................................................ 50 
17.1. 
Case report forms schedule .................................................................................. 50 
18. 
Statistical considerations ............................................................................................. 51 
18.1. 
Primary objective ................................................................................................. 51 
18.2. 
Sample size determination ................................................................................... 51 
18.3. 
Evaluation of primary and secondary objectives ................................................. 52 
18.4. 
Early stopping rules ............................................................................................. 53 
19. 
Criteria for termination of the trial.............................................................................. 53 
19.1. 
Discontinuation of protocol treatment for individual patients ............................. 53 
19.2. 
General criteria for termination of the trial ......................................................... 54 
19.3. 
Withdrawal of consent ......................................................................................... 54 
20. 
Ethics approval procedures and Patient Informed Consent ........................................ 54 
20.1. 
Ethical Review Board/Ethics Committee ............................................................ 54 
20.2. 
Regulatory approval procedures .......................................................................... 55 
20.3. 
Informed consent ................................................................................................. 55 
20.4. 
Confidentiality/Data Protection ........................................................................... 56 
20.5. 
Duration of study ................................................................................................. 56 
21. 
Governance and administrative issues ........................................................................ 56 
21.1. 
Steering Committee ............................................................................................. 56 
21.2. 
Publication ........................................................................................................... 56 
21.3. 
Clinical trial insurance ......................................................................................... 56 
21.4. 
Quality Assurance................................................................................................ 56 
21.5. 
Protocol adherence .............................................................................................. 57 
21.6. 
Record Retention ................................................................................................. 57 
22. 
References ................................................................................................................... 57 
 
 


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Appendices: 
1a. Template for patient information and informed consent form V2 
1b. Addendum to the patient information and informed consent V1 
2. RECIST criteria V1.1 
3. NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 
4. Publication guidelines 


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1. 
Protocol Summary 
 
A phase II trial of erlotinib and bevacizumab in patients with advanced 
non-small cell lung cancer and activating EGFR mutations 
 
 
Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal 
growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive 
progression-free survival between 9 and 14 months when treated with erlotinib. However, 
the presence of EGFR mutations can only imperfectly predict outcome. We hypothesize that 
progression-free survival could be influenced both by the pretreatment EGFR T790M 
mutation and by components of DNA repair pathways.  
We propose a model of treatment whereby patients with EGFR mutations (single or with 
T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus 
bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the 
hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all 
subgroups. 
Objectives: 
1. To determine long-term outcome of patients with advanced non-squamous NSCLC 
harbouring EGFR mutations with or without T790M mutation at diagnosis and 
treated with the combination of erlotinib and bevacizumab. Primary endpoint: 
progression-free survival 
2. To evaluate the efficacy and tolerability of the combination 
3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and 
T790M with progression-free survival 
4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally 
5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab 
Design: This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in 
patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by 
central re-assessment. Patients will be stratified into two subgroups, with and without EGFR 
T790M mutation. The stratification will be done after the inclusion of patients.  
Sample size: 102 patients 
Most important eligibility criteria: 
1. non-squamous cell, non-small-cell lung cancer 
2. metastatic disease or locally advanced and not amenable for radical surgery or 
radiotherapy 
3. centrally confirmed EFGR mutation (exon del19 or L858R) 
4. Measurable or evaluable disease (according to RECIST 1.1 criteria) 
5. Age ≥ 18 years 
6. Adequate haematological, renal and hepatic function 


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Trial treatment: 
Bevacizumab: 15 mg/kg i.v. on day 1 of each 3-week cycle 
Erlotinib: 150 mg p.o., daily 
Cycles of 3 weeks until progression 
Statistical considerations:  
The trial consists of two phase II substudies run in parallel, and requires 102 patients, with 
35 patients with EGFR T790M mutation enrolled in substudy 1, and 67 patients without 
EGFR T790M mutation enrolled in substudy 2.  The first substudy follows Simon’s two-
stage design and a decision can be reached at the first stage, while the second substudy 
follows Fleming’s single stage design. Patients not EGFR mutated at central review will 
stop treatment. These patients will be excluded from final efficacy analysis, and will be 
documented as ineligible. Ineligible patients will be replaced to reach the total sample size, 
per study design. Patients who have been recruited into the trial but are not evaluable for 
efficacy will be replaced (up to 10% of total sample size). 
Duration: The total duration of the trial will be approximately 48 months, with an accrual 
period of 12 months including run-in period of 3 months, accrual and total follow-up of 36 
months. The clinical database and the central tissue bank will be kept for an unlimited time.  
The trial will end with the preparation of the final report, scheduled for month 54 after the 
inclusion of the first patient. Trial subjects will receive trial medication up to 18 months 
after the inclusion of the last patient. All patients who are still benefiting from their 
treatment at that time have to be switched to commercial drug which will be reimbursed by 
Roche. 
Translational research:  
Formalin-fixed, paraffin-embedded tissue will be collected from all enrolled patients. EGFR 
mutation status will be centrally determined or confirmed. T790M will be analyzed as soon 
as the complete patient sample has been enrolled into the trial. BRCA1 mRNA expression 
and AEG-1 will be evaluated where enough tissue is available. 
Serum and plasma samples will be collected at baseline, after 6 weeks (time of first tumor 
evaluation), and at the time of progression. They will be used to search for molecular 
alterations corresponding to the tumor tissue. Samples will be stored locally at -80ºC and 
shipped in batches to the central laboratory. 


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2. 
Flow charts 
2.1. 
Graphical trial design 
 
 


 
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2.2. 
Trial schedule 
 
Scree-
ning 1 
≤ 28 
days 
prior 
enrol-
ment 
At 
enrol-
ment 
Cycle 1 
Cycles 
2, 4, ... 
(even 
cycles) 
Cycles 
3, 5, ... 
(odd 
cycles) 
At pro-
gression 
End of 
treat-
ment 
visit 4 
Follow-
up6 
Days 
 
 
0 
1 
22,64,... 
43,85,... 
 
 
 
Weeks 
 
 
0 
1 
4,10,... 
7,13,... 
 
 
 
Written informed consent 2 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Tumour material 1 
X 
 
 
 
 
 
 
 
 
Blood sample 4 
 
 
X 
 
 
X 4 
X 
 
 
Physical exam, PS, blood 
pressure, weight 
 
X 
 
X 
X 
X 
 
X 
X 
Baseline symptoms 
 
X 
 
 
 
 
 
 
 
Haematology 
 
X 
 
X 
X 
X 
 
X 
 
Renal function: serum 
creatinine, urine dipstick 
 
X 
 
X 
X 
X 
 
X 
 
Hepatic function: ALT, 
AST, AP, Bilirubin  
 
X 
 
X 
X 
X 
 
X 
 
Coagulation: INR 
 
X 
 
 
 
 
 
 
 
Pregnancy test if applicable 
 
X 
 
 
 
 
 
 
 
Tumour assessment 3 
 
X 
 
 
 
X 
X 
X 5 
X 
Adverse events 
 
 
 
X 
X 
X 
 
X 
 
Bevacizumab 
 
 
 
X 
X 
X 
 
 
 
Erlotinib (daily) 
 
 
 
X 
X 
X 
 
 
 
Second-line therapy 
 
 
 
 
 
 
 
 
X 
1 – screening must be done within 28 days before treatment start; tumour material from biopsy and/or original surgery 
2 – before any trial-specific intervention 
3 – CT of thorax and abdomen prior to start of cycles 3, 5, 7, 10, 13, 16, 20, 24, 28; in case of treatment discontinuation without progression weeks 6, 12, 18, 27, 36, 45, 57, 
69, 81 and every 12 weeks until progression. CT scan of brain is not mandatory and only recommended in case of clinically suspected brain metastasis.  
4 – Serum and plasma samples for translational research should be taken at baseline, after 6 weeks (time of first tumor evaluation), and at the time of progression. 
5 – For patients who discontinued study treatment due to toxicity rather than progressive disease, restaging (CT scan chest and abdomen, brain scan if applicable) should be 
repeated if not already performed within 30 days prior to the last dose of study treatment  
6-  Patients who discontinue treatment before progression should be assessed at the same timepoints as patients still on treatment, weeks 6, 12, 18, 27, 36, 45, 57, 69, 81; and 
then every 12 weeks until progression (see section 16.7). Patients with progression should be assessed every 12 weeks (see section 16.10).


 
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3. 
List of abbreviations 
AEG-1 
astrocyte elevated gene 1 
ALT 
Alanine transaminase 
AP 
Alkaline phosphatase 
AST 
Aspartate transaminase 
BRCA1  
breast cancer 1, early-onset 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
EGFR 
epidermal growth factor receptor 
FFPE 
formalin fixed, paraffin embedded 
INR 
International Normalized Ratio 
LLN 
lower limit of normal lab value 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
RDE 
remote data entry 
RECIST 
Response Evaluation Criteria In Solid Tumours 
ULN 
upper limit of normal lab value 
VEGF 
vascular endothelial growth factor 


 
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4. 
Background and Rationale 
4.1. 
EGFR mutations in lung cancer 
Lung cancer is the leading cause of death from cancer in Europe (1). The most common 
type of lung cancer is adenocarcinoma, followed by squamous cell carcinoma, large cell 
carcinoma and small cell carcinoma. More than two thirds of patients with lung cancer are 
diagnosed with advanced, inoperable disease. Until recently, the mainstay of treatment for 
these patients was platinum-based chemotherapy, regardless of tumor histology (2).  
Activating mutations in exon 19 and 21 of the epidermal growth factor receptor gene 
(EGFR) confer hypersensitivity to the tyrosine kinase inhibitors erlotinib and gefitinib in 
patients with advanced NSCLC (3, 4, 5). The Spanish Lung Cancer Group (SLCG) 
previously evaluated the feasibility of large-scale screening for EGFR mutations in patients 
with NSCLC, and analyzed the association between the mutations and the outcome of 
erlotinib treatment (6). From April 2005 through November 2008, lung cancers from 2105 
patients in 129 institutions in Spain were screened for EGFR mutations. The analysis was 
performed in a central laboratory. Patients with tumors carrying EGFR mutations were 
eligible for erlotinib treatment. EGFR mutations were found in 350 of 2105 patients 
(16.6%). Mutations were more frequent in women (69.7%), in patients who had never 
smoked (66.6%), and in those with adenocarcinomas (80.9%) (P<0.001 for all 
comparisons). The mutations were deletions in exon 19 (62.2%) and L858R (37.8%). 
Median progression-free survival and overall survival for 217 patients who received 
erlotinib were 14 months and 27 months, respectively. This study demonstrated that large-
scale screening of patients with lung cancer for EGFR mutations is feasible and can have a 
role in decisions about treatment. 
The SLCG conducted the prospective randomized phase III trial EURTAC comparing 
erlotinib with platinum-based chemotherapy in chemonaive patients with advanced NSCLC 
harboring EGFR mutations. From February 2007 to January 2011, 1227 patients were 
screened for EGFR mutations, and 174 patients were randomly assigned to receive erlotinib 
or platinum-based chemotherapy. The primary endpoint was progression-free survival 
(PFS). Secondary endpoints included response, overall survival and toxicity profiles. 
Preliminary results of the interim analysis were presented at ASCO 2011 (7). One hundred 
and fifty-three patients (76 chemotherapy, 77 erlotinib) were evaluable for the interim 
analysis. Patient characteristics in the chemotherapy arm were: 16 males; median age, 64; 
never smokers, 56; PS 0, 26; PS 1, 41; adenocarcinoma, 67. Patient characteristics in the 
erlotinib arm were: 25 males; median age, 65; never smokers, 54; PS 0, 23; PS 1, 44; 
adenocarcinoma, 73. Response rate was 10.5% to chemotherapy versus 54.5% to erlotinib 
(P<0.0001). PFS in the chemotherapy arm was 5.2 months (95%CI, 4.4-5.8 months) 
compared to 9.4 months (95%CI, 7.9-12.3 months) in the erlotinib arm (HR, 0.42; 
P<0.0001). Median survival was 18.8 months in the chemotherapy arm and 22.9 months in 
the erlotinib arm (HR, 0.80; P=0.42).  
In the pan-Asian phase III trial IPASS, gefitinib was superior to carboplatin-paclitaxel as an 
initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers 
in East Asia. The presence in the tumor of a mutation of the EGFR gene was a strong 
predictor of a better outcome with gefitinib (8). The North-East Japan, West Japan and first-
SIGNAL trials confirmed the superiority of gefitinib over chemotherapy for progression 
free survival in Asian patients with activating EGFR mutations (9). The phase III trial 
OPTIMAL in China compared erlotinib versus chemotherapy with carboplatin and 


 
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gemcitabine in 83 patients with a confirmed EGFR exon 19 deletion or exon 21 L858R 
mutation (10). Median progression-free survival was significantly longer in erlotinib-treated 
patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] versus 4.6 [4.21-5.42] 
months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated 
with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia and 
thrombocytopenia), while the most common grade 3 or 4 toxic effects with erlotinib were 
increased alanine aminotransferase concentrations and skin rash. Chemotherapy was also 
associated with increased treatment-related serious adverse events.  
Based on the results of EURTAC and the Asian trials, frontline therapy with an EGFR 
inhibitor has become a new standard-of-care for patients with advanced NSCLC and 
activating EGFR mutations (11).  
4.2. 
Mechanisms of tumor resistance to erlotinib: T790M and DNA-repair 
In contrast to activating EGFR mutations, the T790M mutation in EGFR exon 20 is 
associated with resistance to EGFR inhibitors (12). The role of other resistance factors 
including diverse and complex molecular signal pathways (MET, Src, AKT and others) is 
less well understood and we focused our previous research on DNA-repair pathways. We 
hypothesized that progression-free survival could be influenced both by the pretreatment 
EGFR T790M mutation and by the expression of BRCA1. BRCA1 (breast cancer 1, early 
onset) repairs DNA double-strand breaks by homologous recombination (13). Experimental 
evidence suggested that BRCA1 overexpression enhances sensitivity to docetaxel and 
resistance to cisplatin. (14). We assessed the T790M mutation in pretreatment diagnostic 
specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations (15). 
The expression of eight genes and two proteins involved in DNA repair and four receptor 
tyrosine kinases was also examined. The EGFR T790M mutation was observed in 45 of 129 
patients (35%). Progression-free survival was 12 months in patients with and 18 months in 
patients without the T790M mutation (P=0.05). Progression-free survival was 27 months in 
patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 
10 months in those with high levels (P=0.02). In the multivariate analysis, the presence of 
the T790M mutation (hazard ratio [HR], 4.35; P=0.001), intermediate BRCA1 levels (HR, 
8.19; P<0.0001), and high BRCA1 levels (HR, 8.46; P<0.0001) emerged as markers of 
shorter progression-free survival. Low BRCA1 levels neutralized the negative effect of the 
pretreatment EGFR T790M mutation and were associated with longer progression-free 
survival to erlotinib.  
To prospectively examine the effect of EGFR mutations and BRCA1 mRNA levels in 
patients with advanced NSCLC, we conducted a prospective non-randomized phase II 
clinical trial, testing the hypothesis that customized therapy would confer improved outcome 
over non-customized therapy (16). We treated 123 metastatic NSCLC patients using a 
customized approach. RNA and DNA were isolated from microdissected specimens from 
paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those 
without EGFR mutations received chemotherapy with or without cisplatin based on their 
BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus 
docetaxel; high, docetaxel alone. Median survival exceeded 28 months for 12 patients with 
EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 
patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-
year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. In an exploratory analysis, 
we also examined the effect of RAP80 and Abraxas, which form a complex and are required 
for the DNA damage reponse (17). Median survival was influenced by RAP80 expression in 
the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, 


 
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median survival exceeded 26 months. RAP80 was a significant factor for survival in patients 
treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05). 
AEG-1 (astrocyte elevated gene 1) is a multifunctional oncogene that plays a role in several 
carcinogenic processes. Through PI3K/Akt, AEG-1 activates IKK, leading to 
phosphorylation and destabilization of the NF-kB inhibitor NFKBIA, which is a gatekeeper 
for EGFR signaling (18, 19). We analyzed BRCA1/AEG-1 in 55 erlotinib-treated EGFR 
mutated NSCLC patients (20). Tumor mRNA expression levels of BRCA1 and AEG-1 were 
assessed by quantitative PCR in 77 erlotinib-treated patients with EGFR mutations. 
Expression levels were dichotomized at the median. PFS was longer in patients with low 
AEG-1 expression (27 vs 12 months; P=0.003). Median survival (MS) was not reached for 
patients with low AEG-1 levels and was 24 m for patients with high levels (P=0.08). Based 
on these results, we generated an AEG-1/BRCA1 risk model: patients with high levels of 
both genes were considered high-risk, patients with low levels of both genes were low-risk, 
and patients with high levels of one and low levels of the other gene were intermediate-risk. 
PFS was not reached in the low-risk group, while it was 18 months for the intermediate-risk 
group and 8 months for the high-risk group (P=0.00006) (hazard rate HR for high- vs low-
risk groups, 6.6; 95%CI, 2-4-18; P<0.00001). Median survival was not reached in the low-
risk group, while it was 31 months for the intermediate-risk group and 18 months for the 
high-risk group (P=0.05). In the multivariate analysis for PFS, the only independent 
prognostic variables were bone metastases (HR, 2.7; 95%CI, 1.1-6.5; P=0.03) and the AEG-
1/BRCA1 risk groups (HR for high-risk group, 7.7 (95%CI, 2.8-21.3; P<0.00001).  
BARD1 (BRCA1 associated RING domain protein 1) couples with BRCA1 and, together 
with the E3 ubiquitin ligases RNF8, RNF168 and RAP80, is essential for DNA repair (20). 
We examined BARD1 expression in 55 EGFR-mutant NSCLC patients treated with 
erlotinib (22). CodeSets (Reporter and Capture probe sets) for 48 genes were custom-
designed by NanoString Technologies. BARD1 levels were significantly associated with 
PFS: low, 23 months; high, 6 months (P=0.03). We generated an AEG-1/BARD1 risk 
model: patients with high levels of both genes were considered high-risk, patients with low 
levels of both genes were low-risk, and patients with high levels of one and low levels of the 
other gene were intermediate-risk. PFS was not reached in the low-risk group, while it was 
16 months for the intermediate-risk group and 6 months for the high-risk group (P=0.004). 
Median survival was not reached in the low-risk group, while it was 21 months for the 
intermediate-risk group and 31 months for the high-risk group (P=0.14). Based on these 
results, we advocate baseline assessment of the EGFR T790M mutation together with 
expression of DNA-repair status to predict outcome and provide individualized treatment to 
patients with EGFR activating mutations.  
4.3. 
Rationale for combination therapy with erlotinib and bevacizumab 
Bevacizumab is a humanized antibody targeting the vascular endothelial growth factor 
VEGF, which plays an important role in tumor angiogenesis. The ECOG 4599 and AVAIL 
trials in patients with metastatic NSCLC demonstrated superior response and survival rates 
with bevacizumab plus chemotherapy, compared with chemotherapy alone (23, 24). The 
safety and tolerability of bevacizumab in combination with chemotherapy in patients with 
NSCLC is well documented in the SAIL and ARIES trials (25, 26). The combination of 
bevacizumab with erlotinib also has a favorable safetly profile in patients with 
adenocarcinoma of the lung, precluding patients with tumor bleeding, or with centrally 
located and cavitating tumors. Several trials have been previously conducted using the 
combination of bevacizumab and erlotinib in molecularly unselected NSCLC patients (27, 
28, 29). The recognition that T790M could represent more than 50% and up to 62% of cases 


 
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with clinical progression to erlotinib leads to the development of new treatment approaches 
to overcome this common mechanism of acquired resistance.  
In preclinical models, gefitinib and erlotinib had similar profiles of in vitro activity and 
caused sustained tumor regressions in vivo in the sensitive HCC827 cell line. In all four 
resistant cell lines including H1975 (L858R plus T790M), the combination of bevacizumab 
and erlotinib was significantly more effective than erlotinib alone (30). This model suggests 
that patients harboring EGFR mutations (del19 or L858R) plus T790M could be sensitive to 
the addition of bevacizumab to erlotinib. We therefore raise the hypothesis that 
bevacizumab could prolong the PFS obtained with erlotinib in the subgroup of patients with 
initial presence of the T790M mutation. 
4.4. 
Circulating DNA 
Tumors are shedding DNA into the bloodstream, opening a way for minimally-invasive 
translational cancer research (31). We and others previously showed that circulating cell-
free DNA in the blood of patients with lung cancer can be readily isolated, quantified, and 
has a prognostic value (32, 33). Moreover, circulating DNA is a source of cancer-specific 
genetic and epigenetic alterations, including gene mutations and methylation (34, 35, 36, 
37). EGFR mutations, including the T790M, have been detected in the circulating DNA in a 
meaningful number of patients with advanced lung cancer and tumor EGFR mutations (38). 
The clearance of EGFR mutations in blood could be a molecular marker of response and the 
reappearance of mutations can herald clinical progression. Although EGFR mutations can 
be detected in serum as well as plasma, there is a significant percentage of patients where 
they are found only in serum or only in plasma. To maximise the likelihood of a successful 
EGFR mutation analysis in blood, the collection of both plasma and serum is essential. 
Therefore, in the present trial, EGFR mutations in serum and plasma are determined at 
baseline and at the time of radiographic response assessments to validate test performance 
and to further study the utility of circulating EGFR mutations to monitor the disease. 
4.5. 
Hypothesis  
Our findings prompt us to propose a model of treatment whereby patients with EGFR 
mutations (single or with T790M) can attain a benefit with longer overall PFS when treated 
with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels 
and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can 
improve the PFS in all subgroups; for example in those with low BRCA1 levels with very 
long PFS, the addition of bevacizumab can further improve long term outcome, but also in 
the poor prognostic group of patients with elevated BRCA1 and the concurrent presence of 
the T790M where, according to our data, the PFS under erlotinib alone is 3 months.  
4.6. 
Further plans 
We postulate that patients with the double EGFR mutation harbour two tumour populations; 
patients with the T790M could display a differential sensitivity to cisplatin based on the 
levels of BRCA1 expression and therefore, customized chemotherapy based on BRCA1 
levels could be indicated in these patients. Hypoxia suppresses homologous recombination 
repair in human cells via transcriptional downregulation of BRCA1 and RAD51. The 
downregulation is caused by stimulating E2F4/p130 occupancy of the BRCA1 and RAD51 
promoters (39, 40, 41). Intriguingly, PARP inhibitors cause BRCA1 and RAD51 
downregulation via induction of E2F4/p130 binding to the BRCA1 and RAD 51 promoters 


 
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(42). Future clinical trials will be planned to further develop a customized approach to the 
targeting of DNA repair in patients with lung cancer.  
5. 
Objectives and endpoints 
5.1. 
Primary objective 
To determine progression free survival of patients with advanced non-squamous NSCLC 
harbouring at diagnosis EGFR mutations with and without T790M mutation, treated with 
the combination of erlotinib and bevacizumab. 
Hypotheses of interest: 
When treated with bevacizumab and erlotinib 
a. Median PFS increases to 18 months for patients with EGFR T790M mutation 
b. Median PFS is approximately 18 months or more in patients without EGFR 
T790M mutation. 
5.2. 
Secondary objectives 
5.2.1. 
To evaluate secondary measures of clinical efficacy including overall survival 
(OS), time to treatment failure (TTF), objective response rate (ORR), disease 
control rate (DCR) and duration of response (DR). 
5.2.2. 
To assess the safety and the tolerability of the erlotinib and bevacizumab 
combination. 
5.2.3. 
To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and 
T790M with progression-free survival.  
5.2.4. 
To monitor EGFR mutations (including T790M) in serum and plasma 
longitudinally. 
5.2.5. 
To evaluate molecular biomarkers related to EGFR TKI and bevacizumab. 
5.2.6. 
To determine the feasibility of re-biopsies at the time of progression and gene-
expression arrays for decision-making for second-line treatment 
5.2.7. 
To study the feasibility of recommending customized second-line chemotherapy 
based on BRCA1 and AEG-1 mRNA levels. 
5.3. 
Primary endpoint 
Progression-free survival. For definition, see section 14.1 
5.4. 
Secondary endpoints 
5.4.1. 
Overall survival (OS) 
5.4.2. 
Time to treatment failure (TTF) 
5.4.3. 
Objective response (OR) 


 
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5.4.4. 
Adverse events graded according to CTCAE V4.0 
5.4.5. 
Disease control (DC) 
5.4.6. 
Duration of response (DR) 
For definitions, see section 14. 
6. 
Trial design, duration and termination 
This is a multinational, multi-center trial of erlotinib plus bevacizumab in patients with 
advanced non-squamous NSCLC harbouring EGFR mutations, including two separate phase 
II substudies. 
Only EGFR mutated patients may enter the study. Approximately 1135 patients with 
advanced non-small cell lung cancer are expected to be screened to include 102 patients 
with activating EGFR mutations. 
Patients may continue treatment on this trial as long as there is evidence of clinical benefit 
in the judgment of the investigator. Trial subjects will receive trial medication up to 18 
months after the inclusion of the last patient. All patients who are still benefiting from their 
treatment at that time have to be switched to commercial drug which will be reimbursed by 
Roche. 
Patient accrual is expected to be completed within 12 months including a run-in-period of 3 
months. Treatment and follow-up is expected to extend the study duration to a total of 48 
months. Patients will be followed until death – thus follow-up estimated up to 3 years 
following the enrolment of the last patient.  
The trial will end with the preparation of the final report, scheduled for month 54 after the 
inclusion of the first patient.  
7. 
Patient selection 
Only patients with a centrally confirmed status of EGFR mutation are eligible. The mutation 
status may first be assessed locally by a certified laboratory, but for all patients tumor 
material has to be submitted to the reference laboratory (see section 9) for immediate 
confirmatory testing. 
Written informed consent needs to be obtained prior to shipment of tissue to the central 
laboratory. 
Patients should only be selected and consented for screening if they fulfil the criteria in the 
next section: 
7.1. 
Inclusion criteria 
Patient characteristics 
7.1.1. 
Age ≥ 18 years 
7.1.2. 
ECOG performance status 0-2 
7.1.3. 
Adequate haematological function: haemoglobin > 9 g/dL, neutrophils count 
>1.5×109/L, platelet count > 100 × 109/L  


 
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7.1.4. 
Adequate coagulation: INR ≤ 1.5  
7.1.5. 
Adequate liver function: Total bilirubin < 1.5 × ULN, ALT and/or AST < 2.5 × 
ULN, alkaline phosphatase < 5 ULN, except in the presence of exclusive bone 
metastases and in the absence of any liver disorder. 
7.1.6. 
Adequate renal function: Calculated creatinine clearance ≧ 50 mL/min (Cockroft-
Gault) and proteinuria < 2+ (dipstick).  
7.1.7. 
Oral swallowing capability, patient capable of proper therapeutic compliance, and 
accessible for correct follow-up. 
7.1.8. 
Life expectancy of at least 2 months. 
7.1.9. 
Women of childbearing age, 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 beginning treatment. Not eligible: Women who are pregnant or in the 
period of lactation.  
7.1.10. All sexually active men and women of childbearing age must use an effective 
contraceptive method during the study treatment and for a period of at least 12 
months following the last administration of trial drugs. Not eligible: sexually active 
men and women of childbearing age who are not willing to use an effective 
contraceptive method during the study. 
7.1.11. Written Informed Consent (IC) must be signed and dated by the patient and the 
investigator prior to any trial-related intervention for  
a) trial treatment 
b) tissue submission for central review and central EGFR testing 
Disease characteristics 
7.1.12. Pathological diagnosis of predominantly non-squamous, non-small-cell lung cancer 
(NSCLC). Not eligible: patients with any other lung cancer subtype, patients with 
mixed NSCLC with predominantly squamous cell cancer, or with any small cell 
lung cancer (SCLC) component. 
7.1.13. TNM version 7 stage IV disease including M1a (malignant effusion) or M1b 
(distant metastasis), or locally advanced disease not amenable to curative treatment 
(including patients progressing after radio-chemotherapy for stage III disease). Not 
eligible: patients who are candidates for radical surgery and/or 
radio(chemo)therapy with curative intention. 
7.1.14. Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: 
patients with only one measurable or evaluable tumor lesion which was resected or 
irradiated prior to enrolment. 
7.1.15. Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R). 
Not eligible: patients with local test result not confirmed by central laboratory. 
Note: if the patient needs immediate treatment, the investigator may register the 
patient based on locally determined mutation status and start treatment before 


 
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confirmation, using trial medication. If the EGFR mutation status is not confirmed 
by the central reference laboratory, the patient will be taken off trial treatment and 
will undergo an end-of-treatment assessment. The patient must be followed up per 
protocol (see section 9). 
7.1.16. Patients with asymptomatic and stable cerebral metastases will be eligible for the 
study. Not eligible: patients with symptomatic or instable cerebral metastases 
requiring medical treatment. 
7.2. 
Exclusion criteria 
Prior/concurrent disease and conditions 
7.2.1. 
Not eligible: patients with increased risk of bleeding, defined by: 
- 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 the study enrolment 
- history or evidence of bleeding diathesis or hereditary coagulopathy 
- history of haemoptysis (defined as at least half a teaspoon’s emission of red 
blood) in the 3 months prior to inclusion) 
- evidence by CT of tumor cavitations, or tumours invading or abutting major 
blood vessels 
- Inadequately controlled hypertension (systolic blood pressure > 150 mm Hg and 
/ or diastolic > 100 mm Hg) 
- prior history of hypertensive crisis or hypertensive encephalopathy 
7.2.2. 
Not eligible: patients with clinically significant cardiovascular diseases, including  
- cerebral vascular accident (<6 months before inclusion) 
- acute myocardial infarction (<6 months before inclusion) 
- unstable angina 
- congestive heart failure class > NYHA II 
- serious cardiac arrhythmia requiring medication during the study and which 
could interfere with regularity of study treatment or is not controlled with 
medication. 
7.2.3. 
Not eligible: patients with a history of thrombosis or thromboembolism in the 6 
months prior to treatment 
7.2.4. 
Not eligible: patients with gastrointestinal problems including  
- intestinal transit problems (such as malabsorption syndrome, chronic intestinal 
inflammatory disease, or other pathologies that can alter absorption of the 
medication 
- history of abdominal fistula, intestinal perforation or intra-abdominal abscess 
within 6 months prior to inclusion 
- uncontrolled active peptic ulcer 


 
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- presence of trachea-oesophageal fistula. 
7.2.5. 
Not eligible: patients with neurologic problems, including  
- evidence of spinal cord compression 
- significant neurological or psychiatric disorders (including dementia and 
epileptic seizures). 
7.2.6. 
Not eligible: Patients who have had in the past 5 years any previous or concomitant 
malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the 
skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. 
7.2.7. 
Not eligible: patients with any known significant ophthalmologic anomaly of the 
ocular surface. The use of contact lenses is not recommended. 
7.2.8. 
Not eligible: patients with other serious diseases or clinical conditions, including 
but not limited to uncontrolled active infection and any other serious underlying 
medical processes that could affect the patient’s capacity to participate in the study. 
7.2.9. 
Not eligible: Known hypersensitivity to bevacizumab or erlotinib or any of its 
excipients. 
Prior, recent or concurrent treatment 
7.2.10. Not eligible: patients who received prior chemotherapy for metastatic disease. 
Patients with prior neoadjuvant or adjuvant chemotherapy or definitive radio-
chemotherapy for localised disease are eligible if chemotherapy has stopped at least 
6 months before entering the study 
7.2.11. Not eligible: patients who received previous treatment for lung cancer with drugs 
targeting EGFR or VEGF.  Patients with previous intraocular treatment with VEGF 
-targeting drugs are eligible.  
7.2.12. Not eligible: patients who received treatment with an investigational drug agent 
during the 3 weeks before enrolment in the study. 
7.2.13. Not eligible: patients with current or recent use (within the last 10 days) of full 
doses of anticoagulants or thrombolytics, either orally or parenterally. Use of 
anticoagulant prophylaxis is permitted (low dose heparin or aspirin <=325 mg, 
prophylactic FXa inhibitors).  
7.2.14. Not eligible: patients with concurrent use of CYP3A4 inducers/inhibitors (such as, 
but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), 
voriconazole, or grapefruit or grapefruit juice).  
8. 
Patient screening and registration 
This trial will use a web-based registration system. Each participating center will access the 
registration system directly. Specific details for registration of patients are in the “BELIEF 
Procedures Manual” which will be available on the ETOP website (www.etop-eu.org). 


 
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8.1. 
Enrolment of patient 
Complete the following steps to enroll a patient on this trial. Please consult the BELIEF 
Procedures Manual for detailed instructions. 
Note that written informed consent has to be obtained from the patient prior to any trial-
specific intervention including submission of tissue for central EGFR testing. 
8.1.1. 
Screening: Verify eligibility (including presence of EGFR mutation if done locally) 
and register the patient in the RDE facility. The date the Informed Consent Form 
and the consent to pathology material submission section of the Informed Consent 
Form were signed by the patient and the date signed by the investigator are both 
required to complete the eligibility checklist. 
8.1.2. 
If EGFR mutation testing is to be done nationally (see section 9), submit tissue 
material to national laboratory for evaluation of EGFR mutation status. Enter 
EGFR mutation status in RDE facility once result has been communicated by 
national laboratory. 
8.1.3. 
The laboratory which has done the EGFR mutation testing (local lab or national 
lab) submits tissue material to central reference laboratory for central evaluation of 
EGFR mutation status (see section 9). The enrolling site must confirm shipment in 
the RDE system.  
8.1.4. 
Enrolment: Within 48 hours of receipt of the tissue material, the central reference 
laboratory will inform the site (e-mail from RDE system) if the material is 
sufficient and usable for EGFR mutation analysis and T790M determination or not. 
If the material is accepted this will trigger the enrolment into the trial and the trial 
treatment can start. 
Note: if the patient needs immediate treatment, the investigator may enroll the patient 
immediately (confirmation of the trial chair required, see BELIEF Procedures Manual for 
detailed instructions) and start treatment before acceptance of tissue by the central Lab, 
using trial medication. Tissue material for central mutation testing has to be submitted as 
soon as possible but no more than 10 working days after the eligibility override. 
If the tissue quality and/or quantity is not accepted by the central reference laboratory a 
second sample has to be sent to the central Lab within 10 days after awareness that the 
samples has been rejected. If the second sample is also not accepted, no second sample can 
be sent or the EGFR mutation status is not confirmed, the patient will be taken off trial 
treatment and undergo an end-of-treatment assessment. The patient must be followed up per 
protocol. 
9. 
Central testing of EGFR mutation status  
Only patients with centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation 
(L858R) are eligible. There are three options for the determination of mutation status: 
1. The mutation status may be assessed locally by a certified laboratory, but must be 
confirmed by the central reference laboratory.  
2. The mutation status may be assessed nationally by a certified laboratory, but must be 
confirmed by the central reference laboratory.  


 
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If the EGFR mutation status is not confirmed by the central reference laboratory, the patient 
will be taken off trial treatment and will undergo an end-of-treatment assessment. Such a 
patient must be followed up per protocol. 
3. Tumour material can also be submitted directly to the central reference laboratory 
for immediate testing without prior local testing.  
9.1. 
Location of central reference laboratory 
 The central reference laboratory is  
Laboratory of Oncology 
Pangaea Biotech SA 
USP Dexeus Institute 
Calle Sabino Arana 5-9 
08028-Barcelona, Spain 
http://www.pangaeabiotech.com/  
If the EGFR mutation status is not confirmed by the central reference laboratory, or the 
submitted FFPE material is found to be not sufficient and usable for EGFR mutation 
analysis and T790M determination, the patient will be taken off trial treatment and will 
undergo an end-of-treatment assessment. The patient must be followed up per protocol. 
9.2. 
Shipping of samples to central laboratory 
Once the patient has consented to the participation, send a formalin fixed, paraffin 
embedded block or alternatively at least 5 sections mounted on penmembrane slides from 
tumour biopsy, original surgery or cell block to the central laboratory (national reference 
laboratory or the central reference laboratory) for EGFR mutation analysis (consult the 
Group/Country specific instructions for your country). Please send the tissue with a 
Haematoxylin/Eosin slide together with the original report of the mutation analysis (if 
applicable) and the Pathology report to the central laboratory. Please consult the BELIEF 
Procedures Manual for detailed instructions. 
9.3. 
Communication of result 
The central reference laboratory (Pangaea Biotech) will communicate within 48 hours of 
receipt of the material if the submitted FFPE material is sufficient and usable for EGFR 
mutation analysis and T790M determination. This confirmation triggers the enrollment of 
the patient into the study and trial treatment can start (exception see note in section 8.1). 
The results of the mutation testing will be communicated within 7 working days; if this is 
not feasible in exceptional cases, the submitting site will be contacted within 7 days to 
explain the reasons.  
10. 
Study drug 
Erlotinib and bevacizumab are the investigational drugs used in this trial. Both will be 
provided by Hoffmann-La Roche.  
The Drug Supply Manual will describe drug supply logistics as well as labelling, 
packaging, handling, drug accountability and destruction of unused drugs. 


 
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11. 
Trial treatments 
Drug therapy is to begin within 7 days of enrolment 
11.1. 
Sequence of treatments 
Patients will be treated with erlotinib and bevacizumab. 
Bevacizumab: 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days) 
Erlotinib: 150 mg p.o., daily 
11.2. 
Dosage, administration and compliance 
11.2.1. Bevacizumab dose / route / regimen 
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. 
Bevacizumab should be given every 3 weeks +/- 3 days. If the administration was pre- or 
postponed the patient should (if possible) return to schedule and the next dose should be 
given 21 days after the planned last administration. 
11.2.2. Erlotinib dose / route / regimen / compliance 
Erlotinib is started at a fixed dose of 150 mg per day.  
Tablets should be taken at a fixed time each day and at least 1 hour before or 2 hours after 
the ingestion of food. Treatment compliance for erlotinib will be monitored by a patient 
diary. Patients will be asked to record the time and date they take each dose in the diary. 
They will be instructed to bring it to each study visit for assessment of compliance. Patients 
will also be instructed to bring all unused erlotinib tablets to each study visit. Please refer to 
the Procedures Manual for details. No routine premedication (e.g. to prevent skin toxicity) 
is recommended for erlotinib.  
Smokers have reduced plasma levels and should be counselled for smoking reduction or 
cessation, the dose of 150 mg must never be increased. 
In case of relevant toxicity, dose reductions are recommended to improve the tolerance.  


 
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11.3. 
Precautions 
Women with childbearing potential and sexually active men must use effective 
contraception during the trial and 12 months thereafter.  
11.4. 
Concomitant treatment  
The following treatments are allowed during the treatment phase of the trial: 
 Approved drugs for other medical indications than cancer including low dose 
heparin or aspirin (≤ 325 mg per day) and FXa inhibitors, except full 
anticoagulation (see section below) 
 Palliative and supportive care, including analgesic radiotherapy 
 Safe alternative medicine if potential interactions with trial drugs can be excluded.  
The following treatments are NOT allowed: 
 Investigational or approved anticancer drugs, including chemotherapy, 
immunotherapy, and hormonal anti-cancer therapy  
 Full-dose oral, intravenous or subcutaneous anticoagulants, asasantin or clopidogrel 
 Medications, herbal extracts or food which can interact with erlotinib (CYP3A4 
inducers/inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit 
juice). 
11.5. 
Treatment delay and dose modification for toxicity 
In case of toxicity, symptomatic treatment and dose interruptions should be used according 
to the following sections. Repeated dose interruptions are allowed as required, for a 
maximum of 6 weeks on each occasion (a delay of a maximum of 6 weeks after the planned 
drug administration is allowed). As long as at least one of the study drugs can be 
continued, the patient remains on trial treatment. In case of doubt please contact 
immediately one of the trial chairpersons. 
If one of the trial drugs is stopped for a reason other than unacceptable toxicity, the case 
needs to be discussed immediately with the trial chair or one of the trial coordinators to 
clarify if the patient can remain on study medication with the other drug.  
11.5.1. Bevacizumab 
There are no recommended dose reductions.  
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 


 
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and if hypertension is confirmed, antihypertensive medication should be started and 
bevacizumab should be delayed until blood pressure drops below 150/100mmHg.  
 Proteinuria Grade 3; resume bevacizumab once grade 2 or less has been attained. 
 Grade 3 or 4 bevacizumab-related events 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  
 Medically significant hypertension not controlled with antihypertensive therapy, 
hypertensive crisis or hypertensive encephalopathyPosterior reversible 
encephalopathy syndrome (PRES), previously called Reversible posterior 
leukoencephalopathy syndrome (RPLS)  
 Severe infusion reactions  
 Recurring grade 3 or 4 bevacizumab-related event  
 A treatment delay of more than 6 weeks 
11.5.2. Erlotinib 
Temporarily suspend erlotinib:  
 In patients who develop an acute onset of new or progressive pulmonary 
symptoms, such as dyspnea, cough or fever, treatment with erlotinib should be 
interrupted pending diagnostic evaluation. 
 in patients with dehydration who are at risk for renal failure 
 in patients with severe bullous, blistering or exfoliative skin conditions 
 in patients with acute or worsening ocular disorders 


 
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 in patients with severe changes in liver function such as doubling of total bilirubin 
and/or tripling of transaminases, especially in the setting of baseline values outside 
normal range 
 in patients with total bilirubin >3 x ULN and/or transaminases  >5 x ULN. Patients 
with hepatic impairment should be closely monitored during therapy. 
Permanently discontinue erlotinib for:  
 Interstitial Lung Disease (ILD) 
 hepatic failure 
 gastrointestinal perforation 
 A treatment delay of more than 6 weeks 
Dose reductions 
When dose reduction is necessary, the erlotinib dose should be reduced in 50 mg 
decrements.  
 Diarrhea can usually be managed with loperamide. Patients with severe diarrhea 
who are unresponsive to loperamide or who become dehydrated may require dose 
reduction or temporary interruption of therapy. Patients with severe skin reactions 
may also require dose reduction or temporary interruption of therapy.  
 In the setting of worsening liver function tests, before they become severe, dose 
reduction with frequent liver function test monitoring should be considered.  
 For other erlotinib-related adverse events greater than or equal to grade 3, erlotinib 
should be dose reduced or delayed until resolution to grade 0-1. If not resolved 
within 4 weeks, erlotinib must be permanently discontinued. If resolved to grade 0-
1, the lower dose can be maintained or again increased to 150 mg maximum. On 
second occurrence of grade 3-4 events, erlotinib should be permanently 
discontinued. 
11.6. 
Treatment duration 
Patients remain on treatment until one of the following events: 
 Documented progression according to RECIST v1.1  
 Unacceptable toxicity 
 Any interruption of both of the study drugs for more than 6 weeks. Patients who 
discontinue only one of the study drugs and continue with the other drug are 
considered to remain on the trial treatment. 
If one of the trial drugs is stopped for a reason other than unacceptable toxicity, the 
case needs to be discussed immediately with the trial chair or one of the trial 
coordinators to clarify if the patient can remain on study medication with the other 
drug.  
 Medical condition that prevents further treatment 
 Significant protocol violation 
 Patient withdraws consent 


 
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 Patient becomes pregnant 
If only one of the two trial drugs has to be stopped and the other drug can be continued, the 
patient remains on the trial. If both drugs have been stopped for any reason, the patient 
enters the follow-up phase of the trial. Up to the time of confirmation of disease 
progression, the schedule of evaluations has to be kept as if the patient were still 
receiving treatment. Patients who discontinue trial treatment should be assessed by the 
investigator who must document the case on the appropriate CRF. Leftover erlotinib tablets 
should be returned by the patient.  
Trial subjects will receive trial medication up to 18 months after the inclusion of the last 
patient. All patients who are still benefiting from their treatment at that time have to be 
switched to commercial drug which will be reimbursed by Roche. 
12. 
Safety of investigational products 
12.1. 
Bevacizumab 
12.1.1. Known adverse reactions 
The following NCI CTC grade 3 to 5 adverse reactions have been reported: 
Very common (≥ 10%): Febrile neutropenia, Leucopenia, Thrombocytopenia, Neutropenia, 
Peripheral sensory neuropathy, Hypertension, Diarrhoea, Nausea, Vomiting, Asthenia, 
Fatigue 
Common (1 – <10%): Sepsis, Abscess, Infection, Anaemia, Dehydration, Cerebrovascular 
accident, Syncope, Somnolence, Headache, Cardiac failure congestive, Supraventricular 
tachycardia, Arterial Thromboembolism (pooled arterial thromboembolic events including 
cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial 
thromboembolic adverse reactions), Deep vein thrombosis, Haemorrhage, Pulmonary 
embolism, Dyspnoea, Hypoxia, Epistaxis, Intestinal Perforation, Ileus, Intestinal 
obstruction, Abdominal pain, Gastrointestinal disorder, Stomatitis, Palmar-plantar 
erythrodysaesthesia syndrome, Muscular weakness, Myalgia, Arthralgia, Proteinuria, 
Urinary Tract Infection, Pain, Lethargy, Mucosal inflammation. 
12.1.2. Contraindications  
Bevacizumab is contraindicated in patients with known hypersensitivity to any components 
of the product, and to chinese hamster ovary cell products or other recombinant human or 
humanised antibodies. 
12.1.3. Gastrointestinal Perforations 
Patients may be at increased risk for the development of gastrointestinal perforation when 
treated with bevacizumab. Bevacizumab should be permanently discontinued in patients 
who develop gastrointestinal perforation. 
Gastrointestinal perforations have been reported in clinical trials with an incidence of less 
than 1% in patients with metastatic breast cancer or non-squamous non-small cell lung 
cancer, up to 2.0% in patients with metastatic renal cell cancer, newly diagnosed 
glioblastoma, and in patients with ovarian cancer receiving front-line treatment, and up to 
2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal 
cancer. Cases of GI perforations have also been observed in patients with relapsed 


 
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glioblastoma. Fatal outcome was reported in approximately a third of serious cases of 
gastrointestinal perforations, which represents between 0.2%-1% of all bevacizumab treated 
patients.  
The presentation of these events varied in type and severity, ranging from free air seen on 
the plain abdominal X-ray, which resolved without treatment, to intestinal perforation with 
abdominal abscess and fatal outcome. In some cases underlying intra-abdominal 
inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis, 
or chemotherapy-associated colitis.  
12.1.4. Fistulae 
Bevacizumab use has been associated with serious cases of fistulae including events 
resulting in death. Patients may be at increased risk for the development of fistulae when 
treated with bevacizumab. Permanently discontinue bevacizumab in patients with 
tracheoesophageal (TE) fistulae or any Grade 4 fistulae.  
In Bevacizumab clinical trials, gastrointestinal fistulae have been reported with an incidence 
of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also 
reported less commonly in patients with other types of cancer. Uncommon (≥0.1% to <1%) 
reports of other types of fistulae that involve areas of the body other than the gastrointestinal 
tract (e.g. bronchopleural, urogenital, biliary fistulae) were observed across various 
indications. Fistulae have also been reported in post-marketing experience.  
Limited information is available on the continued use of bevacizumab in patients with other 
fistulae. In cases of internal fistulae not arising in the GI tract, discontinuation of 
bevacizumab should be considered. 
12.1.5. Haemorrhage 
Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour 
associated haemorrhage. Bevacizumab should be permanently discontinued in patients who 
experience Grade 3 or 4 bleeding during bevacizumab therapy. 
In clinical trials across all indications the overall incidence of NCI-CTC Grade 3-5 bleeding 
events ranged from 0.4% to 6.5% in bevacizumab-treated patients, compared to 0 to 2.9% of 
patients in the chemotherapy control group. The haemorrhagic events that have been 
observed in Bevacizumab clinical studies were predominantly tumour-associated 
haemorrhage and minor mucocutaneous haemorrhage (e.g. epistaxis). 
Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in 
colorectal patients, and have been assessed as tumour-associated haemorrhages.  
Tumour-associated haemorrhages were also seen rarely in other tumour types and locations 
and included cases of central nervous system (CNS) bleeding in patients with CNS 
metastases and in patients with glioblastoma.   
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 patient has not been prospectively evaluated in randomised 
clinical studies. Patients should be monitored for signs and symptoms of CNS bleeding, and 
bevacizumab treatment discontinued in case of intracranial bleeding. 
Across all Bevacizumab clinical trials, mucocutaneous haemorrhages were seen in up to 
50% of patients treated with Avastin. These were most commonly NCI-CTC Grade 1 


 
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epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not 
require any change in the Bevacizumab treatment regimen. Clinical safety data suggest that 
the incidence of minor mucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent.  
There have also been less common events of minor mucocutaneous haemorrhage in other 
locations, such as gingival bleeding or vaginal 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 bevacizumab therapy in these patients. However, patients who developed venous 
thrombosis while receiving bevacizumab therapy did not appear to have an increased rate of 
Grade 3 or above bleeding when treated with full dose of warfarin and bevacizumab 
concomitantly. Nevertheless, bevacizumab should be discontinued in the event of venous or 
arterial thromboembolism requiring full anticoagulation. 
12.1.6. Pulmonary Haemorrhage / Haemoptysis 
Patients with non–small cell lung cancer treated with bevacizumab may be at risk for 
serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent 
pulmonary haemorrhage/haemoptysis (>2.5 ml red blood) should not be treated with 
bevacizumab. Bevacizumab should be discontinued in the event of significant haemorrhage. 
Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in 
studies in patients with non-small cell lung cancer (NSCLC). Possible risk factors include 
squamous cell histology, treatment with antirheumatic/anti-inflammatory drugs, treatment 
with anticoagulants, prior radiotherapy, Bevacizumab therapy, previous medical history of 
atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. 
The only variables that showed statistically significant correlations with bleeding were 
Bevacizumab therapy and squamous cell histology. Patients with NSCLC of known 
squamous cell histology or mixed cell type with predominant squamous cell histology were 
excluded from subsequent studies, while patients with unknown tumour histology were 
included.  
In patients with NSCLC excluding predominant squamous histology, all Grade events were 
seen with a frequency of up to 9% when treated with Bevacizumab plus chemotherapy 
compared with 5% in the patients treated with chemotherapy alone. Grade 3-5 events have 
been observed in up to 2.3% of patients treated with Bevacizumab plus chemotherapy as 
compared with <1% with chemotherapy alone. Major or massive pulmonary 
haemorrhage/haemoptysis can occur suddenly and up to two thirds of the serious pulmonary 
haemorrhages resulted in a fatal outcome 
12.1.7. Hypertension 
An increased incidence of hypertension (all grades) of up to 42.1% was observed in patients 
treated with bevacizumab compared with up to 14% in the comparator arm. In clinical trials 
across all indications the overall incidence of NCI-CTC Grade 3 and 4 hypertension in 
patients receiving Bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension 
(hypertensive crisis) occurred in up to 1.0% of patients treated with Avastin compared to up 
to 0.2% patients treated with the same chemotherapy alone. 
Clinical safety data suggest that the incidence of hypertension is likely to be dose 
dependent. Pre existing hypertension should be adequately controlled before starting 


 
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bevacizumab treatment. There is no information on the effect of bevacizumab in patients 
with uncontrolled hypertension at the time of initiating bevacizumab therapy. Monitoring of 
blood pressure is recommended during bevacizumab therapy. 
In most cases hypertension was controlled adequately using standard antihypertensive 
treatment appropriate for the individual situation of the affected patient. 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. 
Very rare cases of hypertensive encephalopathy have been reported, some of which were 
fatal. The risk of Bevacizumab-associated hypertension did not correlate with the patients’ 
baseline characteristics, underlying disease or concomitant therapy. 
12.1.8. Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been rare reports of bevacizumab-treated patients developing signs and 
symptoms that are consistent with Posterior Reversible Encephalopathy Syndrome (PRES), 
a rare neurological 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. Symptoms usually resolve or 
improve within days, although some patients have experienced neurologic sequelae. The 
safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not 
known. 
12.1.9. Arterial Thromboembolism 
In clinical trials, the incidence of arterial thromboembolism adverse reactions including 
cerebrovascular accidents, transient ischaemic attack (TIA) and myocardial infarction (MI) 
was higher in patients receiving bevacizumab in combination with chemotherapy compared 
to those who received chemotherapy alone. 
In clinical trials, the overall incidence ranged up to 5.0% in the Bevacizumab containing 
arms compared up to 1.7% in the chemotherapy control arms. Fatal outcome was reported in 
0.8% of patients receiving Bevacizumab in combination with chemotherapy compared to 
0.5% of patients receiving chemotherapy alone. Cerebrovascular accidents (including 
transient ischemic attacks) were reported in up to 2.3% of Avastin treated patients versus 
0.5% of patients in the control group: myocardial infarction was reported in 1.4% of Avastin 
treated versus 0.7% of patients in the observed control group.   
Patients receiving Avastin plus chemotherapy with a history of arterial thromboembolism, 
diabetes or age greater than 65 years have an increased risk of developing arterial 
thromboembolic events during Avastin therapy. Caution should be taken when treating such 
patients with Avastin 
Bevacizumab should be permanently discontinued in patients who develop arterial 
thromboembolic reactions. 
12.1.10. Venous Thromboembolism 
In clinical trials across indications, the overall incidence of venous thromboembolic events 
ranged from 2.8% to 17.3% in the Avastin containing arms compared to 3.2% to 15.6% in 


 
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the chemotherapy control arms. Venous thromboembolic events include deep venous 
thrombosis and pulmonary embolism. 
Grade 3-5 venous thromboembolic events have been reported in up to 7.8% of patients 
treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients with 
chemotherapy alone. Patients who have experienced a venous thromboembolic event may 
be at higher risk for a recurrence if they receive Avastin in combination with chemotherapy 
versus chemotherapy alone. 
Patients may be at risk of developing venous thromboembolic reactions, including 
pulmonary embolism under bevacizumab treatment. Bevacizumab should be discontinued in 
patients with pulmonary embolism. 
12.1.11. Congestive Heart Failure 
Reactions consistent with congestive heart failure (CHF) were reported in clinical trials. The 
symptoms ranged from asymptomatic declines in left ventricular ejection fraction to 
symptomatic CHF, requiring treatment or hospitalisation. Most of the patients who 
experienced CHF had metastatic breast cancer (mBC) and had received previous treatment 
with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF 
were present. 
Most patients who developed CHF during mBC trials showed improved symptoms and/or 
left ventricular function following appropriate medical therapy. 
In most clinical trials of Avastin, patients with pre-existing CHF of NYHA II – IV were 
excluded, therefore, no information is available on the risk of CHF in this population. 
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease such as pre-existing coronary artery disease, concomitant cardiotoxic therapy or 
congestive heart failure with bevacizumab. 
12.1.12. 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. 
12.1.13. 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. 
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. 
12.1.14. Proteinuria 


 
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In clinical trials, the incidence of proteinuria was higher in patients receiving bevacizumab 
in combination with chemotherapy compared to those who received chemotherapy alone. 
Grade 4 proteinuria (nephrotic syndrome) was uncommon in patients with Avastin. In the 
event of Grade 4 proteinuria Avastin treatment should be permanently discontinued. 
Proteinuria should be measured before every infusion of bevacizumab using dipstick. If 
proteinuria is CTCAE grade 0-2, bevacizumab can be given. If proteinuria is CTCAE grade 
3, delay bevacizumab and resume only if grade 2 or less has been attained. If proteinuria 
does not resolve, permanently discontinue bevacizumab.  
12.1.15. Hypersensitivity reactions, infusion reactions 
Patients may be at risk of developing infusion / hypersensitivity reactions. Routine 
premedication is not recommended. However, close observation of the patient during and 
following the administration of bevacizumab is recommended as expected for any infusion 
of a therapeutic humanized monoclonal antibody. If a reaction occurs, the infusion should 
be discontinued and appropriate medical therapies should be administered. 
12.1.16. Osteonecrosis of the jaw (ONJ) 
The overall incidence of ONJ in bevacizumab-treated patients is estimated to be less than 1 
in 10,000. The incidence of ONJ in patients with cancer treated with high doses of 
intravenous bisphosphonates has been estimated to be in the range of 1-10 per 100 patients. 
Of 55 cases, 43 were confounded by concomitant chemotherapy, with concomitant 
bisphosphonate use described in 31 cases (56%). The most frequently used bisphosphonate 
was zoledronic acid which is known to be associated with ONJ. In another 12 cases, 
underlying medical conditions such as surgery, trauma, dental extraction, radiotherapy etc. 
provide alternative explanations of the reported event. 
There are multiple risk factors for the development of ONJ in cancer treated patients, and 
the role of bevacizumab in exacerbating these risk factors is uncertain. A causative role of 
bevacizumab in ONJ is uncertain, and cannot be established. 
12.1.17.  
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 Avastin. 
 
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 Avastin as compared 
to those aged ≤ 65 years treated with Avastin. 


 
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12.2. 
Erlotinib 
12.2.1. Known adverse reactions 
The most common adverse reactions (>20%) in patients with non-small cell lung cancer are 
rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, infection and vomiting. 
12.2.2. Interstitial Lung Disease (ILD) 
There have been infrequent reports of serious ILD-like events (including fatalities) in 
patients receiving erlotinib for the treatment of NSCLC, pancreatic cancer, or other 
advanced solid tumours. In the single-agent study in patients with NSCLC, Study BR.21, 
the incidence of serious ILD-like events (0.8%) was the same in the placebo and erlotinib 
groups. No imbalance was noted in the incidence of serious ILD-like events in the 2 large 
first-line NSCLC studies (Studies OSI2298g and BO16411), which utilized a standard 
platinum-based regimen with or without erlotinib. In the combination study with 
gemcitabine in patients with pancreatic cancer, Study PA.3, the incidence of ILD-like events 
was 2.5% versus 0.4% in the erlotinib plus gemcitabine versus the placebo plus gemcitabine 
groups, respectively. The overall incidence of ILD-like events in approximately 32,000 
erlotinib-treated patients from all studies (including uncontrolled studies and studies with 
concurrent chemotherapy) was approximately 1.1%. When cases from a postmarketing 
surveillance study from Japan are excluded (N = 5860; 3.4% incidence), the incidence from 
rest of world was approximately 0.6%. Some examples of reported diagnoses included 
pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, 
interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory 
distress syndrome, alveolitis, and lung infiltration. Most of the cases were associated with 
confounding or contributing factors such as concomitant/prior chemotherapy, prior 
radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary 
infections. 
In the event of acute onset of new or progressive, unexplained pulmonary symptoms such as 
dyspnea, cough, and fever, erlotinib therapy should be interrupted pending diagnostic 
evaluation. If ILD is diagnosed, erlotinib should be discontinued and appropriate treatment 
instituted as necessary, including corticosteroids. 
12.2.3. Diarrhea 
Diarrhea (sometimes severe) has occurred in patients receiving erlotinib and was usually 
managed by loperamide; however, reduction in the dose of erlotinib was occasionally 
necessary. In the event of severe or persistent diarrhea, nausea, anorexia, or vomiting 
associated with dehydration, erlotinib therapy should be interrupted and appropriate 
measures should be taken to intensively treat the dehydration. Since there have been rare 
reports of hypokalemia and/or acute renal failure (including fatalities), secondary to severe 
dehydration, renal function and serum electrolytes (including potassium) should be 
monitored in this setting. 
12.2.4. Gastrointestinal Perforation 
Patients receiving erlotinib are at increased risk of developing gastrointestinal perforation 
(including fatalities), which was observed uncommonly. Patients receiving concomitant 
anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who 
have prior history of peptic ulceration or diverticular disease are at increased risk. Erlotinib 
should be permanently discontinued in patients who develop gastrointestinal perforation. 


 
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12.2.5. Renal Failure 
Rare cases of acute renal failure or renal insufficiency have been reported (including 
fatalities). Many of these cases have been associated with significant dehydration due to 
diarrhea, vomiting, and/or anorexia. Other possible contributing factors have included 
concomitant medications and/or chemotherapy, pre-existing renal disease, or other medical 
conditions associated with renal disease. Periodic monitoring of renal function in patients 
with these risk factors is recommended. 
12.2.6. Myocardial Infarction/Cerebral Vascular Accident 
In the pancreatic cancer Study PA.3, small numerical imbalances in the incidence of stroke 
and myocardial infarction (including fatalities) were noted in patients receiving erlotinib in 
combination with gemcitabine. A causal relationship to erlotinib has not been established. 
12.2.7. Hepatotoxicity 
Liver function abnormalities, including elevated serum ALT, AST, and/or bilirubin, have 
been observed infrequently with single-agent erlotinib and occasionally with erlotinib in 
combination with concomitant chemotherapy, e.g. gemcitabine. Rare cases of hepatic failure 
(including fatalities) have been reported during postmarketing use of erlotinib. Confounding 
factors for severe hepatic dysfunction have included pre-existing liver disease such as 
cirrhosis, viral hepatitis, hepatocellular carcinoma, hepatic metastases, or concomitant 
treatment with potentially hepatotoxic drugs. Periodic monitoring of liver function is 
recommended. Erlotinib dosing should be interrupted if changes in liver function are severe. 
12.2.8. Patients with Hepatic Impairment 
In a pharmacokinetic study (Study OSI-774-104) in patients with moderate hepatic 
impairment (Child-Pugh B) associated with significant liver tumour burden, 10 of 15 
patients died on treatment or within 30 days of the last erlotinib dose. One patient died from 
hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the 
remaining 8 patients died from progressive disease. Six of the 10 patients who died had 
baseline total bilirubin > 3 x ULN suggesting severe hepatic impairment. None of the deaths 
were considered to be related to erlotinib treatment by the investigators. However, treatment 
with erlotinib should be used with extra caution in patients with total bilirubin > 3 x ULN. 
Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh B or C) should be 
closely monitored during therapy with erlotinib. Erlotinib dosing should be interrupted or 
discontinued if changes in liver function are severe such as doubling of total bilirubin and/or 
tripling of transaminases in the setting of pretreatment values outside normal range. 
12.2.9. Thrombotic Microangiopathy/Microangiopathic Haemolytic Anaemia with Throm-
bocytopenia/Haemolytic Uremic Syndrome 
Isolated reports of microangiopathic haemolytic anaemia with thrombocytopenia and 
haemolytic uremia syndrome (HUS) have been received. All patients received erlotinib and 
gemcitabine concurrently. A causal relationship to erlotinib has not been established. 
12.2.10. Bullous and Exfoliative Skin Disorders 
Bullous, blistering and exfoliative skin conditions have been reported, including very rare 
cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some 
cases were fatal. Erlotinib treatment should be interrupted or discontinued if the patient 
develops severe bullous, blistering, or exfoliating conditions. 


 
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12.2.11. Ocular Disorders 
Very rare cases of corneal perforation or ulceration have been reported during use of 
erlotinib. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis 
sicca or keratitis have been observed with erlotinib treatment and may be potential risk 
factors. Erlotinib therapy should be interrupted or discontinued if patients present with 
acute/worsening ocular disorders such as eye pain. 
Infrequent occurrences of keratitis have been observed during erlotinib treatment. Isolated 
reports of uveitis and orbital cellulitis have been reported in patients receiving erlotinib 
therapy. 
Patients who develop irregular or excessive eyelash growth should be monitored for eye 
symptoms such as eye pain. Careful removal of in-growing/abnormal/elongated eyelashes 
should be considered if increased growth leads to scratching and/or irritation of the cornea. 
Patients with a prior history of ocular disorders or additional identifiable risk factors should 
be closely monitored by a physician. 
13. 
Adverse events and reporting 
13.1. 
Adverse event reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events.  The 
severity and causality will be classified according to the NCI CTCAE Version 4. The 
CTCAE 
is 
available 
for 
downloading 
on 
the 
internet, 
see 
Appendix 
3 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An adverse event is defined as any untoward medical occurrence that occurs from the first 
dose of study medication until 30 days after the final dose, 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. 
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events. 
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. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
1 = Grade 1 
Mild 
2 = Grade 2 
Moderate 
3 = Grade 3 
Severe 
4 = Grade 4 
Life-threatening 
5 = Grade 5 
Fatal 
Note: 
 Report the highest grade observed within one period. 


 
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 Baseline symptoms will be recorded on the CRF and will continue to be followed 
up during treatment. 
 Laboratory abnormalities for non-safety parameters will be documented on the 
form AE from grade ≥ 3 only 
 AEs should not be reported in a narrative description. 
13.2. 
Definition of Serious Adverse Event (SAE) 
13.2.1. SAEs during trial treatment 
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 any of the following:  
 is fatal (any cause) 
 life-threatening, 
 requires or prolongs inpatient hospitalization, 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly or birth defect 
 is a secondary malignancy 
 requires significant medical intervention 
Second (non-NSCLC) malignancies are always considered SAEs, no matter when they are 
diagnosed.  These events should be reported on the Serious Adverse Event Forms. 
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. 
An unexpected adverse event is one that is not listed as a known toxicity of the 
investigational drug in the summary of product characteristics. 
A related adverse event is one for which the investigator assesses that there is a reasonable 
possibility that the event is related to the investigational drug. All adverse events judged as 
having a reasonable suspected causal relationship to the trial medication qualify as adverse 
reactions. 
Events not considered to be serious adverse events are hospitalizations occurring under the 
following circumstances:  
 elective surgery;  
 occur on an outpatient basis and do not result in admission (hospitalization < 24 h);  
 are part of the normal treatment or monitoring of the studied treatment; 
 progression of disease (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, 


 
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unless the event is more severe than expected and therefore the investigator 
considers that their clinical significance deserves reporting). 
13.2.2. SAEs after end of trial treatment 
During the follow-up phase (starting 30 days after end of trial treatment), the following 
events have to be reported as SAE: 
 fatal, life-threatening and other medically significant events possibly, probably or 
definitely related to late effects of trial treatment 
 disabling events 
 second primary cancer 
 congenital anomaly 
 Pregnancy 
In the case of pregnancy occurring during the course of the trial or within 1 year after 
treatment discontinuation, the investigator shall immediately notify this by completing the 
pregnancy reporting form. The investigator shall ensure that the case is followed up to the 
end of the pregnancy and supply a final report on the outcome. 
13.3. 
Definition of Serious Adverse Drug Reaction (SADR) 
SADRs are all SAEs considered to be related (possibly, probably, definitely) to the trial 
treatment. 
13.4. 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a serious adverse reaction that is assessed as unexpected on the basis of the 
applicable Swiss product information, the European summary of product characteristics, and 
the Investigators’ Brochure. 
13.5. 
Definition of Adverse Events of Special Interest (AESI)  
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the Products by either Roche or a Regulatory Authority.  
The following adverse events are of special interest and must be documented if observed. 
AESI as specified below must be documented and reported by submitting the completed 
SAE Report Tab (initial and follow-up) in the RDE system within 10 days after knowledge 
of the event (Indicate in “Description” section if “non-serious adverse event of special 
interest” yes or no). 
 Interstitial lung disease (ILD)-like events 
 Haemorrhage (> or equal to grade 3), with a focus on haemoptysis (> or equal to 
grade 2)  and CNS bleeding (> or equal to grade 2) 
 Hypertension  
Patients should be monitored for the development of new hypertension or 
worsening of a pre-existing hypertension by frequent measurements of blood 
pressure and should be handled as follows: 
G1: Prehypertension (systolic BP 120 - 139 mm Hg or diastolic BP 80 - 89 mm 
Hg): record as AE, (continue bevacizumab) 


 
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G2: Stage 1 hypertension (systolic BP 140 - 159 mm Hg or diastolic BP 90 - 99 
mm Hg); medical intervention indicated; recurrent or persistent (≥ 24 hrs); 
symptomatic increase by > 20 mm Hg (diastolic) or to > 140/90 mm Hg if 
previously within normal limits; monotherapy indicated 
Record as AE and on SAE tab indicate in Description section “non-serious adverse 
event of special interest”: yes 
G3 hypertension: Stage 2 hypertension (systolic BP >= 160 mm Hg or diastolic BP 
>=100 mm Hg); medical intervention indicated; more than one drug or more 
intensive therapy than previously used indicated,  
Record as AE and on SAE tab indicate in Description section “non-serious adverse 
event of special interest”: yes/no (according to seriousness) 
> G3 hypertension:  record as AE and always report as SAE. 
 Proteinuria  
G1: Record as AE 
G2 (2+ (dipstick): 1.0-3.4g/24hrs): Record as AE and on SAE tab  indicate in 
Description section “non-serious adverse event of special interest”: yes 
(Assess 24-hour-urine before each scheduled dose until ≤ 1g/24hrs). 
 G3 proteinuria: Record as AE and on SAE tab indicate in Description section 
“non-serious adverse event of special interest”: yes/no (according to seriousness)  
(Assess 24-hour-urine before each scheduled dose until ≤ 1g/24hrs). 
 Arterial (any grade)/venous (> or equal to grade 3)  thromboembolic events  
 Wound healing complications (> or equal to grade 3) 
 Congestive heart failure (> or equal to grade 3) 
 Fistulae (non GI or abscess > or equal to grade 2) 
 Gastrointestinal perforations, abscesses and fistulae (any grade)  
 Reversible posterior leucoencephalopathy syndrome (any grade) 
13.6. 
Reporting SAEs/AESI 
Any SAE must be reported by submitting the completed SAE Initial Report Tab in the RDE 
system within 24 hours of first knowledge of the event (= date of awareness). 
Any AESI must be reported by submitting the completed SAE Initial Report Tab in the 
RDE system within 10 days after first knowledge of the event (= date of awareness). 
Submission is done via the electronic data capture system, or in case of unavailability, by 
sending the SAE form by fax to the ETOP Safety Office: 
+41 31 389 92 29 
The SAE/AESI outcome must be reported within 14 days after onset by online submitting 
the SAE Follow-up Report Tab. In case the SAE/AESI is reported as ongoing after 14 days, 
the follow-up report has to be submitted again with the final outcome. 
In case of SAE/AESI submission by fax, the originals of the SAE forms (both initial and 
follow-up report) will be collected by the monitor. The centres keep a copy for their own 
records. 


 
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The ETOP Safety Office will forward each SAE/AESI to the trial chairs and to Roche and 
notify principal investigators of any SADR meeting the criteria for expedited reporting 
(SUSAR) within the timelines specified in GCP. 
The local Ethics committee must be informed by the principal investigator about local 
SAEs. 
The ETOP Safety Office will inform Roche and other appropriate persons about all 
SAEs/AESIs related to trial medication (per either investigator or ETOP Safety Office 
review) within 24 hours of receipt. 
The ETOP Safety Office will record the SAE/AESI and prepare a summary report of all 
SAEs received at the end of each month. Principal Investigators will receive the summary 
report on a monthly basis. 
14. 
Endpoints definition 
14.1. 
Progression-free survival  
This is the primary endpoint. It is defined as the time from the date of enrolment until 
documented progression or death, whichever occurs first. 
14.2. 
Time to treatment failure  
Defined as time from the date of enrolment to discontinuation of treatment for any reason 
(including progression of disease, treatment toxicity, refusal and death). 
14.3. 
Overall survival  
Defined as time from the date of enrolment until death from any cause. 
14.4. 
Objective response 
Objective response is defined as best overall response (CR or PR) across all assessment 
time-points according to RECIST Criteria 1.1 (see Appendix 2), during the period from 
enrolment to termination of trial treatment.  
14.5. 
Disease control 
Disease control is defined as achieving 
 objective response 
 or stable disease for at least 6 weeks 
14.6. 
Duration of response 
Defined as interval from the date of first documentation of objective response by RECIST to 
the date of first documented progression or relapse.  
14.7. 
Toxicity 
Adverse events classified according to NCI CTCAE version 4.  


 
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15. 
Biological material and translational research 
15.1. 
Mandatory evaluations 
15.1.1. Central pathology review 
The work of the pathologist is basic to the success of all studies.  Each participating site 
should identify a pathologist responsible for trial patients. The pathologist determines the 
diagnosis of non-squamous NSCLC in the biopsy and/or primary resection specimen. The 
central review pathologist will review the submitted specimens and complete the central 
pathology review. 
Central pathology review reports will be available to institution pathologists who wish to 
see them.  Central pathology review will include histopathological parameters (tumour type 
and grade). The blocks will be available for prospective and retrospective studies approved 
by ETOP. 
Central review for all patients will take place at 
Pangaea Biotech SA 
USP Dexeus Institute 
Calle Sabino Arana 5-9 
08028-Barcelona, Spain 
Objectives: 
 Central pathology review  
 Central EGFR mutation testing for all pts 
 Banking of tumour material for future, not yet specified research 
15.1.2. Central EGFR testing 
EGFR mutation status will be determined at the local sites in most cases. For these cases, 
the reference laboratory will do a central determination. The results will be communicated 
to sites.  
Procedures for central EGFR testing: 
 EGFR sensitive mutations will be run according to Pangaea Biotech’s ISO15189 
(DNA sequencing for both exon 19 deletions and exon 21 L858R, plus GeneScan 
for Exon 19 and TaqMan for Exon 21-L858R).  
 T790M will be analyzed using a PNA probe plus TaqMan assay.  
 BRCA1/AEG1 analysis will be performed in RNA isolated from laser capture 
microdissected tumour tissue and quantified using relative expression by Real Time 
Quantitative PCR. Note that BRCA1 analysis in tumour tissues will also be 
performed according to Pangaea Biotech’s accreditation (ISO15189) 
Certified laboratory: 
Pangaea Biotech SA 
USP Dexeus Institute 
Calle Sabino Arana 5-9 
08028-Barcelona, Spain 
With the support of: 


 
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Molecular Biology Laboratory 
Medical Oncology Service 
Hospital Germans Trias i Pujol 
Catalan Institute of Oncology 
Ctra Canyet, s/n 
Badalona, Spain 
Rafael Rosell (rrosell@iconcologia.net) 
Miguel Angel Molina (mamolina@pangaeabiotech.com) 
15.2. 
Optional evaluations 
15.2.1. BRCA1 and AEG-1 
BRCA1 mRNA expression and AEG-1 will be determined on FFPE material (only approx. 
60% of patients will have enough tumour tissue for BRCA1/AEG-1 analysis). 
15.2.2. Biomarker monitoring on serum and plasma samples 
Serum and plasma samples are required for biomarker monitoring and to detect molecular 
alterations corresponding to the tissue. 
15.3. 
Submission of material 
The tissue and blood samples collected during the conduct of the trial must be marked with 
the patient identifier issued by the RDE system and shipped to the central reference 
laboratory (Pangaea Biotech) and will be stored there for an unlimited time. This precious 
material will be used for central quality assurance and made available for translational 
research projects. 
15.3.1. Submission of FFPE material 
The following items should be submitted for all patients: 
1. Pathology Report from primary surgery, if applicable 
2. Tumour block from primary surgery, if applicable  
3. Pathology Report from diagnosis of advanced / metastatic disease, if available 
4. Tumour or cell block from advanced / metastatic disease, if available 
Recommended, but not required:  
5. Tumour or cell block and pathology report from re-biopsy at progression 
As an alternative to the submission of a complete block, at least 5 sections from the block 
mounted on penmembrane slides are acceptable. 
Paraffin-embedded cell blocks produced from malignant effusion are a valuable alternative 
to tumor blocks. Cytology smears alone are not accepted in this trial. 
There is no limitation regarding the age of the tumor sample in this trial. However, recent 
samples are preferred and investigators should consider a new biopsy in patients relapsing 
after surgery.  
The tissue blocks may be returned to the site upon request after four 1mm cores have been 
taken for preparing tissue micro-arrays (TMAs).   


 
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All reports, slides, and blocks must be marked with the identification number issued by the 
RDE system and the pathology number, and any other identification should be erased or 
blackened. 
Please ensure that the blocks are carefully packaged as otherwise they could easily get 
damaged during transport. 
Samples have to be sent to the national reference laboratory or directly to: 
Pangaea Biotech SA 
USP Dexeus Institute 
Calle Sabino Arana 5-9 
08028-Barcelona, Spain 
according to specific instructions in the BELIEF procedures manual. 
15.3.2. Submission of serum and plasma samples 
Blood collection and serum preparation (see BELIEF procedures manual): 
 Take one SST gel containing tube of 8-10 ml blood  
 Keep the tubes for 15-20 minutes at room temperature (until clotting). 
 Centrifuge the tubes (1500 g  x 10 minutes) and collect the upper phase 
(supernatant) that corresponds to the serum fraction. Put the supernatant (serum) 
into appropriately labelled cryovials.  
Blood collection and plasma preparation (see BELIEF procedures manual): 
 
Take one EDTA containing tube of 8-10 ml blood 
 
Invert tube several times 
 
Centrifuge the tube (1500 g  x 10 minutes) and collect the upper phase 
(supernatant) that corresponds to the plasma fraction. Put the supernatant (plasma) 
into appropriately labelled cryovials.  
Serum and plasma samples should be immediately frozen at -80ºC (if a -80ºC is not 
available, please contact ETOP, see BELIEF procedures manual) and kept at the 
participating site until shipment. Shipments will be organized centrally. 
15.4. 
Banking of biological material 
The ETOP and SCLG have established a central repository for tissue blocks/slides as well as 
serum and plasma samples from every patient enrolled in this trial.  The required 
pathological material (described in the previous section) is submitted to, catalogued, and 
maintained in  
Pangaea Biotech SA 
USP Dexeus Institute 
Calle Sabino Arana 5-9 
08028-Barcelona, Spain 
16. 
Trial procedures 
This section gives an overview of procedures, clinical and laboratory evaluations and 
follow-up investigations. 


 
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The trial consists of the following stages:  
16.1.1. Screening: the screening period must occur within 28 days before registration in the 
RDE system. Baseline evaluations must be done within 28 days prior to 
registration. Please consult the BELIEF procedures manual for a flow chart. 
16.1.2. Treatment phase: 
Drug therapy is to begin within 7 days of enrolment. 
Bevacizumab: 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days), and 
erlotinib: 150 mg p.o., daily until progression or unacceptable toxicity. 
Upon disease progression or completion of trial treatment, further therapy will 
be at the discretion of the treating physician. 
16.1.3. End of treatment: an end of treatment visit will occur 30 - 40 days following the 
last dose of study drug. 
16.1.4. Follow-up period: every 3 months following end of treatment visit until death, 
patients will be followed up to document outcome and further lines of treatment. 
Between end of treatment and progression, the visit schedule needs to follow the 
one corresponding to the treatment phase, see section 16.7. 
16.2. 
Baseline evaluations (within 28 days prior to registration) 
16.2.1. Medical history including symptoms, smoking history, medications, comorbidities 
and allergies 
16.2.2. Physical examination including blood pressure [mmHg], ECOG performance status 
(see definition in BELIEF procedures manual), and body weight [kg] 
16.2.3. Baseline symptoms 
16.2.4. Haematology: haemoglobin, leukocytes, platelets 
16.2.5. Renal function: serum creatinine and creatinine clearance calculated according to 
Cockroft-Gault, urine dipstick for proteinuria 
16.2.6. Hepatic function: ALT, AST, AP, Bilirubin 
16.2.7. Coagulation: INR 
16.2.8. Pregnancy test for women with childbearing potential 
16.2.9. CT scan of thorax and upper abdomen with i.v. contrast (alone or in combination 
with PET) to determine measurable disease according to RECIST v1.1 (at least one 
lesion outside of irradiated areas that can be measured in at least one dimension as 
≥ 10 mm, or ≥ 15 mm in case of lymph nodes). In the presence of clinically 
suspected metastases outside the thorax (e.g. brain, bone or lower abdomen), 
additional CT of the affected body part is recommended. 
16.2.10. CT scan of brain is not mandatory and only recommended in case of clinically 
suspected brain metastasis 


 
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16.3. 
Before enrolment 
16.3.1. For central confirmation of EGFR exon 19 deletion (del19) or exon 21 mutation 
(L858R), send to central laboratory: 
 1 block of FFPE tissue from biopsy, surgery or cytology 
 Pathology report 
 Local EGFR mutation report (if applicable) 
16.4. 
Before start of treatment 
16.4.1. Take a blood sample for routine evaluations plus serum and plasma samples for 
translational research 
16.5. 
Routine evaluations before and during trial treatment  
On day 1 of every 3-week treatment cycle: 
16.5.1. Recording of symptoms / adverse events 
16.5.2. Physical examination including blood pressure, performance status, and body 
weight 
16.5.3. Haematology: haemoglobin, neutrophils, platelets 
16.5.4. Serum creatinine 
16.5.5. Hepatic function: ALT, AST, AP, Bilirubin 
16.5.6. Urine dipstick 
16.6. 
Trial-specific evaluations during treatment 
16.6.1. Tumor assessments will occur more frequently during the first cycles, and be 
phased out especially for patients who stay on treatment for a prolonged period. 
They should be performed within 72h before the start of the subsequent cycle. 
Prior to the start of cycles 3, 5, 7, 10, 13, 16, 20, 24, 28 and every 4 cycles until 
progression (weeks 6, 12, 18, 27, 36, 45, 57, 69, 81; and then every 12 weeks): CT 
thorax and upper abdomen 
16.6.2. Blood serum and plasma samples for translational research have to be taken after 6 
weeks (time of first tumor evaluation). 
16.7. 
Evaluations in the follow-up phase before progression 
Patients who discontinue treatment before progression should have the following 
assessments at the same timepoints as patients still on treatment (weeks 6, 12, 18, 27, 36, 45, 
57, 69, 81; and every 12 weeks until progression): 
16.7.1. Physical examination 
16.7.2. CT thorax and upper abdomen (plus further imaging if applicable) 
16.7.3. Documentation of further treatments 


 
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16.8. 
Evaluations at progression 
Each patient will receive trial treatment until documented progression. At progression, do 
the following: 
16.8.1. CT thorax and upper abdomen, document progression on the respective CRF 
16.8.2. Blood serum and plasma samples for translational research 
16.8.3. Tumour re-biopsy should be considered for testing of further predictive markers 
and translational research at the central reference laboratory (Pangaea Biotech) 
16.9. 
End of treatment visit 
At the end of the trial treatment and irrespective of the reason for stopping treatment, a 
post treatment visit at the center is to be scheduled after 30 (to 40) days following last 
treatment day. The following procedures should be performed: 
16.9.1. Recording of symptoms/ adverse events 
16.9.2. Physical examination including blood pressure 
16.9.3. Haematology: haemoglobin, neutrophils, platelets 
16.9.4. Hepatic function: ALT, AST, AP, Bilirubin 
16.9.5. Serum creatinine 
16.9.6. Urine dipstick 
16.9.7. CT thorax and upper abdomen, if not done within the last 30 days 
16.10. Evaluations after progression 
Patients with progression will end trial treatment and should have documented  
 survival and  
 further lines of treatment  
every 12 weeks up to 3 years after the inclusion of the last patient. 


 
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17. 
Case report forms and documentation 
17.1. 
Case report forms schedule 
CRFs will only be available on-line at the Remote Data Entry (RDE) facility. No paper 
forms will be used, with the exception of a paper SAE form in case of system unavailability.  
Tab in the RDE 
To be completed 
Identification 
At screening, prior to enrolment 
Eligibility 
At screening, prior to enrolment 
Baseline 
At enrolment  
Cycle  
At the end of each cycle and at the end of treatment visit 
(30 - 40 days post trial treatment) 
Tumour assessment  
At baseline and at start of cycles 3, 5, 7, 10, 13, 16, 20, 
24, 28; every 12 weeks until progression in case of 
treatment discontinuation; at progression  
Patients who discontinue treatment before progression: at 
weeks 6, 12, 18, 27, 36, 45, 57, 69, 81; and every 12 
weeks until progression 
At end of treatment visit (if not done within the past 30 
days) 
End of treatment 
30 - 40  days after last treatment day 
Adverse event  
At the end of each cycle; 
At the end of treatment visit (30 - 40 days post trial 
treatment) 
Pregnancy  
At first documentation of pregnancy; 
At end of pregnancy 
At end of treatment visit (if applicable) 
SAE initial report  
Within 24h of occurrence of SAE to RDE, or via fax to 
ETOP safety office 
SAE follow-up report  
Within 14 days after onset; in case the SAE is reported as 
ongoing after 14 days, the follow-up report has to be 
submitted again with the final outcome 


 
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Tab in the RDE 
To be completed 
Follow-up  
Patients who discontinue treatment before progression: at 
weeks 6, 12, 18, 27, 36, 45, 57, 69, 81;  
After progression: At every follow-up visit, every 12 
weeks for 3 years 
Consult the BELIEF Procedures Manual for detailed instructions on how to complete, 
save and submit the electronic CRFs. 
18. 
Statistical considerations  
18.1. 
Primary objective 
The goal of the primary analysis is to obtain an estimation of PFS. All eligible and treated 
patients will be included into this analysis. The overall PFS and the PFS according to 
T790M status will be determined. The EAST software package is used for sample size 
calculations (EAST 5, Version 5.4.0.0, Cytel Inc. 2010). 
We hypothesize that the trial treatment with bevacizumab and erlotinib will result in 
 An increase of the median PFS to 18 months for patients with EGFR T790M 
mutation 
 A median PFS of approximately 18 months or more in patients without EGFR 
T790M mutation 
18.2. 
Sample size determination 
The sample size calculations are based on the percentage of patients with EGFR T790M 
mutation and corresponding median PFS by EGFR T790M mutation under erlotinib 
treatment, as presented in the recently published results by Rosell et al (15). 
The trial encompasses two phase II substudies run in parallel, and requires a total of 102 
patients: 
 substudy 1: 35 patients with EGFR T790M mutation  
 substudy 2: 67 patients without EGFR T790M mutation. 
The first substudy follows Simon’s two-stage design and a decision can be reached at the 
first stage, while the second substudy follows Fleming’s single stage design.  
Substudy 1: Patients with EGFR T790M mutation  
The primary objective is the estimation of PFS in patients with EGFR T790M mutation, 
treated with bevacizumab and erlotinib. The median PFS is expected to improve to 18 
months. 
A 12-month PFS of 40%, corresponding to a median of 9 months, will be considered 
inadequate (since a 12 month median PFS is achieved by erlotinib alone), while the target 
value will be a 12-month PFS of 63% (corresponding to a median PFS of 18 months, similar 
to the one observed with erlotinib alone in the subgroup of patients without EGFR T790M 
mutation). Simon’s optimal two-stage design (43), with a significance level of 5% and 


 
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power of 80%, will be used to test the null hypothesis that the 12 month PFS≦40% versus 
the alternative that PFS≧63%.  
If in the first stage from a total of 8 patients, 4 or more patients reach 12 months without a 
progression-defining event, then the substudy will proceed so as to evaluate the 12-month 
PFS for a total of 35 patients. If 19 or more patients reach 12 months without a PFS event, 
treatment with the combination of erlotinib and bevacizumab will warrant further study in a 
Phase III trial in the subgroup of patients with EGFR T790M mutation.  
It is anticipated that the decision on the first stage of substudy 1 will not be reached before 
the study is fully accrued, since 12 months of follow-up will be required for at least 8 
patients with EGFR T790M mutation, while the anticipated full study accrual will be 
completed within 12 months. 
In case, the EGFR T790M mutation is identified on only 30% of the patients (instead of the 
assumed 35%), the decision that can be reached at the end of the study with significance 
level of 5% and power of 80% will correspond to an alternative of PFS≧66% or a median 
PFS≧20 months. 
Substudy 2: Patients without EGFR T790M mutation 
The primary objective is the estimation of PFS in patients with EGFR mutation without 
T790M mutation, treated with bevacizumab and erlotinib. The median PFS is expected to be 
approximately 18 months or higher. 
A 12-month PFS of 50% will be considered inadequate (since 50% is achieved by erlotinib 
alone in the subgroup of patients with EGFR T790M mutation), while the target value will 
be a 12-month PFS of 65% (corresponding to a median PFS of 19 months, similar to the one 
observed with erlotinib alone in the subgroup of patients without EGFR T790M mutation). 
A sample size of 67 patients is required by Fleming’s single stage design (44), with 
significance level of 5% and power of 80%, to test the null hypothesis that the 12-month 
PFS≦50% versus the alternative that PFS≧65%.  
Update October 2013: 
In patients recruited up to September 2013, the observed proportion with EGFR T790M 
mutation is higher than originally anticipated at the design stage due to the use of an 
updated, more sensitive assay. By end of January 2014, the evaluation of PFS will be 
performed for the patients with EGFR T790M mutation enrolled in the first stage of the 
substudy 1.  If based on that evaluation the substudy 1 continues into the second stage, the 
trial will accrue 102 patients as planned. Design characteristics of the two substudies will be 
modified appropriately to accommodate the observed proportion of EGFR T790M mutation.  
An additional analysis based on the original, less sensitive assay will also be performed.  
18.3. 
Evaluation of primary and secondary objectives 
The total study duration will be approximately 48 months: 12 months recruitment period 
including a 3 months run-in period, and at least 36 months treatment and follow-up period. 
The final evaluation of both substudies will be done within 6 months after the last visit of 
the last patient, approximately 54 months after the inclusion of the first patient. 
The primary analysis will be performed separately in the two substudies. The primary 
efficacy analysis will include all eligible patients with at least two treatment cycles 
administered (= efficacy cohort).  Patients who have been recruited into the trial but are not 
evaluable for efficacy will be replaced (up to 10% of total sample size). 


 
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The two subgroups will also be compared with respect to efficacy and tolerability endpoints. 
A secondary analysis will be performed for all registered patients with centrally confirmed 
EGFR mutation, and will be stratified by EGFR T790M mutation status.  
All secondary endpoints will be described for the whole cohort and the two subgroups 
separately. 
Progression free survival (PFS), time to treatment failure (TTF) and overall survival (OS) 
will be estimated by the Kaplan Meier method and compared between the two subgroups by 
means of the logrank test. 
Clinical efficacy will be further described by objective response rate (ORR), disease control 
rate (DCR) and duration of response (DR).   
Safety and the tolerability of the erlotinib and bevacizumab combination will be described 
by tabulation of the CTCAE V4 grade. The safety cohort will encompass all patients who 
have received at least one dose of trial treatment. 
The correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with PFS will 
be evaluated by univariate and multivariate Cox proportional hazards regression.  
The longitudinal development of EGFR mutations (including T790M) in serum and plasma 
will be evaluated descriptively. 
The relation of molecular biomarkers to EGFR TKI and bevacizumab will be explored. 
The feasibility of re-biopsies at the time of progression will be reported. Gene-expression 
arrays for decision-making for second-line treatment will be done in case of available 
material.  
The feasibility of recommending customized second-line chemotherapy based on BRCA1 
and AEG-1 mRNA levels will be explored and reported. 
18.4. 
Early stopping rules 
Substudy 1 contains an early look at the end of the first stage, when 8 patients have reached 
12 months follow-up. If 3 or less patients reach 12 months without a progression-defining 
event, then the results of the substudy will be reported immediately and the Steering 
Committee will decide whether the patients still on treatment should stop it. Otherwise the 
substudy will continue as planned until the final evaluation. 
19. 
Criteria for termination of the trial 
19.1. 
Discontinuation of protocol treatment for individual patients  
Protocol treatment should be stopped in the following situations: 
 Disease progression 
 Occurrence of unacceptable toxicities. Stopping protocol treatment is determined 
by medical judgment of the treating physician. 
 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 
of protocol therapy. Note: Diagnosis of another neoplastic disease (second 
malignant tumor) does not mandate a stop of trial therapy, patients may continue to 


 
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receive protocol treatment after appearance of a second primary tumor, 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. 
19.2. 
General criteria for termination of the trial 
The trial will be stopped if early analyses of the study data show a significant harm, by 
decision of ETOP or Trial Steering Committee. The trial can be terminated at any time for 
safety reasons, insufficient accrual, emerging new data impacting the scientific value of the 
trial or ethical grounds by Roche or ETOP after consultation of the Trial Steering 
Commitee. 
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 timepoint 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 ETOPdata User Manual, 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. 
20. 
Ethics approval procedures and Patient Informed Consent 
The Investigator will ensure that this study 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 study must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” 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 
The protocol and the use of biological samples from patients must have the approval of a 
properly constituted committee or committees responsible for approving clinical studies.  
The 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 registration of the first patient. 


 
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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 
There will be local, regional and country specific differences in the regulations concerning 
the use of biological samples for research.  Each site will be expected to notify ETOP of the 
local regulations and seek the relevant approvals.   
If applicable, in addition to the approval of the Ethics Committee according to national 
legislation, the protocol, other 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 Center 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." 
One signed and dated 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 inclusion to 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 
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, plasma 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. By signing this 
protocol, the investigator agrees to conduct the trial in accordance with Good Clinical 
Practice 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 I), 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 Institutional Review Board/ 
Local Ethics Committee 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.  


 
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20.4. 
Confidentiality/Data Protection 
The samples and data collected will be coded to protect patient confidentiality. Each patient 
will have a unique identifier assigned by the RDE facility. 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 the pertinent Ethics Committee (ERB/IRB) may have access to 
patient data on-site. IBCSG audit or monitoring personnel will also have access to such data 
on-site. 
20.5. 
Duration of study 
Data will be kept in the central database for an unlimited time. The ETOP Foundation 
Council will decide about the eventual discontinuation of this study and deletion of data.  
21. 
Governance and administrative issues 
21.1. 
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 chair and co-chair, trial coordinators, trial 
statisticians, SLCG and ETOP officials, representatives from some participating institutions 
and groups, and a representative from Hoffmann-La Roche. 
21.2. 
Publication 
The results of the trial will be published according to the ETOP publication guidelines 
(appendix 4) 
21.3. 
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. 
21.4. 
Quality Assurance 
ETOP conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The 
Trial Data Manager reviews each CRF as it is received. In addition, the ETOP Medical 
Reviewer reviews each case at specific timepoints.  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 health authority inspectors after 
appropriate notification. 


 
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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 study 
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 IP, compliance with protocol, drug accountability, 
concomitant therapy use, quality of data and storage of plasma and serum samples. 
21.5. 
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 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/REB it cannot be implemented. All protocol deviations will be recorded. 
21.6. 
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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Biometrics, 1982; 38:143-151. 
 

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BELIEF 
ETOP 2-11 
 
An open-label phase II trial of erlotinib and bevacizumab in patients with 
advanced non-small cell lung cancer and activating EGFR mutations 
Bevacizumab and ErLotinib In EGFR mut + NSCLC 
A clinical trial of ETOP 
Coordinated by Grupo Español de Cancer de Pulmón GECP 
(Spanish Lung Cancer Group) 
 
STATISTICAL ANALYSIS PLAN FOR FINAL ANALYSIS  
 
 
SAP VERSION 
1.2 
SAP VERSION DATE 
06 November 2015 
TRIAL STATISTICIANS 
ETOP: Urania Dafni, Marie Kassapian 
SLCG: Maria Sanchez Ronco  
TRIAL PRIMARY INVESTIGATORS 
Rafael Rosell  
Rolf Stahel 
SAP AUTHOR 
Xanthi Pedeli, Zoi Tsourti 
APPROVED BY 
Urania Dafni 
 
 


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TABLE OF CONTENTS 
 
ABBREVIATIONS ...................................................................................................................................... 4 
1. 
INTRODUCTION ............................................................................................................................... 5 
1.1 
Preface .................................................................................................................................... 5 
1.2 
Hypotheses ............................................................................................................................. 5 
1.3 
Purpose of the present Statistical Analysis Plan ..................................................................... 6 
2. 
PLANNED ANALYSES ........................................................................................................................ 7 
3. 
GENERAL CONSIDERATIONS ........................................................................................................... 8 
3.1 
Timing of Analysis ................................................................................................................... 8 
3.2 
Analysis Populations ............................................................................................................... 8 
3.3 
Missing Data ............................................................................................................................ 8 
3.4 
Multiple Comparisons / Multiplicity ....................................................................................... 8 
3.5 
Overall Cohort and Substudy Cohorts .................................................................................... 8 
4. 
SUMMARY OF STUDY DATA ............................................................................................................ 9 
4.1 
Primary and secondary endpoints .......................................................................................... 9 
4.2 
Patient accrual and baseline characteristics ......................................................................... 11 
5. 
EFFICACY ANALYSIS ....................................................................................................................... 13 
6. 
SAFETY ANALYSIS .......................................................................................................................... 14 
7. 
TECHNICAL DETAILS ...................................................................................................................... 16 
8. 
LISTING OF TABLES AND FIGURES ................................................................................................. 17 
REFERENCES .......................................................................................................................................... 27 
APPENDIX .............................................................................................................................................. 28 
IMPORTANT INFORMATION AS DESCRIBED IN THE PROTOCOL ........................................................... 28 
A.1 STUDY OBJECTIVES AND ENDPOINTS ............................................................................................. 28 
A.1.1 
Study Objectives................................................................................................................ 28 
A.1.2 
Endpoints .......................................................................................................................... 29 
A.1.3 
Statistical Hypotheses ....................................................................................................... 29 
A.2 STUDY METHODS ............................................................................................................................ 30 
A.2.1 
General Study Design and Plan ......................................................................................... 30 
A.2.2 
Patient Selection ............................................................................................................... 30 
A.2.3 
Patient Screening and Registration ................................................................................... 31 


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A.2.4 
Early Stopping Rules .......................................................................................................... 31 
A.2.5 
Study Variables.................................................................................................................. 31 
A.2.6 
Primary Comparisons ........................................................................................................ 34 
A.3 SAMPLE SIZE ................................................................................................................................... 35 
A.4 ADVERSE EVENTS ............................................................................................................................ 36 
A.4.1 
Adverse Events (AE) .......................................................................................................... 36 
A.4.2 
Severity Grade ................................................................................................................... 37 
A.4.3 
Serious Adverse Events (SAE) ............................................................................................ 37 
A.4.4 
Adverse Events of Special Interest (AESI) ......................................................................... 39 
 
 
 


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ABBREVIATIONS 
AE 
Adverse Event 
AEG-1 
Astrocyte Elevated Gene 1 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Transaminase 
AP 
Alkanine Phosphatase 
AST 
Aspartate Transaminase 
BRCA1 
Breast Cancer 1, early-onset 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Disease Control 
DCR 
Disease Control Rate 
DR 
Duration of Response 
EGFR 
Epidermal Growth Factor Receptor 
FFPE 
Formalin Fixed, Paraffin Embedded 
INR 
International Normalized Ratio 
NSCLC 
Non-Small Cell Lung Cancer 
OR 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria In Solid Tumours 
SAE 
Serious Adverse Event 
TTD 
Time to treatment Discontinuation 
TTF 
Time to Treatment Failure 
ULN 
Upper Limit of Normal lab value 
 
 


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1. INTRODUCTION 
1.1 Preface 
Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) 
mutations (del 119 or L858R) show an impressive progression-free survival (PFS) between 9 and 14 months 
when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. 
The leading hypothesis of the current project is that PFS could be influenced both by the pre-treatment EGFR 
T790M mutation and by components of DNA repair pathways. To investigate this hypothesis, a model of 
treatment is proposed whereby a combined treatment with erlotinib plus bevacizumab is supposed to benefit 
patients with EGFR mutations (single or with T790M). The trial encompasses two phase II substudies run in 
parallel, as shown in Figure 1. The first substudy follows Simon’s two stage design and a decision can be 
reached at the first stage, while the second substudy follows Fleming’s single stage design. 
 
 
Figure 1. Trial’s design flowchart 
 
1.2 Hypotheses  
Patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated 
with erlotinib plus bevacizumab. More specifically, the hypotheses of interest are that the trial treatment with 
erlotinib plus bevacizumab will result in: 
▪ 
an increase of the median PFS to 18 months for patients with EGFR T790M mutation; 
▪ 
a median PFS of approximately 18 months or more in patients without EGFR T790M mutations. 
 
 
 


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1.3 
Purpose of the present Statistical Analysis Plan  
The purpose of the present Statistical Analysis Plan (SAP) is to provide an analytic and solid 
framework for the primary endpoint evaluation of the BELIEF study (final study), after all 
enrolled patients have reached one year of follow-up. 
A comprehensive description of all the analyses planned for the study is provided in section 
“Planned Analyses”.  
More details on the analysis, in terms of methods, definitions and reporting, are described in 
detail in Sections 3-8. 
The overall objectives and methods of the study, as dictated by its protocol, may be found in 
the Appendix. 
 
 
 
 


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2.  
PLANNED ANALYSES 
The total study duration is estimated to be approximately 48 months: 12 months’ recruitment 
period including a 3 months run-in period, and at least 36 months treatment and follow-up 
period, since, according to the protocol, patients will be followed until death. 
The analyses planned are: 
• Periodic interim analyses for reviewing safety. 
• Formal interim efficacy analysis for evaluating the designed stopping rule of the 
substudy 1 of the trial. 
• Final analysis, including efficacy as well as safety analysis of the results of the clinical 
trial. 
Interim analyses will be conducted, approximately every 6 months, for reviewing the safety 
of the study. ETOP’s Independent Data Monitoring Committee (IDMC), consisting of scientific, 
clinical and biostatistical experts, is responsible for evaluating interim results. Only the IDMC 
is authorised to review interim efficacy and safety analysis results by subgroup of the study. 
The committee is responsible for reviewing accumulating safety data at regular intervals 
(adverse events), monitoring the overall study conduct (e.g. accrual rate), deaths and 
response, and making recommendations as to whether continuing study treatment and 
enrolment is scientifically and ethically appropriate (study is conducted in a manner that does 
not expose participants to undue risk).  
Particularly for substudy1 of EGFR with T790M mutation, a formal interim efficacy analysis 
is planned, according to the trial design, to be conducted after the first 8 patients reach 12 
months of follow-up (if not died or lost to follow-up). According to Simon’s two-stage design, 
in the first-stage, if from the total of 8 patients, 4 or more patients reach 12 months without 
a progression-defining event, then the substudy proceeds so as to evaluate the 12-month PFS 
for a total of 35 patients (initially planned sample size for substudy1).  
In the Simon’s 2nd stage evaluation, the analysis of the (first) 35 evaluable patients reaching 
one-year follow-up will be performed: according to the design if at least 19 out of the 35 
patients reach one-year from enrollment without a progression defining event, treatment 


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with the combination of erlotinib and bevacizumab would be considered promising in the 
subgroup of patients with EGFR T790M mutation.  
 
3. GENERAL CONSIDERATIONS  
3.1 
Timing of Analysis 
The final primary evaluation for all patients of the clinical trial (EGFR with or without T790M 
mutation), will be performed when at least one year from enrolment of all patients is reached. 
3.2 
Analysis Populations 
Efficacy Cohort 
The efficacy cohort will be consisted of all eligible patients enrolled in the trial (ITT 
population). The efficacy cohort will be used for the assessment of patient baseline 
characteristics and all efficacy endpoints. Efficacy analysis will be performed by substudy, as 
well as overall for all eligible, for efficacy, patients. 
Safety Cohort 
The safety cohort will encompass all patients who have received at least one dose of trial 
treatment.  
3.3 
Missing Data 
Missing values will not be replaced by any statistics calculated over non-missing data. 
3.4 
Multiple Comparisons / Multiplicity 
Apart from the adjustment made for the formal planned interim analysis for the subgroup of 
EGFR with T790 mutation patients, no additional adjustments will be made in this study. 
3.5 
Overall Cohort and Substudy Cohorts 
All analyses will be performed overall for all patients in the efficacy or safety cohort, as well 
as for the 2 subgroups of patients corresponding to the two substudies, i.e. patients with EGFR 
with or without T790M mutation. 
Secondary analysis based on subgroups of EGFR mutations Exon19/Exon21 will also be 
performed. 
 


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4. SUMMARY OF STUDY DATA 
4.1  Primary and secondary endpoints 
The primary endpoint according to the study protocol, is the progression-free survival (PFS) 
for all enrolled patients. PFS is defined as the time from the date of enrolment until 
documented progression or death, whichever occurs first.  
 
Secondary endpoints of the study are the following: 
• Time to treatment failure (TTF): Time from the date of enrolment to discontinuation 
of treatment for any reason (including progression of disease, treatment toxicity, 
refusal and death). 
• Overall survival (OS): Time from the date of enrolment until death from any cause. 
• Objective response (OR): The best overall response (CR or PR) across all assessment 
time-points according to RECIST Criteria 1.1, during the period from enrolment to 
termination of trial treatment. 
• Disease control, defined as achieving objective response or stable disease for at least 
6 weeks 
• Duration of response: Interval from the date of first documentation of objective 
response to the date of first documented progression or relapse. 
• Toxicity, that is adverse events classified according to NCI CTCAE version 4. 
 
Apart from the TTF which refers to the ‘study treatment’, that is combination of both 
drugs, time to treatment discontinuation for each drug separately (erlotinib, 
bevacizumab), will also be assessed. Due to the different scheduling for each drug 
(bevacizumab: i.v. at the 1st day of each 3-week cycle; erlotinib: p.o. daily), the following 
cases should be taken into consideration: 
• If erlotinib is permanently discontinued (irrespectively of bevacizumab 
administration): 
End date for erlotininb is the date of last administration of erlotinib 
• If bevacizumab is permanently discontinued (at cycle C), then we further identify the 
cases: 


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o If erlotinib is also discontinued within the same cycle C: 
End date for both drugs is the date of last erlotinib administration 
o If administration of erlotininb is further continued to cycle C+1: 
End date for bevacizumab is day1 of cycle C+1 
o If administration of erlotininb has been discontinued in a previous cycle, before 
cycle C: 
End date for bevacizumab is date of last administration (i.v.) of bevacizumab + 21 
days (corresponding to a 3-week cycle), unless the patient experienced PD, death 
or withdrew from the study during cycle C (in such a case the earlier of those 
dates is used as end date for discontinuation of bevacizumab). 
Note: In all cases, the end date of any drug cannot be later than PD, death or withdrawal 
date. 
 
Another measure of interest to be investigated is relative dose intensity of each of the 
drugs, defined as follows: 
• Relative dose intensity for erlotinib: “Totally administered dose / [150 x total duration 
(in days) of erlotinib treatment]” (for each patient), where ‘Totally administered 
dose’= SUM (administered dose*days of administration). 
• Relative dose intensity for bevacizumab:   “Sum of actual doses for all cycles / sum of 
planned doses of all cycles”, up to the last cycle receiving bevacizumab (for each 
patient). 
Alternatively, relative dose intensity for bevacizumab could be defined as [Sum over 
all cycles of (actual dose per cycle / planned dose per cycle)] /# of cycles” 
 i.e., relative dose intensity for each cycle (of each patient), and then take average (for 
all the cycles of each patient) 
 
 


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4.2  Patient accrual and baseline characteristics  
A flowchart will be created to graphically depict the flow of patients and the phases of the 
trial. Patient accrual, overall and by T790M mutation, will be presented in tabular format for 
each center. In addition, cumulative accrual by T790M mutation and observed vs. expected 
accrual, by T790M mutation, will be graphically displayed.   
With respect to baseline characteristics, first of all, a bar chart with the distribution of T790M 
mutation will be provided. Furthermore, patient baseline characteristics will be summarized 
and presented for all enrolled patients overall and by mutation subgroup. 
All continuous variables will be summarised using the following descriptive statistics:  
n (non-missing sample size), mean, 95% CI for the mean, median, maximum and minimum 
and Interquartile range (IQR). The frequency and percentages  of observed levels will be 
reported for all categorical measures.  
All summary tables will be structured with a column for each subgroup in the order (T790M 
mutated, T790M non-mutated) and a column for the total population, and will be annotated 
with the total population size relevant to that table/treatment, including any missing 
observations. 
The balance of baseline characteristics between the two subgroups will be explored via the 
Fisher’s exact test (for categorical variables) and the Mann-Whitney test for medians (for 
continuous variables). Barplots and histograms will be created, where appropriate, as a 
graphical representation of the findings. 
Table 1 summarizes the baseline characteristics that are considered in the analysis. For 
categorical variables, the corresponding levels of each variable are also documented. 
Table 1. Summary of baseline characteristics 
Categorical characteristics 
Gender 
Male 
Female 
Smoking status 
0 – Never 


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Table 1. Summary of baseline characteristics 
1 – Former (≥100 cig & ≥12 months smoke-free) 
2 – Current 
Tumor histology 
1 – Adenocarcinoma 
2 – Adenocarcinoma with minor squamous cell pattern (possible 
       adenosquamous carcinoma) 
ECOG Performance Status 
0 
1 
2 
Chemotherapy 
Yes 
No 
Radiotherapy 
Yes 
No 
Concomitant treatment  
Yes 
No 
EGFR Mutations 
Exon 19 (DEL19)  
Exon 21 (L858R) 
Localization of tumor metastasis 
Adrenal 
Bone 
Brain 
Kidney 
Liver 
Lung 


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Table 1. Summary of baseline characteristics 
Skin 
Lymph Node(s) 
Other 
Continuous characteristics 
Age (in years) 
 
5. EFFICACY ANALYSIS 
The primary efficacy analysis will be performed in the efficacy cohort, separately in the 2 
subgroups according to T790M status (substudies) as well as overall.  
The goal of the primary analysis is to obtain an estimation of PFS. The overall PFS and PFS 
according to T790M status will be determined by the Kaplan-Meier method and compared 
between the two subgroups (with and without EGFR T790M mutation) by means of the 
logrank test. 
Information on outcome (Progression free survival (PFS), time to treatment failure (TTF) 
(overall and by drug), and overall survival (OS)) will be presented (number of events, 12-
month estimates, medians, 95% CIs), overall and within the two mutation subgroups. The log-
rank test will be used to explore differences in hazard between the two mutation subgroups, 
while observed differences will be graphically depicted via Kaplan-Meier curves. In addition, 
for the T790M mutation subgroup, the number of patients (among the first 35 patients) who 
are progression-free at 12-months will be also separately reported. 
The median follow-up time will be calculated using the reverse censoring method for OS. 
Cox proportional hazard (PH) models will also be applied for PFS, OS and TTF in order to 
explore the significance of EGFR T790M mutation. The influence of baseline characteristics 
and clinical variables of interest (Table 1) will also be explored through corresponding 
adjusted Cox PH models. Backward elimination will be used to conclude on the statistically 
significant terms that should remain into the final models. The variable elimination criterion 
will be a p-value greater than 10%. Estimated effects (e.g. hazard ratios) with confidence 
intervals will be presented. Forest plots will be created as a graphical representation of the 
multivariate models. 


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Clinical efficacy will be further described by objective response rate (ORR), disease control 
rate (DCR) and duration of response (DR), overall and by subgroup.  Regarding DR, information 
on the number of progressions after objective response (%) and median (95% CI) will be 
provided, while DR will be also graphically depicted via Kaplan-Meier curves, by subgroup. 
Relative dose intensity of both erlotinib and bevacizumab will be also described, overall and 
by subgroup. Histograms will be created, as a graphical representation of the findings. A 
watefall plot of best percentage change from baseline in the sum of longest tumour diameters 
will be also presented, by subgroup. Information on OR, will be provided as well.  
The correlation of the biomarkers BRCA1 mRNA and AEG-1 mRNA and T790M with PFS and 
OS will be evaluated by univariate and multivariate Cox PH models. BRCA1 mRNA and AEG-1 
mRNA expressions will also be appropriately discretized and their association with PFS, OS 
and TTF will be further evaluated through survival tables and graphically depicted through 
Kaplan-Meier curves. Discretization of biomarkers will be primarily based on their median 
values, alternative grouping, e.g. based on tertiles, could be further explored, as secondary 
analysis only.  Any additional biomarkers will be considered as secondary analysis. 
Upon data availability, the longitudinal development of EGFR mutations (including T790M) in 
serum will be evaluated descriptively. The relation of molecular biomarkers to EGFR TKI and 
bevacizumab will be explored. The feasibility of re-biopsies at the time of progression will be 
reported. Gene-expression arrays for decision-making for second-line treatment will be done 
in case of available material. The feasibility of recommending customized second-line 
chemotherapy based on BRCA1 and AEG-1 mRNA levels will be explored and reported. 
The feasibility of extracting information on concomitant medications in a systematic way so 
as to correlate it with primary and secondary objectives will be investigated. 
 
6. SAFETY ANALYSIS 
The safety cohort will encompass all patients who have received at least one dose of trial 
treatment. Safety and tolerability of the erlotinib and bevacizumab combination will be 
described by tabulation of the CTCAE V4 grade and graphical representation of the 
corresponding distributions using bar charts.  
All results will be presented overall as well as by mutation subgroup. 


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In particular, safety analysis will include assessment of the experience of adverse events (AE), 
the special cases of serious adverse events (SAE) and adverse events of special interest (AESI), 
the frequency of AEs (overall and separately for targeted and non-targeted AEs),  the numbers 
of patients experiencing specific number of adverse events and their distribution by CTCAE 
V4 grade. Statistical tests will be performed to compare the two mutation groups. 
Further exploration on AEs, with respect to their grade will include the presentation of 
maximum severity of AEs for each patient as well as the distribution of worst degree of 
severity by patient. The distribution of SAEs by provider center will also be presented. 
Note: If the same adverse event is recorded more than once for a specific patient, it will be 
counted only once keeping the one with the higher grade. 
For a closer investigation and for purposes of medical review, information on AEs will also be 
provided by patient. This information will consist of AE description and grade, the related 
cycle number, date of AE onset and end date (if the event is resolved), its potential relation 
to erlotinib and/or bevacizumab treatment, the subgroup each patient belongs to (T790M 
mutated and T790M non-mutated) and his/her specific outcome.  
Summary table of all the adverse events experienced by patients with progression or death 
as well as the narratives of patients with SAE or AESI will also be provided. 
Furthermore, the baseline symptoms experienced by some of the patients, which are not 
counted as adverse events –unless their grade was increased or they appeared as new events 
at a later period of time- will be presented separately. 
Details on the definition of adverse events (as described in the protocol of the study) are 
available in the Appendix. 
 
 
 
 


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7. TECHNICAL DETAILS 
Data will be analyzed using the SAS software package (version 9.3).  
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. 
 
P-values≥0.001 will be reported with two significant digits (e.g. p=0.26, p=0.026, p=0.0032); 
p-values less than 0.001 will be reported as “<0.001”. The mean, 95% confidence limits, 
quantiles, and any other statistics, will be reported to one decimal. Hazard ratios (HRs) and 
their 95% CI’s will be reported to two decimals. Estimated parameters, not on the same scale 
as raw observations (e.g. regression coefficients) will be reported to 3 decimals.  
 
 
 
 


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8. LISTING OF TABLES AND FIGURES 
Table 2 gives a tabulation of the following aspects unique to each table: 
▪ Title 
▪ Population 
▪ Endpoint(s) 
▪ Time Points or details of how to merge/summarize multiple observations 
▪ Covariates or Subgroups used to break down summary statistics 
▪ Which summary statistics will be calculated 
▪ Or, what formal analysis will be used 
For figures the equivalent information is summarized in Table 3 and includes the following: 
▪ Title 
▪ Population 
▪ Type of figure  
▪ Endpoint(s), and which is used for horizontal and vertical co-ordinates 
▪ Statistic(s) used in calculating co-ordinate values used in the figure 
▪ Covariates used within the figure used to determine colors or symbols 
▪ Covariates used to define facets or sub-plots 


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Table 2. Listing of Tables 
Table title 
Population 
Endpoint(s)/ 
Variable(s) 
Time Points or how to 
aggregate 
Covariates or 
Subgroups 
Summary Statistics 
Formal 
Analysis 
Notes 
Accrual by center by 
T790M mutation and 
overall 
Efficacy cohort 
Provider 
NA 
T790M mutation 
n (%) 
NA 
 
Summary of baseline 
characteristics by T790M 
mutation and overall 
Efficacy cohort 
- Gender 
- Smoking status 
- Tumor histology 
- ECOG performance 
status 
- Radiotherapy 
- Chemotherapy 
- Concomitant 
treatment 
- EGFR mutation 
Exon19/Exon21 
- Localization of 
tumour metastasis 
Baseline 
T790M mutation 
n (%) 
Fisher’s exact 
test 
 
Age 
Mean, 95% CI, 
median, min, max, 
IQR 
Mann-
Whitney test 
Time on follow-up (FU)  
and Time on treatment 
(TTF) by T790M 
mutation and overall 
Efficacy cohort 
 
 
FU, TTF 
FU: Time from 
enrolment until last day 
of follow-up 
TTF: Time from 
enrolment until 
discontinuation of 
treatment for any 
reason (progression, 
toxicity, refusal, death) 
T790M mutation 
n (%), 
Median (Interq. 
Range for F-up, 
95% CI for TTF) 
Reverse 
Censoring 
based on 
 OS (f-up) 
Kaplan – 
Meier analysis 
(both) 
 
 


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Table title 
Population 
Endpoint(s)/ 
Variable(s) 
Time Points or how to 
aggregate 
Covariates or 
Subgroups 
Summary Statistics 
Formal 
Analysis 
Notes 
Objective Response (OR) 
by T790M mutation and 
overall 
Efficacy cohort 
 
 
OR 
OR: Best overall 
response (CR or PR) 
across all assessment 
time-points, during the 
time from enrolment 
until termination of 
treatment 
T790M mutation 
n (%) 
NA 
 
Disease Control (DC) by 
T790M mutation and 
overall 
Efficacy cohort 
 
DC 
DC: Defined as achieving 
objective response (OR) 
or stable disease (SD) for 
at least 6 weeks 
T790M mutation 
n (%) 
NA 
 
Duration of Response  
(DR) by T790M mutation 
and overall 
Efficacy cohort  
responders 
only 
DR 
DR: Time from 
documentation of 
response to disease 
progression 
T790M mutation 
n (%) 
NA 
 
Time to Bevacizumab 
discontinuation by 
T790M mutation and 
overall 
Efficacy cohort 
 
Time to Bevacizumab 
discontinuation 
Time to Bev. Discont.: 
Time from first 
administration until 
discontinuation of 
Bevacizumab treatment 
for any reason 
(progression, toxicity, 
refusal, death) 
T790M mutation 
n (%) of 
Bevacizumab 
discontinuations, 
% on Bevacizumab 
at 12 months 
(95% C.I.), Median 
(95% CI) 
Kaplan – 
Meier analysis, 
Log- rank test 
 
Time to Erlotinib 
discontinuation by 
T790M mutation and 
overall 
Efficacy cohort 
 
Time to Erlotinib 
discontinuation 
Time to Erl. Discont.: 
Time from first 
administration until 
discontinuation of 
Erlotinib treatment for 
T790M mutation 
n (%) of Erlotinib 
discontinuations, 
% on Erlotinib at 
12 months 
(95% C.I.), Median 
(95%CI) 
Kaplan – 
Meier analysis, 
Log- rank test 
 


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Table title 
Population 
Endpoint(s)/ 
Variable(s) 
Time Points or how to 
aggregate 
Covariates or 
Subgroups 
Summary Statistics 
Formal 
Analysis 
Notes 
any reason (progression, 
toxicity, refusal, death) 
Descriptives for the 
Relative Dose Intensity 
(RDI) by T790M 
mutation and overall 
Efficacy cohort 
 
-Bevacizumab 
-Erlotinib 
Entire period of patient 
X in the study 
T790M mutation 
Mean, 95% CI, 
median, min, max 
Mann-
Whitney test 
 
Progression-free Survival 
(PFS) according to 
T790M mutation and 
overall 
Efficacy cohort 
 
 
PFS 
PFS: Time from 
enrolment until 
documented progression 
or death without 
documented progression 
or up to last day of 
follow-up, if event has 
not occurred, 
T790M mutation 
n (%) of PFS 
events, PFS% at 
12 months 
(95% C.I.), Median 
(95% CI) 
Kaplan – 
Meier analysis, 
Log- rank test 
Analogous tables for 
PFS, OS, TTF will be 
produced by BRCA1 or 
AEG1 categories, EGFR 
subtypes and brain 
metastatic status in 
the overall cohort as 
well as within T790M 
mutation subgroups 
Overall Survival (OS) 
according to T790M 
mutation and overall 
Efficacy cohort 
 
OS 
OS: Time from 
enrolment until death, 
or up to last day of 
follow-up, if event has 
not occurred 
T790M mutation 
n (%) of deaths, 
OS% at 
12 months 
(95% C.I.), Median 
OS  (95% CI) 
Kaplan – 
Meier analysis, 
Log- rank test 
Time-to-Treatment 
Failure (TTF) according 
to T790M mutation and 
overall 
Efficacy cohort 
 
TTF 
TTF: Time from 
enrolment until 
discontinuation of 
treatment for any 
T790M mutation 
n (%) of TTF 
events, TTF% at 
12 months  (95% 
CI) 
Kaplan – 
Meier analysis, 
Log- rank test 


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Table title 
Population 
Endpoint(s)/ 
Variable(s) 
Time Points or how to 
aggregate 
Covariates or 
Subgroups 
Summary Statistics 
Formal 
Analysis 
Notes 
reason (progression, 
toxicity, refusal, death) 
(95% C.I.), Median 
TTF 
Univariate Cox 
proportional hazards 
model for PFS 
Efficacy cohort 
PFS 
PFS: Time from 
enrolment until 
documented progression 
or death without 
documented progression 
or up to last day of 
follow-up, if event has 
not occurred, 
T790M mutation 
HR (95% CI) 
Cox 
proportional 
hazards 
 
Multivariate Cox 
proportional hazards 
model for PFS  adjusting 
for variables of clinical 
interest 
Efficacy cohort 
PFS 
PFS: Time from 
enrolment until 
documented progression 
or death without 
documented progression 
or up to last day of 
follow-up, if event has 
not occurred, 
T790M mutation, 
statistically 
significant baseline 
covariates 
HR (95% CI) 
Cox 
proportional 
hazards – 
backward 
elimination 
Only statistically 
significant terms will 
be included 
Univariate Cox 
proportional hazards 
model for OS 
Efficacy cohort 
OS 
OS: Time from 
enrolment until death, 
or up to last day of 
follow-up, if event has 
not occurred 
T790M mutation 
HR (95% CI) 
Cox 
proportional 
hazards 
 
Multivariate Cox 
proportional hazards 
model for OS  adjusting 
for variables of clinical 
interest 
Efficacy cohort 
OS 
OS: Time from 
enrolment until death, 
or up to last day of 
follow-up, if event has 
not occurred 
T790M mutation, 
statistically 
significant baseline 
covariates 
HR (95% CI) 
Cox 
proportional 
hazards – 
backward 
elimination 
Only statistically 
significant terms will 
be included 


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Table title 
Population 
Endpoint(s)/ 
Variable(s) 
Time Points or how to 
aggregate 
Covariates or 
Subgroups 
Summary Statistics 
Formal 
Analysis 
Notes 
Results from separate 
Cox models for PFS 
investigating the 
interaction of T790M 
with each of the baseline 
characteristics 
Efficacy cohort 
Baseline characteristics 
At baseline 
T790M mutation 
n vs n, 
HR (95% CI) 
Interaction p-
value 
 
Adverse event overview 
by T790M mutation and 
overall 
Safety cohort 
AE 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) of persons 
who have 
experienced >=1 
AE 
Fisher’s exact 
test 
 
Serious adverse event 
overview by T790M 
mutation and overall 
Safety cohort 
SAE 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) of persons 
who have 
experienced >=1 
SAE 
Fisher’s exact 
test 
 
Adverse events of 
special interest overview 
by T790M mutation and 
overall 
Safety cohort 
AESI 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) of persons 
who have 
experienced >=1 
AESI 
Fisher’s exact 
test 
 
Frequency of serious 
adverse events by 
T790M mutation and 
overall, according to 
CTCAE Version 4 
Safety cohort 
SAE 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) 
NA 
In case of multiple 
reports of the same SAE 
(grouped according to 
CTCAE V4) for a 
particular patient, the 
SAE is counted once. 
Number of patients 
experiencing specific 
number of serious 
adverse events overall 
and by T790M mutation, 
Safety cohort 
SAE 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n 
NA 
 


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Table title 
Population 
Endpoint(s)/ 
Variable(s) 
Time Points or how to 
aggregate 
Covariates or 
Subgroups 
Summary Statistics 
Formal 
Analysis 
Notes 
according to CTCAE 
Version 4 
Serious adverse events 
overview by center 
Safety cohort 
SAE 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
Provider 
n (%) of pts  
n(%) of events 
NA 
 
Adverse events 
(AE/SAE/AESI) according 
to CTCAE Version 4, 
overall and by T790M 
mutation 
Safety cohort 
AE/SAE/AESI 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) 
NA 
- In case of multiple 
reports of the same 
event for a particular 
patient, the AE is 
counted once.  
Number of patients 
experiencing specific 
number of adverse 
events overall and by 
T790M mutation 
according to CTCAE 
Version 4 
Safety cohort 
AE/SAE/AESI 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n 
NA 
 
Targeted adverse events 
according to CTCAE 
Version 4 
Safety cohort 
AE/SAE/AESI 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) 
NA 
 
Non-targeted adverse 
events according to 
CTCAE Version 4 
Safety cohort 
AE/SAE/AESI 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) 
NA 
 
Maximum severity of 
adverse events 
(AE/SAE/AESI) per 
patient overall and by 
T790M mutation  
Safety cohort 
AE/SAE/AESI 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutation 
n (%) 
NA 
 


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Table title 
Population 
Endpoint(s)/ 
Variable(s) 
Time Points or how to 
aggregate 
Covariates or 
Subgroups 
Summary Statistics 
Formal 
Analysis 
Notes 
Adverse event 
information by patient 
Safety cohort 
AE/SAE/AESI 
At baseline; at the end 
of each cycle; at the end 
of treatment visit 
T790M mutated 
NA 
NA 
- If a patient 
experienced the same 
adverse event more 
than one times, the 
highest grade is 
presented. 
- If a patient 
discontinued first 
from one drug and 
then from the other -
and since the 
treatment was 
received as a 
combination of the 2 
drugs-, the date of a 
patient’s 
discontinuation is 
considered to be the 
date he/she 
discontinued from the 
first one. 
Narratives of patients 
with a SAE and/or an 
AESI 
Safety cohort 
SAE/AESI 
NA 
NA 
NA 
NA 
 
 
 
 


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Table 3. Listing of Figures 
Title 
Population 
Type of graph 
Horizontal 
Variables 
Vertical 
Variables 
Groupings 
Statistics 
Facets 
Patients enrolment 
All patients registred 
in the database 
Flowchart 
NA 
NA 
NA 
NA 
NA 
Cumulative Overall Accrual by 
T790M mutation 
Efficacy cohort 
Line graph 
time 
frequency 
NA 
NA 
NA 
Expected vs. observed accrual 
by T790M mutation 
Efficacy cohort 
Line graph 
time 
frequency 
T790M 
mutation 
NA 
NA 
Distribution of T790M 
mutation 
Efficacy cohort 
Bar chart 
percentage 
percentage 
T790M 
mutation 
percentage 
NA 
Time on Follow-up by T790M 
mutation 
Efficacy cohort 
KM 
time 
probability 
T790M 
mutation 
Survival 
estimates 
Subgroups and 
overall 
Waterfall plot of best 
percentage change from 
baseline in the sum of target 
lesion diameters 
Efficacy cohort 
Waterfall plot 
patient 
Change from 
baseline 
PD, SD, PR, CR 
NA 
NA 
Duration of Response by 
T790M mutation for patients 
who reported objective 
response 
Efficacy cohort 
(responders) 
KM 
time 
probability 
T790M 
mutation 
Survival 
estimates 
Subgroups and 
overall 
Time to discontinuation from 
Bevacizumab by T790M 
mutation 
Efficacy cohort 
KM 
time 
probability 
T790M 
mutation 
Survival 
estimates 
Subgroups and 
overall 
Time to discontinuation from 
Erlotinib by T790M mutation 
Efficacy cohort 
KM 
time 
probability 
T790M 
mutation 
Survival 
estimates 
Subgroups and 
overall 
Relative Dose Intensity (RDI) 
of Bevacizumab by T790M 
mutation 
Efficacy cohort 
Histogram 
Relative Dose 
Intensity 
percentage 
T790M 
mutation 
Mean, median, 
range, 
skewness, 
variance 
NA 
Relative Dose Intensity (RDI) 
of Erlotinib by T790M 
mutation 
Efficacy cohort 
Histogram 
Relative Dose 
Intensity 
percentage 
T790M 
mutation 
Mean, median, 
range, 
skewness, 
variance 
NA 


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Title 
Population 
Type of graph 
Horizontal 
Variables 
Vertical 
Variables 
Groupings 
Statistics 
Facets 
Progression-free Survival by 
T790M mutation$ 
Efficacy cohort 
KM 
time 
probability 
T790M 
mutation 
Survival 
estimates 
Subgroups and 
overall 
Overall Survival by T790M 
mutation$ 
Efficacy cohort 
KM 
time 
probability 
T790M 
mutation 
Survival 
estimates 
Subgroups and 
overall 
Time on treatment by T790M 
mutation$ 
Efficacy cohort 
KM 
time 
probability 
T790M 
mutation 
Survival 
estimates 
Subgroups and 
overall 
 
$ Analogous KM plots for PFS, OS, TTF will be produced by BRCA1 or AEG1 categories, EGFR subtypes and brain metastatic status in the overall 
cohort as well as within T790M mutation subgroups 
 


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REFERENCES 
 
TR Fleming (1982). One-sample multiple testing procedure for Phase II clinical trials. 
Biometrics, 38: 143-151. 
 
R Rosell, MA Molina, C Costa, et al (2011). Pretreatment EGFR T790M Mutation and BRCA1 
mRNA Expression in Erlotinib-Treated Advanced Non-Small-Cell Lung Cancer Patients with 
EGFR Mutations. Clin Cancer Res, 17: 1160-1168. 
 
R Simon (1989). Optimal two-stage designs for Phase II clinical trials. Controlled Clinical 
Trials, 10: 1-10. 
 
 
 
 
 
 


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APPENDIX 
IMPORTANT INFORMATION AS DESCRIBED IN THE PROTOCOL 
A.1 STUDY OBJECTIVES AND ENDPOINTS 
A.1.1 Study Objectives 
Primary Objective 
To determine progression-free survival (PFS) of patients with advanced non-squamous NSCLC 
harboring at diagnosis EGFR mutations with and without T790M mutation treated with the 
combination of erlotinib and bevacizumab. 
Secondary Objectives 
i. 
To evaluate secondary measures of clinical efficacy including overall survival (OS), time 
to treatment failure (TTF), objective response rate (ORR), disease control rate (DCR) 
and duration of response (DR). 
ii. 
To assess the safety and tolerability of the erlotinib and bevacizumab combination. 
iii. 
To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M 
with progression-free survival. 
iv. 
To monitor EGFR mutations (including T790M) in serum and plasma longitudinally. 
v. 
To evaluate molecular biomarkers related to EGFR TK1 and bevacizumab. 
vi. 
To determine the feasibility of re-biopsies at the time of progression and gene-
expression arrays for decision-making for second-line treatment. 
vii. 
To study the feasibility of recommending customized second-line chemotherapy 
based on BRCA-1 and AEG-1 mRNA levels.  
 
 
 


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A.1.2 Endpoints 
Primary Endpoint 
The primary endpoint of the study is Progression-free Survival (PFS), defined as the time from 
the date of enrolment until documented progression or death, whichever occurs first. 
Secondary Endpoints 
Secondary endpoints include Overall Survival (OS), Time to treatment failure (TTF), Time to 
treatment discontinuation (TTD), Objective Response (OR), Disease Control (DC), Duration of 
response (DR) and adverse events graded according to CTCAE V4.0. More specifically OS is 
defined as the time from the date of enrolment until death from any cause. In addition, TTF 
is defined as time from the date of enrolment to discontinuation of treatment for any reason, 
including progression of disease, treatment toxicity, refusal and death. As for TTD, two 
different definitions of treatment discontinuation are considered: i) all cause treatment 
discontinuation, and ii) discontinuation of treatment for patient decision. OR is defined as the 
best overall response (CR or PR) across all assessment time-points according to RECIST Criteria 
1.1, during the period from enrolment to termination of trial treatment. DC is defined as 
achieving objective response or stable disease for at least 6 weeks. Finally, DR is defined as 
the interval from the date of first documentation of objective response by RECIST to the date 
of first documented progression or relapse.  
 
A.1.3 Statistical Hypotheses 
The specific statistical hypotheses that are to be tested in order to assess the primary 
objective of the study are listed below. A one-sided significance level of 0.05 will be used for 
statistical testing. 
▪ Substudy 1: Patients with EGFR T790M mutation 
H0 : 
 The 12-months PFS ≤ 40% 
H1 : 
 The 12-months PFS ≥ 63% 
▪ Substudy 2: Patients without EGFR T790M mutation 
H0 : 
 The 12-months PFS ≤ 50% 
H1 : 
 The 12-months PFS ≥ 65% 


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A.2 STUDY METHODS 
A.2.1 General Study Design and Plan 
This is a multinational, multi-center trial of erlotinib plus bevacizumab in patients with 
advanced non-squamous NSCLC harbouring EGFR mutations, including two separate phase II 
substudies. Only EGFR mutated patients may enter the study. Approximately 1135 patients 
with advanced non-small cell lung cancer are expected to be screened to include 102 patients 
with activating EGFR mutations. Patients may continue treatment on this trial as long as there 
is evidence of clinical benefit in the judgment of the investigator. Trial subjects will receive 
trial medication up to 18 months after the inclusion of the last patient. All patients who are 
still benefiting from their treatment at that time have to be switched to commercial drug 
which will be reimbursed by Roche. 
Patient accrual is expected to be completed within 12 months including a run-in-period of 3 
months. Treatment and follow-up is expected to extend the study duration to a total of 48 
months. Patients will be followed until death – thus follow-up estimated up to 3 years 
following the enrolment of the last patient.  
The trial will end with the preparation of the final report, scheduled for month 54 after the 
inclusion of the first patient.  
 
A.2.2 Patient Selection 
Only patients with a centrally confirmed status of EGFR mutation are eligible. The mutation 
status may first be assessed locally by a certified laboratory, but for all patients tumor material 
has to be submitted to the reference laboratory (BELIEF Protocol, Section 9) for immediate 
confirmatory testing. If the EGFR mutation status is not confirmed by the central reference 
laboratory, the patient will be taken off trial and will undergo an end-of-treatment 
assessment. Such a patient will be followed up per protocol. Written informed consent needs 
to be obtained prior to shipment of tissue to the central laboratory. 
Patients should only be selected and consented for screening if they fulfill the inclusion and 
exclusion criteria described in Sections 7.1 and 7.2 of the BELIEF Protocol respectively. 


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A.2.3 Patient Screening and Registration 
This trial will use a web-based registration system. Each participating centre will access the 
registration system directly. Specific details for registration of patients are in the “BELIEF 
Procedures 
Manual” 
which 
will 
be 
available 
on 
the 
ETOP 
website  
(www.etop-eu.org).  
 
A.2.4 Early Stopping Rules 
Substudy 1 contains an early look at the end of the first stage, when 8 patients have reached 
12 months follow-up. If 3 or less patients reach 12 months without a progression-defining 
event, then the results of the substudy will be reported immediately and the Steering 
Committee will decide whether the patients still on treatment should stop it. Otherwise the 
substudy will continue as planned until the final evaluation. 
 
A.2.5 Study Variables 
Trial schedule of events 
 
Baseline evaluations (within 28 days prior to registration) 


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▪ Medical history including symptoms, smoking history, medications, comorbidities and 
allergies 
▪ Physical examination including blood pressure [mmHg], ECOG performance status 
(see definition in BELIEF procedures manual), and body weight [kg] 
▪ Haematology: haemoglobin, leukocytes, platelets 
▪ Renal function: serum creatinine and creatinine clearance calculated according to 
Cockroft-Gault, urine dipstick for proteinuria 
▪ Hepatic function: ALT, AST, AP, Bilirubin 
▪ Coagulation: INR 
▪ Pregnancy test for women with childbearing potential 
▪ CT scan of thorax and upper abdomen with i.v. contrast (alone or in combination with 
PET) to determine measurable disease according to RECIST v1.1 (at least one lesion 
outside of irradiated areas that can be measured in at least one dimension as ≥ 10 
mm, or ≥ 15 mm in case of lymph nodes). In the presence of clinically suspected 
metastases outside the thorax (e.g. brain, bone or lower abdomen), additional CT of 
the affected body part is recommended. 
▪ CT scan of brain is not mandatory and only recommended in case of clinically 
suspected brain metastasis 
 
Before enrolment 
▪ For central confirmation of EGFR exon 19 deletion (del19) or exon 21 mutation 
(L858R), send to central laboratory: 
- 
1 block of FFPE tissue from biopsy, surgery or cytology 
- 
Pathology report 
- 
Local EGFR mutation report (if applicable)  
 
Before start of treatment 
▪ Take a blood sample for routine evaluations plus a serum and plasma sample for 
translational research 
 
Routine evaluations before and during trial treatment 
On day 1 of every 3-week treatment cycle: 


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▪ Recording of symptoms / adverse events 
▪ Physical examination including blood pressure, performance status, and body weight 
▪ Haematology: haemoglobin, neutrophils, platelets 
▪ Serum creatinine 
▪ Hepatic function: ALT, AST, AP, Bilirubin 
▪ Urine dipstick 
 
Trial – specific evaluations during treatment  
These evaluations will occur more frequently during the first cycles, and be phased out 
especially for patients who stay on treatment for a prolonged period. They should be 
performed within 72h before the start of the subsequent cycle: 
▪ Prior to the start of cycles 3, 5, 7, 10, 13, 16, 20, 24, 28 and every 4 cycles until 
progression (weeks 6, 12, 18, 27, 36, 45, 57, 69, 81; and then every 12 weeks) 
▪ CT thorax and upper abdomen 
▪ Blood serum and plasma sample for translational research at the first time of 
documented response 
 
Evaluation in the follow-up phase before progression 
Patients who discontinue treatment before progression should have the following 
assessments at the same timepoints as patients still on treatment (weeks 6, 12, 18, 27, 36, 
45, 57, 69, 81; and every 12 weeks until progression): 
▪ Physical examination 
▪ CT thorax and upper abdomen (plus further imaging if applicable) 
▪ Documentation of further treatments 
 
Evaluation at progression 
Each patient will receive trial treatment until documented progression. At progression, do the 
following: 
▪ CT thorax and upper abdomen, document progression on the respective CRF 
▪ Blood serum and plasma sample for translational research 
▪ Tumor re-biopsy should be considered for testing of further predictive markers and 
translational research at the central reference laboratory (Pangaea Biotech)  


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End of treatment visit 
At the end of the trial treatment and irrespective of the reason for stopping treatment, a 
post treatment visit at the center is to be scheduled after 30 (to 40) days following last 
treatment day. The following procedures should be performed: 
▪ Recording of symptoms 
▪ Physical examination including blood pressure 
▪ Haematology: haemoglobin, neutrophils, platelets 
▪ Hepatic function: ALT, AST, AP, Bilirubin 
▪ Serum creatinine 
▪ Urine dipstick 
▪ CT thorax and upper abdomen, if not done within the last 30 days 
 
Evaluation after progression 
Patients with progression will end trial treatment and should have documented 
▪ survival and 
▪ further lines of treatment 
up to 3 years after the inclusion of the last patient. 
 
A.2.6 Primary Comparisons 
The goal of the primary analysis of the study is to obtain an estimation of PFS. All eligible and 
treated patients will be included in this analysis. The overall PFS and PFS according to T790M 
status will be determined by the Kaplan-Meier method and compared between the two 
subgroups (with and without EGFR T790M mutation) by means of the log-rank test.  
 
 
 
 


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A.3 SAMPLE SIZE 
 
The EAST software package is used for sample size calculations (EAST 5, Version 5.4.0.0, Cytel 
Inc. 2010).  
 
The sample size calculations are based on the percentage of patients with EGFR T790M 
mutation and corresponding median PFS by EGFR T790M mutation under erlotinib treatment, 
as presented in the recently published results by Rosell et al. (2011). 
 
The trial encompasses two phase II substudies run in parallel, and requires a total of 102 
patients: 
▪ Substudy 1: 35 patients with EGFR T790M mutation 
▪ Substudy 2: 67 patients without EGFR T790M mutation 
The first substudy follows Simon’s two-stage design and a decision can be reached at the first 
stage, while the second substudy follows Fleming’s single stage design. 
 
Substudy 1: Patients with EGFR T790M mutation 
The primary objective is the estimation of PFS in patients with EGFR T790M mutation, treated 
with bevacizumab and erlotinib. The median PFS is expected to improve to 18 months. A 12-
month PFS of 40%, corresponding to a median of 9 months, will be considered inadequate 
(since a 12 month median PFS is achieved by erlotinib alone), while the target value will be a 
12-month PFS of 63% (corresponding to a median PFS of 18 months, similar to the one 
observed with erlotinib alone in the subgroup of patients without EGFR T790M mutation).  
 
Simon’s optimal two-stage design (Simon, 1989), with a significance level of 5% and power of 
80%, will be used to test the null hypothesis that the 12 month PFS≤40% versus the alternative 
that PFS≥63%. If in the first stage from a total of 8 patients, 4 or more patients reach 12 
months without a progression-defining event, then the substudy will proceed so as to 
evaluate the 12-month PFS for a total of 35 patients. If 19 or more patients reach 12 months 
without a PFS event, treatment with the combination of erlotinib and bevacizumab will 
warrant further study in a Phase III trial in the subgroup of patients with EGFR T790M 
mutation. 


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It is anticipated that the decision on the first stage of substudy 1 will not be reached before 
the study is fully accrued, since 12 months of follow-up will be required for at least 8 patients 
with EGFR T790M mutation, while the anticipated full study accrual will be completed within 
12 months. 
 
In case, the EGFR T790M mutation is identified on only 30% of the patients (instead of the 
assumed 35%), the decision that can be reached at the end of the study with significance level 
of 5% and power of 80% will correspond to an alternative of PFS≧66% or a median PFS≧20 
months. 
 
Substudy 2: Patients without EGFR T790M mutation 
The primary objective is the estimation of PFS in patients with EGFR mutation without T790M 
mutation, treated with bevacizumab and erlotinib. The median PFS is expected to be 
approximately 18 months or higher. A 12-month PFS of 50% will be considered inadequate 
(since 50% is achieved by erlotinib alone in the subgroup of patients with EGFR T790M 
mutation), while the target value will be a 12-month PFS of 65% (corresponding to a median 
PFS of 19 months, similar to the one observed with erlotinib alone in the subgroup of patients 
without EGFR T790M mutation). 
 
A sample size of 67 patients is required by Fleming’s single stage design (Fleming, 1982), with 
significance level of 5% and power of 80%, to test the null hypothesis that the 12-month 
PFS≤50% versus the alternative that PFS≥65%. 
 
 
A.4 ADVERSE EVENTS 
 
A.4.1 Adverse Events (AE) 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the NCI CTCAE Version 4. The CTCAE is 
available 
for 
downloading 
on 
the 
internet, 
see 
Appendix 
3 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html ). 


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An adverse event is defined as any untoward medical occurrence that occurs from the first 
dose of study medication until 30 days after the final dose, 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. Symptoms of the 
targeted cancer (if applicable) should not be reported as adverse events. 
 
A.4.2 Severity Grade 
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. 
 
Severity grade for other adverse events not covered in the toxicity grading scale: 
 
1 =Grade 1 
Mild 
2 =Grade 2 
Moderate 
3 =Grade 3 
Severe 
4 =Grade 4 
Life- threatening 
5 =Grade 5 
Fatal 
 
A.4.3 Serious Adverse Events (SAE) 
 
SAEs during trial treatment 
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 any of the following: 
▪ is fatal (any cause) 
▪ life-threatening, 
▪ requires or prolongs inpatient hospitalization, 


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▪ results in persistent or significant disability/incapacity 
▪ is a congenital anomaly or birth defect 
▪ is a secondary malignancy 
▪ requires significant medical intervention 
Second (non-NSCLC) malignancies are always considered SAEs, no matter when they are 
diagnosed. These events should be reported on the Serious Adverse Event Forms. 
 
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. 
 
An unexpected adverse event is one that is not listed as a known toxicity of the investigational 
drug in the summary of product characteristics. 
 
A related adverse event is one for which the investigator assesses that there is a reasonable 
possibility that the event is related to the investigational drug. All adverse events judged as 
having a reasonable suspected causal relationship to the trial medication qualify as adverse 
reactions. 
 
Events not considered to be serious adverse events are hospitalizations occurring under the 
following circumstances: 
▪ elective surgery; 
▪ occur on an outpatient basis and do not result in admission (hospitalization < 24h); 
▪ are part of the normal treatment or monitoring of the studied treatment; 
▪ progression of disease. 
 
SAEs after end of trial treatment 
During the follow-up phase (starting 30 days after end of trial treatment), the following events 
have to be reported as SAE: 
▪ fatal, life-threatening and other medically significant events possibly, probably or 
definitely related to late effects of trial treatment 


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▪ disabling events 
▪ second primary cancer 
▪ congenital anomaly 
▪ pregnancy 
In the case of pregnancy occurring during the course of the trial or within 1 year after 
treatment discontinuation, the investigator shall immediately notify this by completing the 
pregnancy reporting form. The investigator shall ensure that the case is followed up to the 
end of the pregnancy and supply a final report on the outcome. 
 
A.4.4 Adverse Events of Special Interest (AESI) 
 
The following adverse events are of special interest and will be documented if observed: 
▪  Interstitial lung disease (ILD)-like events 
▪ Haemorrhage, with a focus on haemoptysis and CNS bleeding 
▪ Hypertension 
▪ Proteinuria 
▪ Arterial/venous thromboembolism events 
▪ Wound healing complications 
▪ Congestive heart failure 
▪ Fistulae 
▪ Gastrointestinal perforations 
▪ Reversible posterior leucoencephalopathy syndrome