Clinical trial NCT00130728
Conditions: Non-Small Cell Lung Cancer
Keywords: NSCLC Avastin Tarceva Lung Cancer
Sponsor: Genentech, Inc.
Start date: 2005-06-08; Completion date: 2019-12-23
Enrollment: 636 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, multicenter, placebo-controlled, double-blind, randomized study. Approximately 650 patients will be randomized in a 1:1 ratio to one of two treatment arms.

Detailed description:

Arms: arm 1: oral erlotinib HCl 150 mg/day orally + intravenous infusion of bevacizumab at a dose of 15 mg/kg on the first day of each 3-week cycle arm 2: oral erlotinib HCl 150 mg/day orally + intravenous infusion of placebo at a dose of 15 mg/kg on the first day of each 3-week cycle
Interventions: intervention 1: bevacizumab intervention 2: erlotinib HCl intervention 3: placebo
Intervention descriptions: intervention 1: intravenous infusion of bevacizumab at a dose of 15 mg/kg on the first day of each 3-week cycle intervention 2: oral erlotinib HCl 150 mg/day orally intervention 3: intravenous infusion of placebo at a dose of 15 mg/kg on the first day of each 3-week cycle

Protocol documents:
Prot_000.pdf: 
 
Official Title: A Phase III, Multicenter, Placebo-Controlled, Double-Blind, 
Randomized Clinical Trial to Evaluate the Efficacy of Bevacizumab in 
Combination With Tarceva® (Erlotinib) Compared With Tarceva Alone 
for Treatment of Advanced Non−Small Cell Lung Cancer (NSCLC) 
After Failure of Standard First-Line Chemotherapy 
NCT Number: NCT00130728 
Document Date: Protocol Version A6: 11-October-2012 
 
 


 
Title
11-Oct-2012 05:38:38
Date and Time (UTC)
Company Signatory
Approver's Name
 
 
 
PROTOCOL AMENDMENT APPROVAL 
 
 
CONFIDENTIAL 
 
This is a Genentech, Inc., document that contains confidential information.   
It is intended solely for the recipient clinical investigator(s) and must not be disclosed to any other 
party.  This material may be used only for evaluating or conducting clinical investigations; any 
other proposed use requires written consent from Genentech, Inc. 
 
Bevacizumab and Erlotinib—Genentech, Inc. 
P OSI3364g-A6 
 
TITLE: 
A PHASE III, MULTICENTER, 
PLACEBO-CONTROLLED, DOUBLE-BLIND, 
RANDOMIZED CLINICAL TRIAL TO EVALUATE 
THE EFFICACY OF BEVACIZUMAB IN 
COMBINATION WITH TARCEVA® (ERLOTINIB)  
COMPARED WITH TARCEVA ALONE FOR 
TREATMENT OF ADVANCED NON−SMALL CELL 
LUNG CANCER (NSCLC) AFTER FAILURE OF 
STANDARD FIRST-LINE CHEMOTHERAPY 
PROTOCOL NUMBER: 
OSI3364g 
VERSION NUMBER: 
A6 
IND NUMBER: 
7023 
TEST PRODUCT: 
Bevacizumab (RO4876646) and Erlotinib (RO508231) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  2 February 2005 
DATES AMENDED: 
Version A1:  26 April 2005 
Version A2:  31 October 2005 
Version A3:  3 March 2006 
Version A4:  30 November 2006 
Version A5:  12 March 2009 
Version A6:  See electronic date stamp below 


 
 
 
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PROTOCOL AMENDMENT, VERSION A6: 
RATIONALE 
The results of the final analysis of the BETA Lung trial (OSI3364g), an international, 
randomized, placebo-controlled, Phase III trial, were presented at the 2008 Chicago 
Lung meeting by Dr. John Hainsworth on behalf of the BETA investigators.  The addition 
of bevacizumab to erlotinib in the BETA lung study provided evidence of clinical activity 
by doubling progression free survival and the overall response rate.  However, this 
clinical benefit was not associated with an improvement in survival. 
At the time of this amendment, there are 4 patients receiving single-agent erlotinib in this 
study. All of the patients remaining in the study are located in the United States. 
Protocol Study OSI3364g has been amended because the study has been completed 
and no further patient data will be collected, except for serious adverse event reporting 
via MedWatch Food and Drug Administration 3500 Forms, no longer with the CRFs, and 
will be handled according to instructions in Section 5.4 . 
Additional changes to the protocol are as follows: 
• 
Despite being unblinded in 2008, some patients are still receiving study drugs from 
treatment bottles assigned via the interactive voice response system labeled as 
“OSI-774 25mg, 100mg or 150mg” as per study protocol.  Upon enactment of this 
amendment, patients will be receiving study drugs directly from Astellas Pharma 
US, Inc. labeled as “erlotinib” at their current dosage. 
• 
Upon enactment of Amendment 6, no dose adjustments will be permitted.  Any 
patient requiring a dose modification because of an adverse event or disease 
progression should be terminated from the study and treated following the 
physican’s usual standard of care.  
The sample Informed Consent Form has also been revised to reflect the changes to the 
study protocol. 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
Bevacizumab and Erlotinib—Genentech, Inc. 
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PROTOCOL AMENDMENT, VERSION A6: 
 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 2.2:  SECONDARY OBJECTIVES 
The secondary objectives of this Phase III study were as follows: 
• 
To evaluate the safety of combining bevacizumab with Tarceva in patients with 
previously treated advanced NSCLC, including patients with squamous cell 
carcinoma, patients with treated brain metastases, and patients receiving full-dose 
anticoagulation with low-molecular-weight heparin or fondaparinux. 
Note:  See Section 4.1.2 for the eligibility criteria regarding squamous cell 
carcinoma patients. 
Note:  The safety profile of patients who remain on protocol treatment at the enactment of 
amendment 5 will be evaluated to better characterize the long term safety of the 
bevacizumab and erlotinib combination. 
Note: Upon enactment of Amendment 6, safety data collection will be restricted 
to the reporting of serious adverse events via MedWatch FDA 3500 forms 
(Appendi x D ) and will not be captured in the CRF. 
 
SECTION 3.3.4:  Safety Outcome Measures 
The safety outcome measures for this study were the following: 
• 
Incidence and severity of adverse events and serious adverse events 
• 
Changes in laboratory values  
Patient safety after Amendment 5 will be assessed through summaries of serious adverse events. 
Patient safety after Amendment 6 will be restricted to the spontaneous reporting of 
serious adverse events via MedWatch FDA 3500 forms and will not be captured in the 
CRF.  
SECTION 3.4:  SAFETY PLAN 
Upon enactment of Amendment 6, data collection will be restricted to reporting of 
serious adverse events via MedWatch FDA 3500 forms (not in the CRF), and handled 
according to instructions in Section 5.4. SAE data will be collected via the safety 
database only. Prior to Amendment 6, the safety plan was as below. 
See Section 4.3.4and Section 5 for complete details of the safety evaluation for this 
study. 


 
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A number of measures have been taken to ensure the safety of patients participating in 
this study.  These measures were addressed through the exclusion criteria 
(see Section 4.1.3) and routine monitoring as follows. 
Patients enrolled in this study were evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study.  Safety 
evaluations consisting of medical interviews, recording of concomitant medications and 
adverse events, physical examinations, blood pressure, and laboratory measurements 
(performed by local laboratories, see Section 4.5 and  Appendix A) have been 
conducted.  Patients have been evaluated for adverse events (all grades), serious 
adverse events, and adverse events requiring study drug interruption or discontinuation 
at each study visit while on study drug.  Patients discontinued from the treatment phase 
of the study for any reason were evaluated ~30 days (28−42 days) after the decision to 
discontinue treatment (see Section 4.5.3).  Patients with an ongoing Grade 4 or serious 
adverse event at the time of discontinuation from study treatment were and will continue 
to be followed until the event is resolved or determined to be irreversible by the 
investigator (see Section 4.5.3 ). 
Specific monitoring procedures were as follows: 
• 
Hypertension was monitored through routine evaluation of blood pressure. 
• 
In patients with bleeding, a hemostasis evaluation was performed as clinically 
indicated.  In patients with hemoptysis, bevacizumab should be permanently 
discontinued and protocol guidelines followed (see Section 4.3.4 and Table 2). Early 
use of bronchoscopy to identify the site of bleeding should also be considered. 
• 
Patients with a history of brain metastases were monitored for the development of 
symptomatic Grade  ≥ 2 CNS hemorrhage (NCI CTCAE, Version 3.0).  Symptomatic 
is defined as clinical symptoms that are determined by the investigator to be directly 
referable to a CNS hemorrhage.  Bevacizumab should be discontinued and protocol 
guidelines followed in patients who develop symptomatic Grade ≥ 2 CNS 
hemorrhage (see Section 4.3.4 and Table 2). 
• 
Patients requiring full-dose anticoagulation could be treated with 
low-molecular-weight heparin or fondaparinux; these patients were and have been 
monitored for Grade ≥ 3 hemorrhage events.  Full-dose anticoagulation with 
warfarin is prohibited; however, prophylactic doses were allowable. 
• 
Bevacizumab should be discontinued and protocol guidelines followed in patients 
who develop symptomatic Grade ≥ 2 CNS hemorrhage or Grade ≥ 3 hemorrhage 
(see Section 4.3.4 and Table 2).  
• 
Because of the potential for drug–drug interaction between Tarceva and warfarin, 
patients who received concomitant prophylactic/low-dose warfarin therapy were to 
be monitored closely for INR changes or bleeding. 
• 
Chronic use of full-dose nonsteroidal anti-inflammatory drugs (NSAIDs) was not 
allowed while on study treatment.  If required, the patient must be discontinued from 
bevacizumab/placebo. 


 
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• 
Aspirin up to, but not exceeding, 325 mg per day could be given to patients at high 
risk for arterial thromboembolic disease.  Patients developing signs or symptoms of 
arterial thromboembolic events (see Table 2) while on study treatment were asked 
to discontinue bevacizumab/placebo. 
• 
Proteinuria was monitored through regular urinalysis and urinary protein to 
creatinine ratio.  Screening for proteinuria at ex-U.S. sites was performed with a 
urine dipstick (patients found to have ≥ 3+ proteinuria by dipstick had to undergo a 
24-hour urine collection) 
• 
Symptoms consistent with ILD, such as new onset dyspnea, cough, or fever without 
an obvious cause were to be evaluated.  In the event that ILD was suspected, study 
treatment was to be discontinued and the patient given appropriate medical 
management.  Although there is no proven therapy, systemic corticosteroids are 
often provided.  Tarceva should not be restarted in patients suspected of having 
drug-related ILD. 
• 
NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in 
patients receiving Tarceva therapy.  Patients were asked to seek medical advice 
promptly if they experienced eye irritation during Tarceva therapy. 
 
See Section 4.3.4 for detailed instructions about the management of study drug-related 
toxicities.  The DMC monitored the safety of this study by reviewing serious adverse 
events every month and during the two interim analyses.  Members of the DMC were 
external to Genentech and followed a charter that outlines the Committee’s composition 
and the members’ roles and responsibilities. 
Safety monitoring for patients who remain on study treatment after the final analysis will be 
conducted by Genentech or Genentech’s agent.  
SECTION 3.7:  ETHICAL CONSIDERATIONS 
Genentech performed will perform safety reviews after the final analysis.  
The final analysis of OSI3364g showed that the addition of bevacizumab to erlotinib 
improved PFS and ORR.  However, this clinical benefit was not associated with an 
improvement in survival. 
Amendment 5 allowed  was designed to give investigators and patients who had have not 
progressed the option to continue active study treatment until disease progression, while 
continuing to provide long-term data on the safety of the bevacizumab and erlotinib 
combination.  
Forty-eight patients remained on study treatment at the time of the final BETA analysis.  
Some had been on study for more than 1 year.  The continued collection of safety 
information on these long-term non-progressing patients allowed will allow for a better 
description of the long-term safety profile of the bevacizumab and erlotinib combination. 


 
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6/P OSI3364g-A6 
 
All placebo treatment in the BETA trial will be discontinued to remove the risks and 
discomforts associated with infusion therapy.  
Investigators and patients are not obligated to remain on study treatment.  They may 
choose to discontinue trial participation given the failure of the study to meet its primary 
endpoint of improved overall survival. 
Upon enactment of Amendment 6, data collection will be restricted to spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms (not in the case 
report form [CRF]), and handled according to instructions in Section 5.4. SAE data 
will be collected via the safety database only. 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Note: This study has been fully recruited and all subjects were unblinded to study drug 
following the final analysis. Upon enactment of Amendment 6, the interactive voice 
response system (IVRS) will be cancelled. Prior to enactment of Amendment 6, 
treatment assignment and unblinding were managed as below. 
After written informed consent was obtained and eligibility established (with archival 
tissue identified and available for research testing), the study site obtained the patient’s 
identification number and treatment assignment from the IVRS.  Patients could be 
randomized up to 5 days prior to receiving their first dose of study treatment.  A 
hierarchical dynamic randomization scheme was used to ensure an approximately equal 
sample size for the two treatment arms overall, within each of the four categories defined 
by baseline ECOG performance status (0/1 vs. 2) and smoking history (never vs. 
current/previous), within each sex, and within each study site. 
Genentech, the investigator, and the patient were blinded to treatment assignment.  
Unblinding of treatment assignment prior to final study analysis was permitted only for a 
serious study drug–related toxicity.  All cases of safety unblinding required the approval 
of the Medical Monitor.  After the final analysis, unblinding information was provided to 
all sites with patients receiving study treatment.  Unblinding information for patients who 
had completed study treatment prior to the final analysis was provided upon request. 
If a patient discontinued Tarceva therapy because of unmanageable toxicity, an 
unblinding request could be made to determine the treatment assignment.  Study 
bevacizumab/placebo was discontinued and subsequent therapy provided at the 
discretion of the treating clinician. 
Requests for unblinding may be made by calling the Medical Monitor directly during 
business hours (PST) at the following telephone number: 
 
 
Medical Monitor:  
, M.D. 
 
 
Telephone No.:  
 


 
Bevacizumab and Erlotinib—Genentech, Inc. 
7/P OSI3364g-A6 
 
 
 
Alternate Contact:  
, Pharm.D. 
 
 
Telephone No.:  
 
Approval of the request and unblinding of study drug assignment will occur only during 
business hours. 
Any toxicities associated or possibly associated with bevacizumab treatment were and 
should be managed according to standard medical practice.  Discontinuation of 
bevacizumab has no immediate therapeutic effect.  Bevacizumab has a terminal half-life 
of 2–3 weeks; therefore, its discontinuation results in slow elimination over several 
months.  There is no available antidote for bevacizumab.  The iInvestigators were 
allowed to hold administration of study drug while waiting for a decision on unblinding to 
be made. 
SECTION 4.3.1:  Formulation 
b. Tarceva 
Tarceva will continues to be supplied by Astellas OSI Pharmaceuticals US on behalf of 
OSI Pharmaceuticals LLC, Inc. and F. Hoffmann-La Roche, Ltd.  The oral tablets are 
conventional, immediate-release tablets containing erlotinib as hydrochloride salt.  In 
addition to the active ingredient (erlotinib), tablets contain lactose (hydrous), 
microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, magnesium 
stearate, and the film coating Opadry® White, which is composed of hypromellose, 
hydroxypropyl cellulose, and titanium dioxide.  Tablets containing 25 mg, 100 mg, and 
150 mg of Tarceva are available.  Erlotinib will be provided in a bottle.  Each bottle 
will contain or blister pack contains 30 tablets, a quantity sufficient for 4 consecutive 
weeks of dosing, with overage.  For further details, see the Tarceva® Investigator 
Brochure or Package Insert (see Appendix B). 
SECTION 4.3.3:  Dosage Modification 
Upon enactment of Amendment 6, no dose adjustments will be permitted. Any patient 
requiring a dose modification due to an AE or PD should be terminated from the study 
and treated following the physician’s usual standard of care. Prior to Amendment 6, 
dose modifications were handled as below. 
SECTION 4.3.4:  Management of Toxicities Related to Study Treatment 
Upon enactment of Amendment 6, no dose adjustments will be permitted. Any patient 
requiring a dose modification due to an AE or PD should be terminated from the study 
and treated following the physician’s usual standard of care.  Prior to Amendment 6, 
toxicities related to study treatment were managed were handled as below. 
SECTION 4.4:  CONCOMITANT AND EXCLUDED THERAPIES 
Upon enactment of Amendment 6, no information on concomitant therapies will be 
collected.  Prior to Amendment 6, information on concomitant therapies were collected 
as below.  


 
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SECTION 4.5:  STUDY ASSESSMENTS 
The conduct below was required during the BETA trial.  This should be continued for all 
patients who remain on study treatment after the final analysis until Amendment 5 is 
approved.  After the approval of Amendment 5, treatment assessments should be based 
on the investigator’s clinical judgment or conducted in accordance with institutional 
guidelines. 
Upon enactment of Amendment 6, data collection will be restricted to spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms, not in the CRF, 
and handled according to instructions in Section 5.4.  Prior to Amendment 6, 
assessments were conducted as below. 
SECTION 4.5.3:  Study Treatment Discontinuation Visit 
Following termination of the study no further information will be collected upon 
enactment of Amendment 6.  Patients will be followed according to the physician’s 
usual standard of care.  Prior to Amendment 6, the study termination visit and follow-
up assessments were conducted as below. 
SECTION 4.8:  STATISTICAL METHODS 
The statistical methods noted below were utilized during the interim and final 
analyses for OSI3364g when appropriate.  The safety of patients who remain on 
study after the final analysis will be monitored by Genentech or a company 
representative.  See Section 4.8.8.  Reporting of safety data after the final analysis is 
described in Section 5.5. Upon enactment of Amendment 6, no further analysis will be 
done. Data collection will be restricted to the spontaneous reporting of serious adverse 
events via MedWatch FDA 3500 forms and will not be captured in the CRF. 
SECTION 4.8.5:  Safety Analyses 
Upon enactment of Amendment 6, data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms (not in the CRF), 
and handled according to instructions in Section 5.4.  Prior to Amendment 5 safety 
assessments were conducted as below. 
Safety was assessed through summaries of adverse events and laboratory test results.  
Patients who receive any amount of study treatment will be included in the safety 
assessment.  Safety results were summarized by the treatment patients actually 
received for all patients, for patients with squamous cell carcinoma, for patients with 
brain metastases treated prior to enrollment, and for patients receiving full-dose 
anticoagulation with low-molecular-weight heparin or fondaparinux. 
Safety data collected after the final analysis will bewas reviewed and summarized for 
inclusion in the Investigator’s Brochure by Genentech or Genentech’s agent. 


 
Bevacizumab and Erlotinib—Genentech, Inc. 
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a. Adverse Events 
As clinical data and AEs will no longer be collected in the clinical database, no AEs 
will be recorded on the CRF. 
SECTION 4.8.8:  Interim Analyses 
Genentech and or a company representative will monitor the safety of patients who remain on 
study after the final analysis.  The focus will be on serious adverse events. 
Upon enactment of Amendment 6, data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms and will not be 
captured in the CRF. 
SECTION 5:  ASSESSMENT OF SAFETY 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF. The plan below was utilized prior to the final analysis 
of OSI3364g. 
The plan below was utilized prior to the final analysis of OSI3364g.  The assessment 
plan should be continued for all patients who remain on study treatment after the final 
analysis, unless stated otherwise.   
Adverse event collection subsequent to the activation of Amendment 5 will be limited to the 
collection of serious adverse events (SAEs).  The period of collection will end 30 days after study 
treatment discontinuation. This will focus the safety evaluation of the bevacizumab and Tarceva 
combination during this period on events of greatest clinical significance. 
SECTION 5.1.2:  Serious Adverse Events 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF. 
SECTION 5.2:  METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF. The plan below was utilized prior to the final analysis 
of OSI3364g. 
SECTION 5.3.2:  Specific Instructions for Recording Adverse Events on the 
Case Report Form 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF. 




 
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SECTION 6.2:  STUDY COMPLETION 
Study OSI3364g is considered complete and no further patient data will be collected, except for 
serious adverse event reporting via MedWatch FDA 3500 Forms, (not in the CRF), and will be 
handled according to instructions in Section 5.4  
SECTION 6.3:  INFORMED CONSENT 
The Informed Consent Form has been revised to reflect the changes made to the protocol under 
Amendment 6.  Following submission and IRB approval of Amendment 6, only those patients 
who are currently receiving study treatment will be required to be reconsented with the amended 
Informed Consent Form. 
SECTION 6.5:  STUDY MONITORING REQUIREMENTS 
Upon enactment of Amendment 6, all necessary study monitoring and site management will be 
performed remotely.  
SECTION 6.9:  STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be provided by Genentech and 
Astellas Pharmaceuticals.  The recipient will acknowledge receipt of the drug by 
returning the INDRR 1 form indicating shipment content and conditionenclosed 
paperwork that is received with study medication shipments.  Damaged supplies will be 
replaced. 
Accurate records of all study drug dispensed from and returned to the study site should 
be recorded by using the Drug Inventory Log. 
All partially used or empty containers should be disposed of at the study site according 
to institutional standard operating procedure only after study drug reconciliation has 
been performed and disposal has been authorized by a Genentech representative.  
Return unopened, expired, or unused study drug with the Inventory of Returned Clinical 
Material form as directed by Genentech. 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
The Protocol Amendment Acceptance Form has been updated to include the current 
administrative contacts. 
U.S. Sites: 
Non U.S. Sites: 
 
Covance 
PPD LLC 
Attn:  
 
3151 South 17th Street 
6 Roxborough Way 
Wilmington, NC  28412 
Maidenhead, Berkshire 
Telephone:  
 
SL6 3UD  United Kingdom 
APPENDIX D:  MedWatch Form FDA 3500 
Appendix D has been appended to the protocol.   
SAMPLE INFORMED CONSENT FORM ADDENDUM 
The sample Informed Consent Form has been created to inform of the changes to the 
protocol. 


 
 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
PROTOCOL SYNOPSIS .................................................................................... 17 
1. 
BACKGROUND .......................................................................................... 23 
1.1 
Introduction............................................................................ 23 
1.2 
Clinical Experience with Bevacizumab .................................. 25 
1.2.1 
Safety Profile ......................................................................... 26 
1.2.2 
Efficacy Results in Non−Small Cell Lung Cancer .................. 28 
1.3 
Clinical Experience with Tarceva........................................... 28 
1.3.1 
Safety Profile ......................................................................... 28 
1.3.2 
Efficacy Results in Non−Small Cell Lung Cancer .................. 30 
1.3.3 
EGFR Mutations in Non−Small Cell Lung Cancer ................. 31 
1.4 
Bevacizumab and Tarceva Combination Studies .................. 31 
2. 
OBJECTIVES.............................................................................................. 33 
2.1 
Primary Objective .................................................................. 33 
2.2 
Secondary Objectives............................................................ 34 
3. 
STUDY DESIGN ......................................................................................... 34 
3.1 
Description of the Study......................................................... 34 
3.2 
Rationale for Study Design.................................................... 36 
3.3 
Outcome Measures ............................................................... 37 
3.3.1 
Primary Efficacy Outcome Measure ...................................... 37 
3.3.2 
Secondary Efficacy Outcome Measures................................ 37 
3.3.3 
Pharmacokinetic Outcome Measures.................................... 37 
3.3.4 
Safety Outcome Measures .................................................... 37 
3.4 
Safety Plan ............................................................................ 38 
3.5 
Control Group........................................................................ 39 
3.6 
Minimization of Bias............................................................... 40 
3.7 
Ethical Considerations........................................................... 40 
3.8 
Administrative Structure......................................................... 43 
3.9 
Compliance with Laws and Regulations ................................ 43 
4. 
MATERIALS AND METHODS .................................................................... 43 


 
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4.1 
Patients.................................................................................. 43 
4.1.1 
Patient Selection.................................................................... 43 
4.1.2 
Inclusion Criteria.................................................................... 43 
4.1.3 
Exclusion Criteria................................................................... 45 
4.2 
Method of Treatment Assignment and Blinding..................... 47 
4.3 
Study Treatment.................................................................... 48 
4.3.1 
Formulation............................................................................ 48 
4.3.2 
Dosage, Administration, and Storage .................................... 49 
4.3.3 
Dosage Modification .............................................................. 51 
4.3.4 
Management of Toxicities Related to Study 
Treatment .............................................................................. 52 
4.4 
Concomitant and Excluded Therapies................................... 58 
4.4.1 
Concomitant Therapies and Procedures ............................... 59 
4.4.2 
Excluded Therapies............................................................... 60 
4.5 
Study Assessments ............................................................... 60 
4.5.1 
Screening and Pretreatment Assessments............................ 60 
4.5.2 
Assessments During Treatment ............................................ 62 
4.5.3 
Study Treatment Discontinuation Visit................................... 64 
4.5.4 
30-Day Post−Study Treatment Discontinuation 
Visit........................................................................................ 65 
4.5.5 
Follow-Up Assessments ........................................................ 65 
4.6 
Study Drug Discontinuation ................................................... 66 
4.7 
Study Termination ................................................................. 66 
4.8 
Statistical Methods ................................................................ 66 
4.8.1 
Analysis of the Conduct of the Study..................................... 67 
4.8.2 
Analysis of Treatment Arm Comparability.............................. 67 
4.8.3 
Efficacy Analyses .................................................................. 67 
4.8.4 
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 69 
4.8.5 
Safety Analyses..................................................................... 71 
4.8.6 
Missing Data.......................................................................... 71 
4.8.7 
Determination of Sample Size ............................................... 72 
4.8.8 
Interim Analyses .................................................................... 72 
4.9 
Data Quality Assurance......................................................... 73 


 
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5. 
ASSESSMENT OF SAFETY....................................................................... 74 
5.1 
Specification of Safety Variables ........................................... 74 
5.1.1 
Adverse Events ..................................................................... 74 
5.1.2 
Serious Adverse Events ........................................................ 75 
5.2 
Methods and Timing for Assessing and 
Recording Safety Variables ................................................... 75 
5.2.1 
Adverse Event Reporting Period ........................................... 76 
5.2.2 
Assessment of Adverse Events............................................. 76 
5.3 
Procedures for Eliciting, Recording, and 
Reporting Adverse Events..................................................... 78 
5.3.1 
Eliciting Adverse Events ........................................................ 78 
5.3.2 
Specific Instructions for Recording Adverse 
Events on the Case Report Form .......................................... 78 
5.4 
Expedited Reporting Requirements for Serious 
Adverse Events ..................................................................... 81 
5.5 
Type and Duration of Follow-up of Patients after 
Adverse Events ..................................................................... 82 
6. 
INVESTIGATOR REQUIREMENTS............................................................ 82 
6.1 
Study Initiation....................................................................... 83 
6.2 
Study Completion .................................................................. 83 
6.3 
Informed Consent .................................................................. 84 
6.4 
Institutional Review Board or Ethics Committee 
Approval ................................................................................ 85 
6.5 
Study Monitoring Requirements ............................................ 85 
6.6 
Case Report Forms ............................................................... 85 
6.7 
Source Data Documentation.................................................. 86 
6.8 
Use of Computerized systems............................................... 86 
6.9 
Study Medication Accountability............................................ 87 
6.10 
Disclosure of Data ................................................................. 87 
6.11 
Retention of Records............................................................. 87 
7. 
REFERENCES ........................................................................................... 89 
 


 
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LIST OF TABLES 
Table 1 
Tarceva Dose Level Reductions ................................................. 52 
Table 2 
Dosage Modification Criteria and Guidelines for 
Management of Study Treatment–Related Toxicities ................. 53 
Table 3 
Adverse Event Grading (Severity) Scale..................................... 77 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema............................................................................. 36 
 
 
LIST OF APPENDICES 
Appendix A  Study Flowchart.............................................................................. 94 
Appendix B  Tarceva® Package Insert............................................................... 96 
Appendix C  Final Study Results ...................................................................... 121 
Appendix D  MedWatch Form FDA 3500 ......................................................... 122 


 
 
 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, MULTICENTER, 
PLACEBO-CONTROLLED, DOUBLE-BLIND, 
RANDOMIZED CLINICAL TRIAL TO EVALUATE 
THE EFFICACY OF BEVACIZUMAB IN 
COMBINATION WITH TARCEVA® (ERLOTINIB) 
COMPARED WITH TARCEVA ALONE FOR 
TREATMENT OF ADVANCED NON−SMALL CELL 
LUNG CANCER (NSCLC) AFTER FAILURE OF 
STANDARD FIRST-LINE CHEMOTHERAPY 
PROTOCOL NUMBER: 
OSI3364g 
VERSION NUMBER: 
A6 
IND NUMBER: 
7023 
TEST PRODUCT: 
Bevacizumab (RO4876646) and Erlotinib (RO508231) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the original form to the appropriate address provided below. 
Please retain a copy for your study files. 
 
U.S. Sites: 
 
 
 
PPD LLC 
 
3151 South 17th Street 
 
Wilmington, NC  28412 
 
Telephone:  
 
 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, PLACEBO-CONTROLLED, 
DOUBLE-BLIND, RANDOMIZED CLINICAL TRIAL TO 
EVALUATE THE EFFICACY OF BEVACIZUMAB IN 
COMBINATION WITH TARCEVA® (ERLOTINIB) COMPARED 
WITH TARCEVA ALONE FOR TREATMENT OF ADVANCED 
NON−SMALL CELL LUNG CANCER (NSCLC) AFTER 
FAILURE OF STANDARD FIRST-LINE CHEMOTHERAPY 
 
PROTOCOL NUMBER: 
OSI3364g 
STUDY DRUGS: 
Bevacizumab 
Tarceva® (Erlotinib) 
PHASE: 
III 
INDICATION: 
Advanced NSCLC after failure of standard first-line 
chemotherapy 
IND: 
7023 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080-4990  U.S.A. 
 
objectives 
Primary Objective 
The primary objective of this Phase III study was to evaluate the efficacy of combining 
bevacizumab with Tarceva (erlotinib) relative to Tarceva monotherapy in patients receiving 
second-line therapy for advanced NSCLC.  Efficacy will be assessed by measuring overall 
survival. 
The addition of bevacizumab to erlotinib in the BETA lung study was not associated with an 
improvement in overall survival.  However, bevacizumab when combined with erlotinib improved 
progression-free survival (PFS) and overall response rate (ORR), demonstrating evidence of 
clinical activity.   
 
Secondary Objectives 
The secondary objectives of this Phase III study were as follows: 
• 
To evaluate the safety of combining bevacizumab with Tarceva in patients with previously 
treated advanced NSCLC, including patients with squamous cell carcinoma, patients with 
treated brain metastases, and patients receiving full-dose anticoagulation with 
low-molecular-weight heparin or fondaparinux. 
Note:  See Section 4.1.2 for the eligibility criteria regarding squamous cell carcinoma 
patients. 
Upon enactment of Amendment 6, patients still benefiting from their treatment will continue to receive 
it until disease progression, but no CRF data will be collected anymore. Serious Adverse Events will be 
collected spontaneously via MedWatch FDA 3500 forms ( Appendix D) and will no longer be captured in 
the CRF. 
 


 
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• 
To evaluate the efficacy of combining bevacizumab with Tarceva relative to Tarceva 
monotherapy in patients with previously treated advanced NSCLC, as measured by PFS, 
ORR, and duration of response 
• 
To evaluate the pharmacokinetic behavior of Tarceva and the combination of bevacizumab 
with Tarceva in a subset of patients with previously treated advanced NSCLC 
• 
To evaluate the association of survival, PFS, and treatment effect with markers of epidermal 
growth factor receptor (EGFR) expression, as measured by immunohistochemistry (IHC), 
EGFR gene copy number measured by fluorescence in situ hybridization (FISH), and other 
molecular markers of EGFR pathway activity in archival tissue samples 
 
study Design 
This is a Phase III, multicenter, placebo-controlled, double-blind, randomized study.  Six 
hundred thirty-six patients were randomized in a 1:1 ratio to one of two treatment arms: 
• 
Arm 1:  Tarceva + placebo 
• 
Arm 2:  Tarceva + bevacizumab 
 
Outcome MeasureS 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study was overall survival, defined as the period 
from the date of randomization until the date of patient death from any cause. 
The addition of bevacizumab to erlotinib in the BETA lung study was not associated with an 
improvement in overall survival.  However, bevacizumab when combined with erlotinib improved 
PFS and ORR, demonstrating evidence of clinical activity.  See Appendix C. 
 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures were as follows: 
• 
PFS, defined as the time from randomization to documented disease progression, as 
determined by the investigator using the Response Evaluation Criteria in Solid Tumors 
(RECIST), or death on study treatment, whichever occurs first 
• 
Objective response, as determined by the investigator using RECIST 
• 
Duration of objective response, defined as the period from the date of initial partial or 
complete response (as determined by the investigator using RECIST) until the date of 
disease progression or death from any cause on study treatment 
• 
Evaluation of the relationship between molecular exploratory markers and efficacy 
outcomes 
 
Pharmacokinetic Outcome Measures 
The pharmacokinetic outcome measures for erlotinib and its metabolite (OSI-420) were as 
follows: 
• 
Maximum concentration at steady state (Cmax,ss)  
• 
Time of the maximum concentration at steady state (Tmax,ss) 
• 
Minimum concentration at steady state (Cmin,ss)  
• 
Apparent clearance at steady state 
• 
Area under the erlotinib time−concentration curve (AUC0–tau) 
The pharmacokinetic outcome measures for bevacizumab were as follows: 
• 
Maximum concentration (Cmax) 
• 
Minimum concentration (Cmin) 
 


 
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Safety Outcome Measures 
The safety outcome measures for this study were the following: 
• 
Incidence and severity of adverse events and serious adverse events 
• 
Changes in laboratory values  
Upon enactment of Amendment 6, data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms and will no longer be 
captured in the CRF. 
 
Safety Plan 
Upon enactment of Amendment 6, data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms and will no longer be 
captured in the CRF.  Prior to Amendment 6, the safety plan was as below. 
Patients enrolled in this study were evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study.  Safety evaluations consisting of 
medical interviews, recording of concomitant medications and adverse events, physical 
examinations, blood pressure, and laboratory measurements (performed by local laboratories, 
see Section 4.5 and Appendix A) have been conducted.  Patients have been evaluated for 
adverse events (all grades), serious adverse events, and adverse events requiring study drug 
interruption or discontinuation at each study visit while on study drug.  Patients discontinued 
from the treatment phase of the study for any reason were evaluated ~30 days (28–42 days) 
after the decision to discontinue treatment (see Section 4.5.3).  Patients with an ongoing 
Grade 4 or serious adverse event at the time of discontinuation from study treatment were 
followed until the event is resolved or determined to be irreversible by the investigator (see 
Section 4.5.3). 
 
Study Treatment 
The dose of bevacizumab in this study continues to be 15 mg/kg administered by IV infusion on 
the first day of each 3-week cycle (± 4 days; the interval between infusions must not be < 17 
days).  The bevacizumab dose should be based on the patient’s weight at screening (within 7 
days prior to randomization) and should remain the same throughout the study (± 5% dosing 
variation).  If bevacizumab/placebo administration fell outside of the 4-day visit window, for 
reasons other than toxicity management, the site had to obtain a protocol waiver prior to the 
infusion.  The patient’s schedule was then adjusted so that the subsequent 
bevacizumab/placebo infusion was given 3 weeks after the re-scheduled infusion. 
Protocol waivers are no longer required for changes in treatment.  Changes in the treatment 
dose or schedule may be made based upon the investigator’s judgment and the institutional 
guidelines of the site.  Placebo dosing will be discontinued for all patients on the Tarceva and 
placebo arm of the trial without evidence of progression as of the enactment of BETA lung trial 
Amendment 5.   
The initial bevacizumab/placebo dose was delivered over 90 (± 10) minutes as a continuous IV 
infusion on Day 0.  If a patient experienced an infusion-associated adverse event, he or she 
could be pre-medicated for the next study drug infusion; however, the infusion time could not be 
decreased for the subsequent infusion.  If the first infusion was tolerated without 
infusion-associated adverse events, the second infusion could be delivered over 60 minutes 
(± 10 minutes).  If a patient experienced infusion-associated adverse events with the 60-minute 
infusion, all subsequent doses were to be given over 90 minutes.  If the 60-minute infusion was 
well tolerated, all subsequent infusions could be delivered over 30 ± 10 minutes.  If a patient 
experienced infusion-associated adverse events with the 30-minute infusion, all subsequent 
doses were to be given over 60 minutes.  If the patient continued to experience infusion-
associated adverse events with the 90-minute infusion, the patient’s symptoms were managed 
per institutional standard of care. 
Upon enactment of Amendment 6, no dose adjustments will be permitted. If a patient needs a 
reduced dose, she/he will be withdrawn from the study and will be treated following the 
physician’s usual standard of care 
 


 
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Concomitant Therapy AND CLINICAL PRACTICE 
All concomitant medications administered within 14 days preceding the initial study treatment 
administration on this study through the 30-day Post−Study Treatment Discontinuation Visit 
were recorded.  The reason(s) for treatment, dosage, and dates of treatment should have been 
reported to the investigator and recorded as instructed on the study-specific Case Report Forms 
(CRFs). 
Patients using oral contraceptives, hormone replacement therapy, or other maintenance therapy 
were asked to continue their use.  Patients received full supportive care, including 
hematopoietic growth factors, transfusions of blood and blood products, antibiotics, 
anti-emetics, etc., when appropriate.  Use of anti-tumor therapies was permitted after study 
treatment discontinuation. 
Patients who experience infusion-associated temperature elevations to ≥ 38.5°C (101.3°F) or 
other infusion-associated symptoms may be treated symptomatically with acetaminophen, 
diphenhydramine, meperidine, or other medications as clinically indicated, including ≤ 48 hours 
of treatment with corticosteroids. 
It is recommended that patients with indwelling venous catheters receive prophylaxis against 
catheter thrombosis in accordance with the local standard of care.  Full-dose anticoagulation 
using low-molecular-weight heparin or fondaparinux is permitted, starting either prior to study 
enrollment or during study participation.  Because of a potential drug–drug interaction between 
Tarceva and warfarin, it is preferable that patients receive low-dose warfarin for this purpose.  
Patients receiving prophylactic or low-dose warfarin or its equivalent require close INR 
monitoring. 
Because of the bleeding risk associated with bevacizumab, chronic use of aspirin at a dose of 
> 325 mg/day and full-dose NSAIDs are to be avoided. 
Prolonged use of systemic corticosteroids for the treatment of skin toxicities is discouraged.  
Patients who are taking corticosteroids for reasons other than skin toxicity at study entry may 
continue their use.   
 
Statistical Methods 
Primary Efficacy Analysis 
Analyses of overall survival and PFS included all patients who were randomized.  For objective 
response and clinical benefit, only patients with measurable disease at baseline were included 
in the analysis.  For duration of response, only responders were included in the analysis.  All 
analyses were based on the treatment arm to which patients were randomized. 
The primary efficacy endpoint was overall survival, defined as the period from the date of 
randomization (as entered in the IVRS) until the date of patient death from any cause.  All 
deaths were included, regardless of whether they occur during treatment or following treatment 
discontinuation.  For patients who have not died, survival data were censored at the date of last 
contact.   
The two-sided log-rank test, stratified by the randomization stratification factors, was used to 
perform hypothesis testing for assessing the primary study objective.  The randomization 
stratification factors were ECOG performance status (0/1 vs. 2), smoking history (never vs. 
current/previous), sex (male vs. female), and study site; however, because of the large number 
of study sites in this trial, study sites will not be included in any efficacy analyses adjusted for 
randomization stratification factors.  Levels of the stratification factors reported on the CRF were 
used in the analysis.  A sensitivity analysis stratified using levels reported on the IVRS was 
performed.  Both analyses were based on the treatment arm to which the patients have been 
randomized.   
An interim efficacy analysis was conducted when approximately 67% of the required deaths 
(280 deaths) occurred.  Overall survival was tested at the significance level determined using 
the Lan-DeMets alpha spending function with an O’Brien-Fleming boundary so that the overall 
type I error rate will be maintained at the 0.05 level.  The DMC recommended that the study 
continue as planned.  The final efficacy analysis was conducted when 418 deaths occurred. 
The unstratified log-rank test was performed as a sensitivity analysis.  The Kaplan-Meier 
methods were used to estimate median overall survival for each treatment arm.  Cox 


 
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proportional hazard models, using two models (with and without stratification by the 
randomization stratification factors), were employed to estimate the hazard ratio (i.e., the 
magnitude of treatment effect and 95% CI).   
Upon enactments of Amendment 6, all the remaining patients in the study receive single 
agent open-label erlotinib. No further analysis will be done. 
 
Safety Analyses 
Safety was assessed through summaries of adverse events and laboratory test results.  
Patients who receive any amount of study treatment will be included in the safety assessment.  
Safety results were summarized by the treatment patients actually received for all patients, for 
patients with squamous cell carcinoma, for patients with brain metastases treated prior to 
enrollment, and for patients receiving full-dose anticoagulation with low-molecular-weight 
heparin or fondaparinux. 
Safety data collected after the final analysis will be reviewed and summarized for inclusion in 
the Investigator’s Brochure by Genentech or Genentech’s agent. 
Upon enactment of Amendment 6, safety data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms and will not  be captured 
in the CRF. 
 
Missing Data 
For overall survival, patients who were lost to follow-up were analyzed as censored 
observations on the date of last contact. 
Details of the analyses of missing data were provided in the Statistical Analysis Plan.  
 
Determination of Sample Size 
This was a Phase III study to evaluate the efficacy and safety of bevacizumab in combination 
with Tarceva relative to Tarceva alone in advanced NSCLC.  A 33% improvement in survival 
was considered a clinically significant outcome.  To calculate the number of deaths required in 
this study, the following assumptions were made: 
• 
Two-sided log-rank test 
• 
83% power at the 5% significance level 
• 
Hazard ratio of bevacizumab + Tarceva versus control (Tarceva alone)  
of 0.75 corresponding to a 33% improvement in median overall survival from 8 to 
10.67 months 
• 
Median overall survival for the control arm is hypothesized based on data from 
Study BR.21, taking into account the difference in patient population. 
• 
An interim efficacy analysis will be performed when 67% of the required deaths have 
occurred.  The significance level will be determined using the Lan-DeMets alpha spending 
function with an O’Brien-Fleming boundary. 
• 
Five percent of patients will withdraw consent for survival follow-up or will be lost to follow-
up. 
With these assumptions, 417 deaths were required for the final analysis.   
 
Interim Analyses 
The eligible patient population was expanded to include selected patients with squamous cell 
carcinoma, patients with brain metastases treated prior to enrollment, and patients receiving 
full-dose anticoagulation with low-molecular-weight heparin or fondaparinux.  A DMC monitored 
the safety of these and all other patients on this trial.  The DMC reviewed safety summaries 
prepared by an external statistical data coordinating center, including monthly serious adverse 
event reports and thorough interim safety reports.  Members of the DMC were external to 
Genentech and followed a charter that outlined their role and responsibilities.  Study personnel 
remain blinded to study results until the formal unblinding took place in October 2008. 
All patients were monitored clinically at 3-week intervals and radiographically at 6-week 
intervals through Week 24, at which point scans were followed at 12-week intervals.  Patients 


 
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with a history of brain metastases also under went head CT scans or MRI scans every 6 weeks 
after Day 0 (beginning at Week 6) through Week 24 and then every 12 weeks thereafter.  
Summaries of collected serious adverse events were reviewed by the DMC monthly for all 
patients, for patients with squamous cell carcinoma, and for patients with brain metastases 
treated prior to enrollment.  
All NCI CTCAE Grade ≥ 3 hemoptysis and symptomatic Grade ≥ 2 CNS hemorrhage events 
were to be reported as serious adverse events.  Grade ≥ 3 hemoptysis events were closely 
monitored for patients with squamous cell carcinoma; enrollment for this subpopulation was to 
be discontinued if the incidence was unacceptable (for the stopping guidance, see the DMC 
charter).  Symptomatic Grade ≥ 2 CNS hemorrhage events was closely monitored for patients 
with brain metastases treated prior to enrollment; accrual for this subpopulation was to be 
stopped if the incidence was unacceptable (for the stopping guidance, see the DMC charter).  
Symptomatic Grade ≥ 3 hemorrhage events was closely monitored for patients fully 
anticoagulated with low-molecular-weight heparin or fondaparinux; accrual for this 
subpopulation was to be stopped if the incidence of such events was unacceptable.   
Two interim analyses were conducted.  The first interim analysis was conducted after 
123 patients had been enrolled and followed for at least 2 months.  Only safety data were 
assessed in this analysis.  The DMC reviewed the interim safety report on 10 July 2006 and 
recommended that the study continue as planned.  
The second interim analysis was conducted when approximately 67% of the required deaths 
(280 deaths) occurred.  Both safety and overall survival were assessed in this analysis.  Formal 
comparisons between the two treatment arms of the incidence of Grade 3−5 and Grade 5 
hemoptysis were made.  If the incidence in the Tarceva + bevacizumab arm was unacceptable, 
the study would have been stopped (for the stopping guidance, see the DMC charter).  The 
significance level for the overall survival comparison was determined using the Lan-DeMets 
alpha spending function with an O’Brien-Fleming boundary of 0.0124 at 67% event time and 
0.0462 at the final analysis.  The overall survival result was not positive, so the study was 
continued until 417 deaths occurred. 
All summaries/analyses by treatment arm for the DMC review were performed by an 
independent Data Coordinating Center (DCC).  The study team remained blinded to the 
treatment assignment until study unblinding. 
Upon enactment of Amendment 6, safety data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms and will not be captured 
in the CRF. 
 
 


 
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1. 
BACKGROUND 
1.1 
INTRODUCTION 
Lung cancer is the leading cause of cancer-related death in North America (Pazdur et al. 
2004).  Eighty percent of lung cancer is non−small cell lung cancer (NSCLC), and ~75% 
of patients with NSCLC present with advanced stage disease (unresectable or 
metastatic disease).  The overall 5-year survival rate for patients who develop lung 
cancer in the United States is 14%, having only slightly improved over the past 20 years 
(DeVita et al. 2001).  Patients who present with Stage IIIB and Stage IV disease have 
fairly equal and dismal prognoses, with 5-year survival rates of 6% to 8% (Mountain 
1997).  Median survival for patients with metastatic NSCLC is historically ~4 months 
when treated with best supportive care (Bunn et al. 1998). 
Advances made in the last decade with the development of cytotoxic therapies for 
NSCLC have had little impact on overall survival in patients with advanced stage 
disease.  Platinum-based doublet chemotherapy (primarily carboplatin/paclitaxel in the 
United States) has remained the standard front-line treatment of advanced disease, with 
multiple randomized trials confirming a median survival of 8 months and response rates 
averaging 26% (Schiller et al. 2002).  Although newer chemotherapeutic agents 
(gemcitabine, vinorelbine, docetaxel) have been able to improve the quality of patients’ 
lives and prolong survival (Bunn et al. 1998; Bunn and Kelly 1998; Carney 1998; 
Sweeney and Sandler 1998), patients will eventually become refractory to or suffer 
dose-limiting toxicity from cytotoxic therapy. 
Therapeutic options for patients after relapse were limited to best supportive care or 
palliation until a trial comparing docetaxel with best supportive care showed that patients 
with NSCLC could benefit from second-line chemotherapy after cisplatin-based first-line 
regimens failed (Shepherd et al. 2000).  Benefit was measured in terms of prolongation 
of time to disease progression and overall survival, improvement in symptoms, reduction 
in the need for cancer-related medicines (in particular narcotic pain medications), and 
improvement in several quality-of-life indices.  A second trial comparing docetaxel with 
ifosfamide or vinorelbine confirmed that docetaxel provides a benefit, with an 
improvement in 1-year survival (30% vs. 20%; Fossella et al. 2000).  The benefit of 
docetaxel monotherapy does not extend beyond second-line treatment.  Patients 
receiving docetaxel as third-line treatment or beyond showed no prolongation of survival 
(Shepherd et al. 2000). 
In August 2004, another cytotoxic agent, pemetrexed (Alimta®), received approval from 
the Food and Drug Administration (FDA) as second-line therapy for patients with 
advanced NSCLC.  This approval was based on a randomized Phase III trial involving 
571 patients that compared single-agent pemetrexed with single-agent docetaxel 
(Hanna et al. 2004).  Although this trial did not demonstrate statistical non-inferiority vs. 
docetaxel with respect to efficacy, the two agents produced similar response rates and 


 
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progression-free, median, and 1-year survival.  In addition, pemetrexed was associated 
with a lower incidence of toxicity than docetaxel. 
Despite these chemotherapeutic advances, many advanced stage patients are still 
unable to tolerate these cytotoxic therapies, and their prognosis remains poor.  
Therefore, efforts are ongoing to develop effective regimens without significantly 
increasing toxicity.  Strategies that target tumor cell growth, such as inhibiting tumor 
angiogenesis or targeting the cell surface receptors responsible for modulating tumor 
cell proliferation, have the potential to demonstrate increased target specificity and 
therefore, presumably, less overall toxicity.  One of these agents, Tarceva® (erlotinib), is 
a small molecule inhibitor of the epidermal growth factor receptor (EGFR), an important 
receptor for signaling tumor cell proliferation.  In the pivotal Phase III study BR.21, 
Tarceva was shown to improve overall survival in second- and third-line NSCLC patients 
versus placebo (Shepherd et al. 2004).  Furthermore, the trial showed that Tarceva was 
well tolerated and associated with a longer time to symptom deterioration compared with 
placebo.  Based on the data from this trial, in November 2004, the FDA approved 
Tarceva for the treatment of patients with locally advanced or metastatic NSCLC 
following failure of at least one prior chemotherapy regimen. 
Bevacizumab, another targeted agent, is a recombinant monoclonal antibody that 
targets vascular endothelial growth factor (VEGF), a critical factor in tumor angiogenesis 
(Ferrara and Davis-Smyth 1997).  Bevacizumab (Avastin®) was approved by the FDA for 
first- and second-line treatment of metastatic colorectal carcinoma in combination with 
intravenous (IV) 5-fluorouracil−based chemotherapy in February 2004 and June 2006, 
respectively.  Bevacizumab also demonstrated encouraging activity in NSCLC in a 
randomized Phase II trial (AVF0757g) when administered in combination with 
carboplatin and paclitaxel (Johnson et al. 2004).  In this study, patients receiving 
chemotherapy + bevacizumab had higher response rates, longer median time to 
progression (TTP), and a modest increase in survival.  Based on these data, the Eastern 
Cooperative Oncology Group (ECOG) conducted a first-line Phase III trial (E4599) with 
carboplatin/paclitaxel ± bevacizumab in non-squamous NSCLC.  The results from this 
trial demonstrated that the combination provided a significant improvement in overall 
survival (Sandler et al. 2005).  (Please refer to the respective Investigator Brochures for 
additional information on the physical and pharmaceutical properties and a review of 
nonclinical studies for each agent.) 
This Phase III study was designed to evaluate the combination of the aforementioned 
targeted agents (the anti-angiogenic agent bevacizumab plus the EGFR inhibitor 
Tarceva) against Tarceva alone.  It was hypothesized that the potential complementary 
mechanisms of tumor control of these two agents, both active in NSCLC, might translate 
into added efficacy of the combination over single-agent Tarceva’s proven clinical benefit 
while maintaining tolerability.  In this trial, efficacy was assessed in terms of overall 
survival.  Efficacy was also evaluated in terms of progression-free survival (PFS), 
objective response rate (ORR), duration of objective response, and clinical benefit. 


 
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The final analysis of the BETA lung trial was conducted in October, 2008.  The trial did 
not demonstrate an improved overall survival for patients treated with Tarceva and 
bevacizumab compared with those treated with Tarceva and placebo.  However, there 
was evidence of clinical activity evidenced by improvements in PFS and objective 
response (see Appendix C). 
1.2 
CLINICAL EXPERIENCE WITH BEVACIZUMAB 
Bevacizumab has been studied in at least 3500 patients in a number of Phase I, II, and 
III clinical trials.  These clinical trials have included patients with a number of tumor 
types, including colorectal, breast, lung, and renal carcinoma.  The following discussion 
summarizes bevacizumab’s safety profile and presents efficacy results pertinent to this 
trial.  Please refer to the Avastin® Investigator Brochure or Package Insert for 
descriptions of all completed Phase I, II, and III trials. 
In a large Phase III study (AVF2107g) of patients with metastatic colorectal cancer, the 
addition of bevacizumab to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy 
resulted in a clinically and statistically significant increase in duration of survival, with a 
hazard ratio (HR) of death of 0.660 (median survival 15.6 vs. 20.3 months; p < 0.0001).  
Similar increases were seen in PFS (6.2 vs. 10.6 months; p < 0.0001), overall response 
rate (35% vs. 45%; p < 0.0029), and duration of response (7.1 vs. 10.4 months; 
p < 0.0014) for the combination arm versus the chemotherapy only arm (Hurwitz et al. 
2004). 
Based on the survival advantage demonstrated in Study AVF2107g, bevacizumab was 
designated for priority review and was approved by the U.S. FDA for first-line treatment 
in combination with IV 5-FU−based chemotherapy for patients with metastatic colorectal 
cancer (CRC). 
The approval of bevacizumab for the second-line treatment of metastatic colorectal 
carcinoma was based upon results of a randomized, controlled, multicenter, Phase III 
trial of 829 patients with advanced or metastatic CRC who had received previous 
treatment with irinotecan and 5-FU as initial therapy for metastatic disease or as 
adjuvant therapy (Study E3200).  The study showed that patients who received 
bevacizumab plus the 5-FU-based chemotherapy regimen known as FOLFOX4 
(oxaliplatin/5-FU/leucovorin) had a 25% reduction in the risk of death (the primary 
endpoint; hazard ratio of 0.75 [95% CI 0.63, 0.89], p = 0.001 stratified logrank test), which 
was equivalent to a 33% improvement in overall survival, compared with patients who 
received FOLFOX4 alone.  Median survival for patients receiving bevacizumab plus 
FOLFOX4 was 13.0 months, compared with 10.8 months for those receiving FOLFOX4 
alone (Giantonia et al. 2005) 
In October of 2006, bevacizumab was approved for the first-line treatment of 
non-resectable, locally advanced, or metastatic non-squamous NSCLC.  This approval 


 
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was based on the results of the Eastern Cooperative Group (ECOG) Study 4599.  The 
results of this trial are described in Section 1.2.2  
In February 2008, bevacizumab given in combination with paclitaxel was approved for 
the first-line treatment of metastatic breast carcinoma.  This approval was based on the 
results of the ECOG Study 2100, a Phase III trial conducted in 722 patients.  In this trial, 
the combination of bevacizumab and paclitaxel increased PFS to 11.3 months compared 
to 5.8 months with paclitaxel alone (hazard ratio [HR], 0.48; P< .0001).  The combination 
was not associated with an improvement in overall survival.  The overall survival was 
26.5 months with bevacizumab and paclitaxel compared to 24.8 months for paclitaxel 
alone (HR, 0.87; P=0.14). 
1.2.1 
Safety Profile 
In the Phase I and II studies, four potential bevacizumab-associated safety concerns 
were identified:  hypertension, proteinuria, thromboembolic events, and hemorrhage.  
Completed Phase II and Phase III studies of bevacizumab have further defined the 
safety profile of this agent in patients with metastatic malignancies.  Also during the 
Phase III studies, three new possible bevacizumab-associated safety concerns were 
identified:  congestive heart failure in patients who had been exposed to anthracyclines, 
gastrointestinal perforations, and wound healing complications. 
Hypertension:  In Study AVF2107g, hypertension of any grade occurred in 22.4% of 
patients receiving IFL + bevacizumab compared with 8.3% receiving IFL + placebo.  
National Cancer Institute Common Toxicity Criteria (NCI-CTC) Grade 3 hypertension 
(requiring oral anti-hypertensive medication) was reported in 11.0% of patients receiving 
IFL + bevacizumab compared with 2.3% of patients receiving IFL + placebo.  The overall 
incidence of hypertension adverse events in Study AVF0757g was 17.6% (5.9% 
Grade 3) in the 15 mg/kg/q3 wk arm vs. 3.1% in the control arm.  Across clinical studies, 
the incidence of NCI-CTC Grade 3 or 4 hypertension ranged from 8% to 18%.  Oral 
medications have been used to manage the hypertension when indicated.  Grade 4 
hypertensive events are rare; however, hypertensive encephalopathy associated with 
fatal outcome has been reported.  In addition, reversible posterior leukoencephalopathy 
syndrome (RPLS) has been described in association with moderate hypertension 
(Glusker et al. 2006). 
Proteinuria:  Proteinuria, ranging from asymptomatic and transient events detected on 
routine dipstick urinalysis to nephrotic syndrome, has been seen in all clinical trials to 
date.  The majority of proteinuria events have been Grade 1 or 2.  In Studies AVF0757g 
and ECOG 3200, the incidence of NCI-CTC Grade 3 or 4 proteinuria, characterized 
as > 3.5 gm/24 hr, ranged up to 1.8% in bevacizumab-treated patients. 
Gastrointestinal perforation: Gastrointestinal perforation was not seen in the 
bevacizumab Phase I or II clinical trials; however, in the Phase III metastatic CRC trials, 
the incidence of gastrointestinal perforation, fistula formation, and/or intra-abdominal 


 
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abscess in patients receiving bevacizumab was 2.4%.  These episodes occurred at 
various timepoints during treatment.  The typical presentation was reported as 
abdominal pain associated with symptoms such as constipation and emesis. 
In post-marketing clinical studies and reports, gastrointestinal perforation, fistula 
formation and/or intra-abdominal abscess occurred in patients receiving bevacizumab 
for colorectal and for other types of cancer.  Of the reported events, approximately 30% 
were fatal.  Patients with gastrointestinal perforation, regardless of underlying cancer, 
typically presented with abdominal pain, nausea, and fever.  Events were reported at 
various timepoints during treatment ranging from 1 week to greater than 1 year from 
initiation of bevacizumab, with most events occurring within the first 50 days. 
Hemorrhage:  In the Phase II NSCLC trial (Johnson et al. 2004), 6 of 
66 bevacizumab-treated patients experienced life-threatening hemoptysis or 
hematemesis.  Four of these events were fatal.  An analysis of possible risk factors for 
life-threatening bleeding identified squamous cell histology (4 of 6 bleeds occurred in 
patients with squamous cell histology, whereas only 13 of 66 treated patients had 
squamous cell histology) and centrally located cavitary and/or necrotic lesions as 
potential risk factors. 
At the ASCO Annual Meeting of the American Society of Clinical Oncology (ASCO) in 
2006, a retrospective analysis of clinical and radiographic risk factors associated with the 
development of pulmonary hemorrhage in bevacizumab-treated NSCLC patients was 
reported (Sandler et al. 2006).  The authors suggested a potential association of 
pulmonary hemorrhage with hemoptysis and tumor cavitation.  However, the number of 
cases was too small to make a conclusive statement. 
On this basis, the enrollment of patients with squamous cell NSCLC in this trial is limited 
to those with lesions at low risk for life-threatening hemorrhage.  Patients at low risk are 
defined as those with peripheral lung lesions or extrathoracic lesions.  Patients with 
squamous histology with lesions other than peripheral are not recommended for study 
participation.  The definition for a peripheral lung lesion is given in Section 4.1.3  
Congestive heart failure:  Congestive heart failure (CHF), defined as NCI-CTC 
Grade 2−4 left ventricular dysfunction, has been reported in patients receiving 
bevacizumab.  The risk of CHF appears to be higher in patients receiving bevacizumab 
who have received prior or concurrent anthracyclines.  Prior radiation therapy to the 
chest wall may also increase the risk of CHF in these patients.   
Additional safety signals:  Other safety concerns seen to date—asthenia, pain, 
headache, fever, chills, rash, infection, epistaxis, and mouth ulceration—are not thought 
to be clinically significant because they rarely or never required treatment or study drug 
discontinuation. 


 
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Please refer to the Avastin® Investigator Brochure or Package Insert for additional 
details regarding safety experience with bevacizumab. 
1.2.2 
Efficacy Results in Non−Small Cell Lung Cancer 
In a randomized, Phase II study in advanced NSCLC (Study AVF0757g) (Johnson et al. 
2004), 99 patients with Stage IIIB, Stage IV, or recurrent NSCLC were randomized to 
receive either paclitaxel/carboplatin alone or paclitaxel/carboplatin + bevacizumab (either 
at 7.5 mg/kg or 15 mg/kg every 3 weeks).  In that study, the best confirmed response 
rate was higher for the high-dose bevacizumab arm compared with the control arm 
(investigator assessment, 32% vs. 19%).  Time to disease progression was also higher 
for the high-dose bevacizumab arm (investigator assessment; median 225 days vs. 
129 days for the control).  When patients with squamous cell NSCLC histology were 
excluded, the confirmed response rate, time to progression, and overall survival were 
higher for high-dose bevacizumab compared with the control arm.  Based on these 
results, ECOG conducted a first-line Phase III trial with 
paclitaxel/carboplatin + bevacizumab in non-squamous cell NSCLC, ECOG Study 4599.  
An interim analysis of the data from this trial met its primary efficacy endpoint of 
improving overall survival, or a reduction in the risk of death, compared with 
chemotherapy alone.  The rate of bevacizumab-related pulmonary hemorrhage in ECOG 
Study 4599 was 1.8% (Sandler 2005). 
The Avastin® in Lung (AVAIL) trial, a Phase III trial in which 1043 patients were enrolled, 
supported the results of ECOG 4599 by demonstrating an improved PFS for patients 
randomized to receive bevacizumab at 1 of 2 doses (7.5 mg/kg or 15 mg/kg) with 
chemotherapy, gemcitabine, and cisplatinum, compared with chemotherapy alone.  
The median PFS was 6.7 months in the 7.5 mg/kg bevacizumab arm and 6.5 months in 
the 15 mg/kg bevacizumab arm compared with 6.1 months in the chemotherapy alone 
arm.  The hazard ratios were 0.75 (P = .002) for the lower dose and 0.82 (P = .03) for 
the higher dose.  
Please refer to Section 1.4 and the Avastin Investigator Brochure or Package Insert for 
additional details regarding the efficacy of bevacizumab in treating NSCLC. 
1.3 
CLINICAL EXPERIENCE WITH TARCEVA 
Tarceva has been studied in at least 4000 patients in a number of Phase I, II, and III 
clinical trials.  The following section summarizes Tarceva’s safety profile and presents 
efficacy results pertinent to this trial.  Please refer to the Tarceva® Investigator Brochure 
or Package Insert (see Appendix B) for descriptions of all completed Phase I, II, and III 
trials. 
1.3.1 
Safety Profile 
Multiple Phase II and III trials of Tarceva have been conducted in patients with 
advanced, refractory malignancies.  Of the 731 NSCLC patients enrolled in the second- 


 
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and third-line trial of single-agent Tarceva versus placebo, nearly 500 received Tarceva 
at 150 mg/day.  Seventy-five percent of the patients experienced rash (8% were Grade 3 
rash).  Gastrointestinal events also occurred frequently; these included diarrhea (54%, of 
which 6% were Grade 3). 
Rash:  A papular, pustular rash manifesting most often on the face and upper trunk was 
common across all studies, but rash was rarely the cause of study drug discontinuation.  
The median time to onset of rash was 8 days.  The rash may be associated with 
erythema, pain, pruritus, dryness, and less commonly, stomatitis and keratitis. 
Diarrhea:  Diarrhea was the dose-limiting toxicity at 200 mg/day, but it is generally mild 
(Grade 1 or 2) and manageable at 150 mg/day.  The overall incidence of diarrhea in the 
Phase III study of single-agent Tarceva in NSCLC (Study BR.21) was 54%, of which 6% 
was Grade 3 or 4. 
Rare cases of acute renal failure or renal insufficiency (including fatalities) with or 
without hypokalemia have been reported.  Some have been secondary to severe 
dehydration due to diarrhea, vomiting, and/or anorexia, while others have been 
confounded by concurrent chemotherapy use.  Periodic monitoring of renal function and 
serum electrolytes is recommended in patients at risk of dehydration. 
Interstitial lung disease:  Non-fatal and fatal cases of interstitial lung disease (ILD) have 
been reported in association with the use of Tarceva in patients with NSCLC.  The 
diagnosis of ILD is rarely definitive in cancer patients, who often have concurrent, 
confounding medical problems.  However, a broad search (using 24 separate terms felt to 
be possibly reflective of a diagnosis of ILD) of the global safety database in April 2004 has 
identified 23 cases of possible ILD, irrespective of investigator-assessed causality.  With at 
least 4000 patients previously treated with Tarceva, this represents a reporting incidence 
of 0.70%.  Of these 23 cases, 16 have been assessed by the investigator as possibly 
related to study drug. 
Hepatotoxicity:  Cases of hepatic failure and hepatorenal syndrome, including fatalities, 
have been reported during use of Tarceva, particularly in patients with baseline hepatic 
impairment.  These reports have been collected during postmarketing surveillance.  
The incidence appears to be rare. 
Drug interactions:  Tarceva is 92%–95% protein bound and metabolized by hepatic 
cytochromes CYP3A4 and CYP1A2 and pulmonary cytochrome CYP1A1.  Therefore, a 
potential for drug–drug interaction exists when Tarceva is co-administered with drugs 
that are highly protein bound or that are CYP3A4 inhibitors or inducers.  In addition to 
these possibilities, altered coagulation parameters have been reported in patients 
receiving Tarceva in combination with warfarin. 


 
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Other serious and nonserious adverse events have been reported. Details are provided 
in the Tarceva® Investigator Brochure and Package Insert (see Appendix B). 
1.3.2 
Efficacy Results in Non−Small Cell Lung Cancer 
Study BR.21, an international study conducted by the NCIC-CTG, randomized 
previously treated patients with advanced or metastatic NSCLC in a 2:1 ratio to 
single-agent Tarceva at 150 mg/day versus placebo (Shepherd et al. 2004).  Enrollment 
was completed in January 2003, with a total of 731 patients enrolled. 
The trial met its primary endpoint of improving overall survival in second- and third-line 
NSCLC patients.  Patients receiving Tarceva had a median survival of 6.7 months 
compared with 4.7 months for those receiving placebo (a 42.5% improvement; 
HR = 0.73; p = 0.001).  The trial also met its secondary endpoints, including 
improvements in time to symptom deterioration, PFS, and ORR.  The ORR was 8.9% in 
Tarceva-treated patients versus < 0.9% in placebo-treated patients. 
Two other Phase III randomized studies in first-line NSCLC patients evaluated Tarceva 
in combination with platinum-based doublet chemotherapy.  A total of 1059 (1079 
randomized) previously untreated patients received carboplatin/paclitaxel with either 
Tarceva or placebo in the TRIBUTE study (OSI2298g), conducted in the United States 
(Herbst et al. 2004).  An additional 1159 (1172 randomized) patients received 
cisplatin/gemcitabine plus either Tarceva or placebo in the TALENT study (BO16411), 
which was conducted in 27 countries in Europe and other locations outside of the United 
States (Gatzemeier et al. 2004).  Neither study met its primary endpoint of improved 
overall survival or its secondary endpoints of improved time to disease progression and 
overall response rate. 
Preliminary data suggest that patients with no prior smoking history respond particularly 
well to EGFR inhibitors, as assessed by both response and survival.  The TRIBUTE 
study collected smoking history at entry.  “Never-smokers” randomized to receive 
Tarceva with chemotherapy had a median survival of 22 months as opposed to 
10 months for never-smokers in the placebo arm (Miller et al. 2004). 
Analysis of the impact of EGFR expression status on the treatment effect on clinical 
outcome of patients receiving Tarceva is limited because EGFR status is known for only 
one third of patients enrolled in Study BR.21.  For this study, positive EGFR expression 
status was defined as having ≥ 10% of cells staining for EGFR in contrast to the 1% 
cutoff specified in the DAKO EGFR pharmDx™ kit instructions. 
Tarceva prolonged survival in the EGFR-positive subgroup (n = 185; HR = 0.68; 95% 
confidence interval [CI] = 0.49, 0.94) and the subgroup whose EGFR status was 
unmeasured (n = 405; HR = 0.77; 95% CI = 0.61, 0.98), but did not appear to have an 
effect on survival in the EGFR-negative subgroup (n = 141; HR = 0.93; 95% CI = 0.63, 
1.36).  However, the CIs for the EGFR-positive, unmeasured, and EGFR-negative 


 
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subgroups are wide and overlap, so that a survival benefit due to Tarceva in the 
EGFR-negative subgroup cannot be excluded.  Tumor responses were observed in all 
EGFR subgroups:  11.3% in the EGFR-positive subgroup, 9.5% in the EGFR 
unmeasured group, and 3.8% in the EGFR-negative subgroup.   
An improvement in PFS was demonstrated in the EGFR-positive subgroup (HR = 0.49; 
95% CI = 0.35, 0.68), the EGFR unmeasured subgroup (HR = 0.60; 95% CI = 0.47, 0.75), 
and less certain in the EGFR-negative subgroup (HR = 0.80; 95% CI = 0.55, 1.16; US PI). 
1.3.3 
EGFR Mutations in Non−Small Cell Lung Cancer 
The recent identification of mutations within the EGFR in the tumor tissue of a subset of 
patients with NSCLC and the association of these mutations with sensitivity to gefitinib 
(Lynch et al. 2004; Paez et al. 2004) support the hypothesis that these are activating 
mutations that also render the tumors sensitive to the effects of EGFR tyrosine kinase 
inhibitors.  For the two reports pooled, mutated EGFR was observed in 13 of 14 patients 
who responded to gefitinib and in none of the 11 patients who were treated and did not 
respond.  The relationship of mutation to prolonged stable disease or survival duration 
has not been prospectively evaluated.  Patients were selectively identified for this 
analysis based on a rapid or dramatic response.  Data from large numbers of unselected 
patients prospectively enrolled in clinical trials are needed to more fully understand the 
clinical significance of these mutations. 
The association between the presence of EGFR mutations and clinical response was 
also seen with Tarceva, as reported in an analysis of patients enrolled in the TRIBUTE 
study (Eberhard et al. 2004).  Of the 228 patients with available tissue, 29 had evidence 
of EGFR mutations, for a prevalence of 12.7%.  Among these 29 patients, the 15 who 
received chemotherapy + Tarceva had a trend toward prolonged TTP and improved 
response rate compared with the 14 who received chemotherapy only (p = 0.092 and 
p < 0.01, respectively).  Patients with EGFR-mutant tumors, irrespective of whether they 
received Tarceva or placebo with chemotherapy, survived longer (median survival not 
reached) than patients with wild-type EGFR (MS 9.6 and 11.7 months, p < 0.001), 
suggesting that EGFR mutation is a positive prognostic factor independent of EGFR 
inhibitor therapy. 
The improved TTP and response rate have not translated into improved survival for 
patients with EGFR-mutant tumors receiving chemotherapy + Tarceva compared with 
patients receiving chemotherapy alone (p = 0.958).  However, the number of patients 
with available tissue was small, and the duration of follow-up was short compared with 
the longer survival of all patients with EGFR mutations irrespective of treatment arm. 
1.4 
BEVACIZUMAB AND TARCEVA COMBINATION STUDIES 
The strategy of combining therapeutic agents in cancer treatments has been successful 
in multiple tumor types, including NSCLC.  A new series of clinical studies are now being 
designed and conducted to evaluate the combination of bevacizumab with Tarceva, 


 
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particularly in NSCLC and renal cell carcinoma.  This approach has scientific rationale 
because the two agents target different pathways involved in tumor growth, and 
nonclinical studies in xenograft models have demonstrated that the combination of 
bevacizumab and Tarceva results in greater efficacy than either agent alone (data on 
file, provided by 
, Genentech, Inc.).  Furthermore, because little to no overlap 
in toxicity profile between the two agents has been observed to date, the combination is 
expected to be well tolerated and may provide greater benefit than either agent alone for 
patients who are unable to receive cytotoxic therapy.  
OSI2486s:  Study OSI2486s is a recently completed investigator-sponsored Phase I/II 
study (OSI2486s) evaluating the combination of bevacizumab and Tarceva in patients 
with relapsed or refractory NSCLC of non-squamous histology (Herbst et al. 2005).  The 
Phase I portion of the study evaluated three dose combinations to determine the 
tolerability and pharmacokinetic profile of each agent when combined.  Patients whose 
disease had progressed following at least one chemotherapy regimen for Stage IIIB/IV 
disease were treated with 100 mg/day Tarceva + 7.5 mg/kg bevacizumab, 100 mg/day 
Tarceva + 15 mg/kg bevacizumab, or 150 mg/day Tarceva + 15 mg/kg bevacizumab (with 
bevacizumab administered every 3 weeks in all regimens).  A total of 12 patients were 
enrolled and treated in the Phase I portion (3, 3, and 6 per cohort, respectively).  No 
dose-limiting toxicities were observed, and the pharmacokinetic profiles of both drugs did 
not appear to be affected by the combination.  As a consequence, the recommended 
Phase II dose was established as 150 mg/day Tarceva + 15 mg/kg bevacizumab every 
3 weeks, and 28 additional patients were subsequently treated with these doses. 
A total of 40 patients were enrolled in the Phase I and II portions, with 34 patients 
treated with full doses of both agents.  Patient characteristics were as follows:  median 
age 59 years (range:  36–72 years), 21 female/ 19 male, 30 patients with 
adenocarcinoma histology, 9 patients with no prior smoking history, 22 patients who 
received two or more prior regimens, and 3 patients who received four or more prior 
regimens.  The most commonly reported adverse events were rash, diarrhea, and 
proteinuria.  Importantly, there were no reports of hemoptysis.  Preliminary data 
indicated no pharmacokinetic interaction between these two agents.  The observed 
response rate was 20%, with a disease control rate (partial response and stable 
disease) of 85% and median overall survival of 12.6 months.  Based on the data from 
this single-arm, Phase I/II study, the combination of bevacizumab and Tarceva is well 
tolerated at maximum doses.   
The combination has encouraging activity, supporting a larger, controlled study 
to assess the efficacy and tolerability of the regimen. 
OSI2950g:  Study OSI2950g is a completed Genentech-sponsored, Phase II, 
multicenter, randomized, placebo-controlled study evaluating the efficacy (based on 
PFS) of combining bevacizumab with docetaxel, premetrexed, or Tarceva relative to 
docetaxel monotherapy in patients with previously treated advanced NSCLC.  Eligible 


 
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patients have histologically confirmed non-squamous NSCLC and have experienced 
disease progression during or following one platinum-based regimen for advanced stage 
disease (Stage IIIB or IV).  Additional eligibility criteria include no previous anti-
angiogenesis agents or EGFR inhibitors, an ECOG performance status of 0 or 1, and no 
active central nervous system metastases.  Patients are randomized in a 1:1:1 ratio to 
one of three treatment arms: 
• 
Arm 1:  docetaxel or premetrexed + placebo 
• 
Arm 2:  docetaxel or premetrexed + bevacizumab 
• 
Arm 3:  bevacizumab + Tarceva 
The primary results of Study OSI2950g were presented at the ASCO Annual Meeting 
in 2006.  The observed data favored the addition of bevacizumab to either 
chemotherapy or erlotinib over chemotherapy alone in the treatment of relapsed NSCLC.  
The authors went on to note that the trial was not powered to detect such a difference.  
Importantly, no new or unexpected safety signals for bevacizumab or Tarceva were 
noted during the trial.  The toxicity profile of the bevacizumab +  erlotinib combination 
showed a lower incidence of serious adverse events when compared with both of the 
chemotherapy-containing groups.  The authors’ final statement was a call for a definitive 
Phase III trial of this combination (Fehrenbacher et al. 2006). 
AVF3120s:  Study AVF3120s is an investigator-sponsored Phase II study currently 
being conducted to evaluate the combination of 10 mg/kg bevacizumab every 
2 weeks + 150 mg/day Tarceva in patients with metastatic renal cell carcinoma 
(Hainsworth et al. 2004).  Eligible patients have metastatic clear-cell renal cell carcinoma 
and no more than one previous systemic chemotherapy regimen.  Patients are 
evaluated for response after 8 weeks.  At that time, patients with a response or stable 
disease continue treatment for 12 months or until tumor progression.  The preliminary 
efficacy data from this single-arm, Phase II study of 58 evaluable patients suggest a 
response rate of 25%, a 1-year PFS of 43%, and an 18-month survival of 60%.  The 
most commonly observed toxicities include rash, diarrhea, proteinuria, and bleeding 
(usually Grade 1 or 2). 
AVF2938g:  Study AVF2938g, a Genentech-sponsored, Phase II, randomized study 
conducted to evaluate the combination of bevacizumab + Tarceva versus bevacizumab 
alone in patients with metastatic renal cell carcinoma, did not demonstrate clinical 
benefit for those patients receiving the bevacizumab + Tarceva combination.  Similarly, 
there was no increase in toxicity in those patients treated with the combination 
(Bukowski et al. 2006). 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this Phase III study was to evaluate the efficacy of combining 
bevacizumab with Tarceva (erlotinib) relative to Tarceva monotherapy in patients 


 
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receiving second-line therapy for advanced NSCLC.  Efficacy will be assessed by 
measuring overall survival. 
The addition of bevacizumab to erlotinib in the BETA lung study was not associated with 
an improvement in overall survival.  However, bevacizumab when combined with 
erlotinib improved PFS and ORR, demonstrating evidence of clinical activity.   
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this Phase III study were as follows: 
• 
To evaluate the safety of combining bevacizumab with Tarceva in patients with 
previously treated advanced NSCLC, including patients with squamous cell 
carcinoma, patients with treated brain metastases, and patients receiving full-dose 
anticoagulation with low-molecular-weight heparin or fondaparinux. 
Note:  See Section 4.1.2 for the eligibility criteria regarding squamous cell 
carcinoma patients. 
Note: Upon enactment of Amendment 6, safety data collection will be restricted 
to the reporting of serious adverse events via MedWatch FDA 3500 forms 
(Appendix D) and will not be captured in the CRF. 
• 
To evaluate the efficacy of combining bevacizumab with Tarceva relative to Tarceva 
monotherapy in patients with previously treated advanced NSCLC, as measured by 
PFS, ORR, and duration of response 
• 
To evaluate the pharmacokinetic behavior of Tarceva and the combination of 
bevacizumab with Tarceva in a subset of patients with previously treated advanced 
NSCLC 
• 
To evaluate the association of survival, PFS, and treatment effect with markers of 
epidermal growth factor receptor (EGFR) expression, as measured by 
immunohistochemistry (IHC), EGFR gene copy number measured by fluorescence 
in situ hybridization (FISH), and other molecular markers of EGFR pathway activity 
in archival tissue samples 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase III, multicenter, placebo-controlled, double-blind, randomized study.  Six 
hundred thirty-six patients were randomized in a 1:1 ratio to one of two treatment arms: 
• 
Arm 1:  Tarceva + placebo 
• 
Arm 2:  Tarceva + bevacizumab 
 
Treatment assignment to study drug (bevacizumab or placebo) was blinded for 
Genentech, the investigator, and the patient.  All patients had to have cytologically or 
histologically confirmed NSCLC and had to consent to allow analysis of their archival 


 
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diagnostic tissue, if available.  For safety reasons, patients with squamous cell histology 
were allowed to enroll only if they had limited disease that placed them at low risk for 
life-threatening hemorrhage.  Their lung lesions had to be peripheral or their disease 
extrathoracic.  Patients with brain metastases were allowed to enroll only if their brain 
metastases had been previously treated and they are not receiving dexamethasone. 
Furthermore, all patients must have experienced disease progression (clinical or 
radiographic progression, as assessed by the investigator) during or following standard 
first-line chemotherapy or chemoradiotherapy for NSCLC.  (Note:  Patients receiving 
neo-adjuvant and adjuvant therapy for Stage I–IIIA disease prior to their first-line 
regimen were eligible for study participation provided they also received first-line therapy 
[for unresectable, metastatic disease] and demonstrated progression during or after that 
first-line therapy.) 
Patients were allowed to remain in the treatment phase of the study until documented 
radiographic or clinical disease progression, or until unmanageable toxicity (in the latter 
case and if the causal drug is bevacizumab/placebo, Tarceva may be continued until 
documented disease progression or unmanageable toxicity).  Patients have been 
followed for survival until death, loss to follow-up, or study termination by Genentech.   
A data monitoring committee (DMC) periodically reviewed safety data for all patients, for 
patients with brain metastases treated prior to enrollment, and for patients with 
squamous cell carcinoma throughout the study, including monthly serious adverse event 
reviews.  This function was carried out by the Genentech Medical Monitor after 
November 2008. 
Two interim analyses were conducted during the study.  The first was conducted after 
123 patients had been enrolled and followed for at least 2 months.  Only safety data 
were assessed in this analysis.  The DMC reviewed the interim safety report on 
10 July 2006 and recommended that the study continue as planned.  The second interim 
analysis was conducted when approximately 67% of the required deaths (280 deaths) 
occurred.  Both safety and overall survival were assessed in this analysis. The DMC 
reviewed the interim report on 7 February 2008 and recommended that the study 
continue as planned.  The final analysis was conducted in October 2008 and the results 
presented publicly in November 2008.  See Appendix C. 
The study is represented schematically in Figure 1 .  Study assessments and 
procedures are detailed in Section 4.5  and Appendix A . 


 
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Figure 1 Study Schema 
Arm 1 
(Tarceva +  
Placebo)
Arm 2 
(Tarceva +  
Bevacizumab) 
1:1 randomization 
stratified by ECOG PS, 
smoking history, sex, and 
study site 
Treatment Phase 
Eligible patients (n = ~ 650) 
Patients with NSCLC (patients 
with squamous cell NSCLC 
are eligible if their lung lesions 
are peripheral and/or their 
disease is extrathoracic) in the 
second-line setting 
Follow-Up Phase 
 
 
3.2 
RATIONALE FOR STUDY DESIGN 
The rationale for this study design is based on a hypothesis that combining bevacizumab 
with Tarceva should result in improved efficacy compared with Tarceva monotherapy in 
the setting of advanced NSCLC after failure of standard first-line chemotherapy.  The 
proposed design included a placebo for bevacizumab in order to eliminate reporting and 
ascertainment bias in the final data analysis.  The primary objective of this study was 
overall survival. 
The control arm of Tarceva alone is FDA approved for the treatment of patients with 
locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy 
regimen, based on data from Study BR.21 (see Section 1.3 or Shepherd et al. 2004).  
Based on data from Study OSI2486s (see Section 1.4 or Herbst et al. 2005), it was 
hypothesized that the combination treatment arm would be well tolerated and provide 
greater benefit than Tarceva alone.  Intensive pharmacokinetic analyses were performed 
in this study to evaluate the pharmacokinetic behavior of Tarceva and of the combination 
of the two agents.   
Tumor biopsy material from patients enrolled in this study was requested in order to 
measure selected markers of EGFR and/or VEGF pathway activity that are thought to 
play an important role in clinical outcome. 
Study OSI3364g did not include a chemotherapy arm, as the comparison of 
chemotherapy versus Tarceva in the treatment of second-line NSCLC is being 
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3.3 
OUTCOME MEASURES 
3.3.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study was overall survival, defined as the 
period from the date of randomization until the date of patient death from any cause. 
The addition of bevacizumab to erlotinib in the BETA lung study was not associated with 
an improvement in overall survival.  However, bevacizumab when combined with 
erlotinib improved PFS and ORR, demonstrating evidence of clinical activity.  See 
Appendix C. 
3.3.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures were as follows: 
• 
PFS, defined as the time from randomization to documented disease progression, 
as determined by the investigator using the Response Evaluation Criteria in Solid 
Tumors (RECIST), or death on study treatment, whichever occurs first 
• 
Objective response, as determined by the investigator using RECIST 
• 
Duration of objective response, defined as the period from the date of initial partial 
or complete response (as determined by the investigator using RECIST) until the 
date of disease progression or death from any cause on study treatment 
• 
Evaluation of the relationship between molecular exploratory markers and efficacy 
outcomes 
 
3.3.3 
Pharmacokinetic Outcome Measures 
The pharmacokinetic outcome measures for erlotinib and its metabolite (OSI-420) were 
as follows: 
• 
Maximum concentration at steady state (Cmax,ss)  
• 
Time of the maximum concentration at steady state (Tmax,ss) 
• 
Minimum concentration at steady state (Cmin,ss)  
• 
Apparent clearance at steady state 
• 
Area under the erlotinib time−concentration curve (AUC0–tau) 
 
The pharmacokinetic outcome measures for bevacizumab were as follows: 
• 
Maximum concentration (Cmax) 
• 
Minimum concentration (Cmin) 
 
3.3.4 
Safety Outcome Measures  
The safety outcome measures for this study were the following: 
• 
Incidence and severity of adverse events and serious adverse events 
• 
Changes in laboratory values  


 
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Patient safety after Amendment 6 will be restricted to the spontaneous reporting of 
serious adverse events via MedWatch FDA 3500 forms and will not be captured in the 
CRF.  
3.4 
SAFETY PLAN 
Upon enactment of Amendment 6, data collection will be restricted to reporting of 
serious adverse events via MedWatch FDA 3500 forms (not in the CRF), and handled 
according to instructions in Section 5.4. SAE data will be collected via the safety 
database only.  Prior to Amendment 6, the safety plan was as below. 
See Section 4.3.4 and Section 5 for complete details of the safety evaluation for this 
study. 
A number of measures have been taken to ensure the safety of patients participating in 
this study.  These measures were addressed through the exclusion criteria 
(see Section 4.1.3) and routine monitoring as follows. 
Patients enrolled in this study were evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study.  Safety 
evaluations consisting of medical interviews, recording of concomitant medications and 
adverse events, physical examinations, blood pressure, and laboratory measurements 
(performed by local laboratories, see Section 4.5 and Appendix A) have been 
conducted.  Patients have been evaluated for adverse events (all grades), serious 
adverse events, and adverse events requiring study drug interruption or discontinuation 
at each study visit while on study drug.  Patients discontinued from the treatment phase 
of the study for any reason were evaluated ~30 days (28−42 days) after the decision to 
discontinue treatment (see Section 4.5.3).  Patients with an ongoing Grade 4 or serious 
adverse event at the time of discontinuation from study treatment were followed until the 
event is resolved or determined to be irreversible by the investigator (see Section 4.5.3). 
Specific monitoring procedures were as follows: 
• 
Hypertension was monitored through routine evaluation of blood pressure. 
• 
In patients with bleeding, a hemostasis evaluation was performed as clinically 
indicated.  In patients with hemoptysis, bevacizumab should be permanently 
discontinued and protocol guidelines followed (see Section 4.3.4  and Table 2 ).  
Early use of bronchoscopy to identify the site of bleeding should also be considered. 
• 
Patients with a history of brain metastases were monitored for the development of 
symptomatic Grade  ≥ 2 CNS hemorrhage (NCI CTCAE, Version 3.0).  Symptomatic 
is defined as clinical symptoms that are determined by the investigator to be directly 
referable to a CNS hemorrhage.  Bevacizumab should be discontinued and protocol 
guidelines followed in patients who develop symptomatic Grade ≥ 2 CNS 
hemorrhage (see Section 4.3.4  and Table 2 ). 


 
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• 
Patients requiring full-dose anticoagulation could be treated with 
low-molecular-weight heparin or fondaparinux; these patients were and have been 
monitored for Grade ≥ 3 hemorrhage events.  Full-dose anticoagulation with 
warfarin is prohibited; however, prophylactic doses were allowable. 
• 
Bevacizumab should be discontinued and protocol guidelines followed in patients 
who develop symptomatic Grade ≥ 2 CNS hemorrhage or Grade ≥ 3 hemorrhage 
(see Section 4.3.4  and Table 2).   
• 
Because of the potential for drug–drug interaction between Tarceva and warfarin, 
patients who received concomitant prophylactic/low-dose warfarin therapy were to 
be monitored closely for INR changes or bleeding. 
• 
Chronic use of full-dose nonsteroidal anti-inflammatory drugs (NSAIDs) was not 
allowed while on study treatment.  If required, the patient must be discontinued from 
bevacizumab/placebo. 
• 
Aspirin up to, but not exceeding, 325 mg per day could be given to patients at high 
risk for arterial thromboembolic disease.  Patients developing signs or symptoms of 
arterial thromboembolic events (see Table 2) while on study treatment were asked 
to discontinue bevacizumab/placebo. 
• 
Proteinuria was monitored through regular urinalysis and urinary protein to 
creatinine ratio.  Screening for proteinuria at ex-U.S. sites was performed with a 
urine dipstick (patients found to have ≥ 3+ proteinuria by dipstick had to undergo a 
24-hour urine collection) 
• 
Symptoms consistent with ILD, such as new onset dyspnea, cough, or fever without 
an obvious cause were to be evaluated.  In the event that ILD was suspected, study 
treatment was to be discontinued and the patient given appropriate medical 
management.  Although there is no proven therapy, systemic corticosteroids are 
often provided.  Tarceva should not be restarted in patients suspected of having 
drug-related ILD. 
• 
NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in 
patients receiving Tarceva therapy.  Patients were asked to seek medical advice 
promptly if they experienced eye irritation during Tarceva therapy. 
 
See Section 4.3.4 for detailed instructions about the management of study drug-related 
toxicities.  The DMC monitored the safety of this study by reviewing serious adverse 
events every month and during the two interim analyses.  Members of the DMC were 
external to Genentech and followed a charter that outlines the Committee’s composition 
and the members’ roles and responsibilities. 
3.5 
CONTROL GROUP 
The control group consisted of patients receiving Tarceva in combination with placebo 
(Arm 1). 


 
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3.6 
MINIMIZATION OF BIAS 
To reduce bias, patients were randomized to two treatment arms (Tarceva + placebo 
and Tarceva + bevacizumab) using an interactive voice response system (IVRS).  
Genentech, the investigator, and the patient was blinded to treatment assignment of 
bevacizumab versus placebo. 
3.7 
ETHICAL CONSIDERATIONS 
The prognosis for patients with previously treated advanced NSCLC is poor, with a 
median survival of ~4 months among untreated patients (Bunn et al. 1998).  Single-
agent Tarceva showed a significant survival benefit in Study BR.21 (Shepherd et al. 
2004); therefore, patients receiving Tarceva + placebo will receive an FDA-approved 
treatment with proven efficacy in this setting. 
A quality-of-life assessment using the European Organization for Research and 
Treatment of Cancer (EORTC) QLQ-C30 and the lung cancer module QLQ-LC13 tools 
was an integral part of Study BR.21.  Patients treated with Tarceva monotherapy had a 
significantly longer time to symptom deterioration, cough, dyspnea, and pain compared 
with patients receiving placebo. 
A survival benefit for bevacizumab in the front-line treatment of non-squamous cell 
NSCLC was demonstrated in ECOG Study 4599 (Sandler et al. 2005).  A Phase I/II 
investigator-sponsored study of Tarceva + bevacizumab in non–squamous cell NSCLC 
(Herbst et al. 2005) and preliminary results from Study OSI2950g (Fehrenbacher et al. 
2006) suggest that this benefit may extend to patients treated in the second-line setting. 
Study OSI3364g was designed to test the hypothesis that the addition of bevacizumab 
increases the survival benefit of Tarceva. 
In the Phase II NSCLC trial, AVF0757g, 6 of the 66 bevacizumab-treated patients 
experienced life-threatening hemoptysis or hematemesis (Johnson et al. 2004).  Four of 
these events were fatal.  Of these patients, 4 had squamous cell histology.  This 
corresponded to a 31% rate of hemorrhage (4 of 13 patients) in patients with squamous 
cell disease.   
A case-control evaluation performed to determine which clinical and/or radiographic 
factors contributed to these events concluded that squamous cell histology and 
bevacizumab treatment were the principal risk factors for major pulmonary hemorrhage 
(Novotny et al. 2001). 
In Study E4599 (the Phase III trial of bevacizumab in first-line NSCLC patients), 
excluding those with predominant squamous histology, 10 of 427 patients (2.3%) in the 
bevacizumab + chemotherapy arm experienced Grade 3−5 pulmonary hemorrhage 
compared with 2 of 441 patients (0.5%) in the chemotherapy-alone arm.  


 
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Five of the 10 events in the bevacizumab + chemotherapy arm occurred within 9 weeks 
of treatment initiation.  The remaining events occurred at Week 15 or later.  The two 
events occurring in the chemotherapy-alone arm occurred at Week 16 or later.  A 
retrospective analysis of pulmonary hemorrhage cases from Studies E4599 and 
AVF0757g did not conclusively identify clinical or radiographic criteria associated with an 
increased risk for severe pulmonary hemorrhage.  Hemoptysis and tumor cavitation 
were felt to be potentially associated. 
Based on the case-control analysis from Study AVF0757g, squamous NSCLC was the 
principal risk factor for severe pulmonary hemorrhage.  Patients with squamous NSCLC 
have been excluded from subsequent clinical trials with bevacizumab, thus limiting 
clinical experience in this setting. 
Of the 145,000 patients diagnosed with NSCLC annually, 20%−30% will have squamous 
cell histology.  Treatment of these patients remains an area of significant unmet need 
(Fraire 1996; Hammar 1993; Linnoila and Aisner 1995). 
The risk for pulmonary hemorrhage in patients with squamous cell NSCLC, 
demonstrated in Study AVF0757g, may not be uniform.  Nine of the 13 patients with 
squamous cell history enrolled did not bleed, suggesting that it may be possible to 
identify a subset of patients with squamous cell histology at lower risk for hemorrhage 
when treated with bevacizumab.  
The squamous cell NSCLC population anticipated to have the lowest risk for severe or 
life-threatening pulmonary bleeding has extra-thoracic disease (i.e., liver, adrenal, bone) 
and/or small volume disease in the peripheral lung parenchyma.  Restriction of treatment 
to this population may mitigate against severe bleeding and broaden the availability of a 
potentially effective, well-tolerated therapy, bevacizumab combined with Tarceva, to 
patients with unmet medical need. 
Of patients with NSCLC, 25%–30% will develop brain metastases during the course of 
their disease (Langer 2005).  Patients with brain metastases will comprise an 
increasingly large proportion of the NSCLC population as patients live longer as the 
result of more effective therapies (Gaspar et al. 2005). 
Patients with brain metastases were previously excluded from receiving bevacizumab 
because of the potential risk of bleeding. 
In ECOG Study 4599, patients with brain metastases were ineligible for study 
participation; however, 38 of the 878 enrolled patients, 19 in each treatment group, 
developed brain metastases during the trial.  Two of the 19 patients in the bevacizumab 
group had non-fatal bleeding events.  No bleeding events were noted in the other 
treatment group. 


 
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The spontaneous bleeding rate of 10% in bevacizumab-treated patients is similar to the 
incidence of spontaneous hemorrhage reported in patients with brain metastases of 
various tumor types, ranging from 0.8% to 14% (Mandybur 1997; Bitoh et al. 1984).  This 
rate drops to as low as 0%–1.2% in series of patients treated with whole brain 
radiotherapy (WBRT), stereotactic radiosurgery, and surgery (Andrews et al. 2004; Noel 
et al. 2003; Maor et al. 2000).  This suggests a lower spontaneous hemorrhage rate in 
patients with treated brain metastases. 
The prognosis for patients with advanced or recurrent NSCLC is poor; the treatment 
options and the ability of patients to tolerate second- and third-line therapies are limited.  
Study OSI3364g was designed to investigate the role of Tarceva with or without 
bevacizumab in the setting of second-line treatment of NSCLC in an attempt to develop 
an effective second-line therapy without significant associated toxicity.  The study has 
been amended to include the enrollment of patients with squamous cell carcinoma at low 
risk for pulmonary hemorrhage and patients with treated brain metastases (except those 
who have an ongoing requirement for treatment with dexamethasone at screening) to 
address the unmet medical need of a larger population of patients. 
Patient safety continues to be of principal concern in Study OSI3364g given the novelty 
of the combination and the demonstrated risk for hemorrhage with bevacizumab therapy.  
Frequent safety monitoring of the treated population during the treatment period by a 
DMC is a component of this study.  The DMC reviewed serious adverse events monthly 
and full safety data until the final analysis.  They had the ability to recommend study 
continuance based upon their findings (see Section 4.8.8).  Special attention was paid to 
hemorrhage events. 
Genentech performed safety reviews after the final analysis.  
The final analysis of OSI3364g showed that the addition of bevacizumab to erlotinib 
improved PFS and ORR.  However, this clinical benefit was not associated with an 
improvement in survival. 
Amendment 5 allowed investigators and patients who had not progressed the option to 
continue active study treatment until disease progression, while continuing to provide 
long-term data on the safety of the bevacizumab and erlotinib combination.  
Forty-eight patients remained on study treatment at the time of the final BETA analysis.  
Some had been on study for more than 1 year.  The continued collection of safety 
information on these long-term non-progressing patients allowed for a better description 
of the long-term safety profile of the bevacizumab and erlotinib combination. 
All placebo treatment in the BETA trial will be discontinued to remove the risks and 
discomforts associated with infusion therapy.  


 
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Investigators and patients are not obligated to remain on study treatment.  They may 
choose to discontinue trial participation given the failure of the study to meet its primary 
endpoint of improved overall survival. 
Upon enactment of Amendment 6, data collection will be restricted to spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms (not in the case 
report form [CRF]), and handled according to instructions in Section 5.4. SAE data 
will be collected via the safety database only. 
3.8 
ADMINISTRATIVE STRUCTURE 
This study has been sponsored by Genentech and managed with the support of a 
contract research organization (CRO) that provided clinical data management and 
monitoring support.  Six hundred thirty-six patients were enrolled at approximately 
200 centers in the United States, Europe, and the rest of the world.  Randomization 
occurred through the IVRS (see Section 4.2). 
3.9 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted according to the International Conference on Harmonisation 
E6 Guideline for Good Clinical Practice (GCP) and any national requirements.  
4. 
MATERIALS AND METHODS 
The materials and methods below were utilized prior to the final analysis of 
OSI3364g.  These should be continued for all patients who remain on study 
treatment after the final analysis, unless stated otherwise. 
4.1 
PATIENTS 
4.1.1 
Patient Selection 
Enrollment in the BETA lung trial has been completed. 
Patients were eligible for this second-line therapy study if they had recurrent or refractory 
(progression through at least two cycles of a given chemotherapeutic regimen) NSCLC 
following standard first-line chemotherapy or chemoradiotherapy.  This guideline was 
based on a number of the life-threatening and fatal hemorrhagic events in NSCLC 
patients, which were associated with these characteristics.  This was incorporated as a 
guideline for this study because it is difficult to objectively quantify.  Additional specific 
inclusion and exclusion criteria are listed below. 
4.1.2 
Inclusion Criteria 
Patients had to fulfill all of the following criteria to be eligible for study entry: 
• 
Signed written informed consent  


 
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• 
Cytologically or histologically confirmed NSCLC 
Patients had to have histologically or cytologically confirmed NSCLC.  Tumors of 
mixed histology were categorized by the predominant cell type unless small cell 
elements were present, in which case the patient was not eligible for study 
participation.  Cytologic or histologic elements may have been established on 
metastatic tumor aspirates or biopsy. 
Patients with squamous cell carcinoma were eligible provided that their disease 
was extrathoracic or that their intrathoracic disease consists of peripheral lesions 
only.  A peripheral lesion was defined as a lesion (or lesions) in which the 
epicenter of the tumor was ≤ 2 cm from the costal or diaphragmatic pleura in a 
3-dimensional orientation based on each lobe of the lung, and  > 2 cm from the 
trachea, main, and lobar bronchi.  
Squamous cell carcinoma patients were eligible for study participation 
irrespective of the proximity of their adenopathy to the costal or diaphragmatic 
pleura or major airways.  Patients with hilar adenopathy were eligible for study 
participation. 
Patients with squamous cell carcinoma had to have a copy of the screening 
computed tomography (CT) or magnetic resonance imaging (MRI) scans (either 
as copy films or digital images) reviewed by Genentech or its designee prior to 
randomization.  Patients were not randomized until Genentech or its designee 
confirmed eligibility.  
Patients with a history of brain metastases were eligible for study participation, as 
long as their brain metastases had been treated and they did not have an 
ongoing requirement for treatment with dexamethasone at screening.  Treatment 
had to be with WBRT (e.g., 3000 cGy over 2 weeks) and might include 
neurosurgery, or stereotactic radiosurgery.  Radiotherapy and stereotactic 
radiosurgery had been completed at least 4 weeks prior to Day 0 (see 
Section 4.3.2).  Neurosurgery had be completed at least 24 weeks prior to Day 0, 
and brain biopsy must be completed at least 12 weeks prior to Day 0.   
• 
Clinical or radiographic progression during or after first-line chemotherapy or 
chemoradiotherapy for NSCLC 
Patients receiving neo-adjuvant and adjuvant therapy for Stage I–IIIa disease 
prior to their first-line regimen were eligible for study participation provided they 
had also received first-line therapy (for unresectable, metastatic disease) and 
had demonstrated progression during or after that first-line therapy. 
• 
Consent to provide archival tissue for analysis was required for participation in this 
study.  Patients who consented to provide tissue but whose archival tissue was 
found to be inadequate (e.g., stained slides) remained eligible for study 
participation). 
• 
ECOG performance status of 0, 1, or 2 
• 
Age ≥ 18 years  


 
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• 
Use of an acceptable means of contraception for men and women of childbearing 
potential 
• 
INR no greater than 1.3 and an aPTT no greater than the upper limits of normal 
within 28 days prior to enrollment for patients not on low-molecular-weight heparin 
or fondaparinux.  Patients on low-molecular-weight heparin or fondaparinux were 
not required to meet INR or aPTT limits.   
4.1.3 
Exclusion Criteria 
Patients meeting any of the following criteria were ineligible for study entry: 
• 
Squamous cell carcinoma, except for patients with no intrathoracic disease or small 
peripheral lesions only  
A peripheral lung lesion was defined as any lesion meeting the following criteria:  
A lesion (or lesions) in which the epicenter of the tumor was ≤ 2 cm from the 
costal or diaphragmatic pleura in a 3-dimensional orientation based on each lobe 
of the lung, and > 2 cm from the trachea, main, and lobar bronchi. 
Adenopathy was not considered when assessing the peripheral nature of a 
patient’s squamous cell carcinoma.  Patients were eligible for study participation 
irrespective of the proximity of their adenopathy to the costal or diaphragmatic 
pleura or major airways.  
• 
Prior treatment with an investigational or marketed inhibitor of the EGFR pathway or 
anti-angiogenesis agent   
Angiogenesis inhibitors include (but are not limited to) bevacizumab, thalidomide, 
CP 547632, SU 11248, and PTK 787. 
• 
Systemic chemotherapy, radiotherapy, or investigational treatment within 28 days 
prior to randomization 
• 
Local palliative radiotherapy within 14 days prior to randomization or persistent 
adverse effects from radiotherapy that have not resolved to Grade 2 or less 
following completion of treatment 
• 
Whole brain radiotherapy or stereotactic radiosurgery for brain metastases within 
4 weeks of Day 0 (see Section 4.3.2) 
• 
Neurosurgery for brain metastases within 24 weeks of Day 0 (see Section 4.3.2) 
• 
Brain biopsy within 12 weeks of Day 0 (see Section 4.3.2) 
• 
Current use of dexamethasone for treatment associated with brain metastases 
• 
History of gross hemoptysis (defined as bright red blood of at least 1/2 teaspoon or 
2.5 mL per episode) within 3 months prior to randomization unless definitively 
treated with surgery or radiation 


 
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• 
History of any of the following within 6 months prior to Day 0:  serious systemic 
disease, including myocardial infarction, uncontrolled hypertension (systolic blood 
pressure > 150 mm Hg or diastolic blood pressure > 100 mm Hg taken per the JNC 7 
guidelines [see http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm]), 
unstable angina, New York Heart Association (NYHA) Grade 2 or greater CHF, 
unstable symptomatic arrhythmia requiring medication (patients with chronic atrial 
arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are 
eligible), clinically significant peripheral vascular disease, abdominal fistula, 
gastrointestinal perforation, or intra-abdominal abscess 
Patients with evidence of hypertension during study screening were to be 
evaluated for uncontrolled hypertension in accordance with the JNC 7 guidelines. 
• 
Evidence of bleeding diathesis or coagulopathy or other serious or acute internal 
bleeding within 6 months prior to randomization 
• 
CNS bleeding; history or clinical evidence of CNS stroke (hemorrhagic or 
thrombotic) within the last 6 months 
• 
Progressive neurologic symptoms in patients with a history of brain metastases 
• 
Full-dose anticoagulation with warfarin 
Patients who required full-dose anticoagulation could be treated with 
low-molecular-weight heparin or fondaparinux.  Patients fully anticoagulated with 
warfarin during the study were discontinued from bevacizumab/placebo. 
• 
Chronic daily use of aspirin (> 325 mg/day) or other full-dose NSAIDs with 
anti-platelet activity 
Treatment with other antiplatelet agents (e.g., dipyridamole, ticlopidine, 
clopidogrel, and/or cilostazol) was permitted. 
• 
In-patient surgical procedure, open biopsy, or significant traumatic injury within 
28 days prior to randomization (placement of a central line is not considered 
surgery, and could be placed on the same day as study drug administration) 
• 
Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior 
to randomization 
• 
Anticipation of need for a major surgical procedure during the course of the study 
• 
Serious, non-healing wound, ulcer, or bone fracture 
• 
Inability to take oral medication or requirement for IV alimentation or total parenteral 
nutrition with lipids, or prior surgical procedures affecting absorption 
• 
Any of the following abnormal hematologic values (within 1 week prior to 
randomization) 
ANC ≤ 1000 cells/μL 
Platelet count ≤ 100,000 cells/μL 
Hemoglobin ≤ 9.0 g/dL 
INR ≥ 1.5 × upper limit of normal (ULN)  


 
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• 
Any of the following abnormal liver function tests (within 1 week prior to 
randomization) 
Serum bilirubin ≥ 1.5 × ULN  
Albumin ≤ 2.5 g/dL 
Serum ALT ≥ 2 × ULN (unless clearly due to liver metastases, then 5 × ULN) 
Serum AST ≥ 2 × ULN (unless clearly due to liver metastases, then 5 × ULN) 
• 
Other baseline laboratory values 
Uncontrolled hypercalcemia (≥ 11.5 mg/dL) 
Urinary protein/creatinine ratio ≥ 1 (spot urine) 
Serum creatinine ≥ 2.0 × ULN  
• 
Pregnancy or breast-feeding 
Because of the possible teratogenic effect, pregnant women and women who are 
currently breast-feeding may not participate in this study.  All women of 
childbearing potential must have a negative pregnancy test within 1 week prior to 
randomization. 
• 
Presence of another invasive cancer within 5 years prior to randomization, except 
for adequately treated basal or squamous cell skin cancer, or carcinoma in situ of 
the cervix 
• 
Evidence of confusion or disorientation, or history of major psychiatric illness that 
may impair the patient’s understanding of the Informed Consent Form or their ability 
to comply with study requirements 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Note: This study has been fully recruited and all subjects were unblinded to study drug 
following the final analysis. Upon enactment of Amendment 6, the interactive voice 
response system (IVRS) will be cancelled.  Prior to enactment of Amendment 6, 
treatment assignment and unblinding were managed as below. 
After written informed consent was obtained and eligibility established (with archival 
tissue identified and available for research testing), the study site obtained the patient’s 
identification number and treatment assignment from the IVRS.  Patients could be 
randomized up to 5 days prior to receiving their first dose of study treatment.  A 
hierarchical dynamic randomization scheme was used to ensure an approximately equal 
sample size for the two treatment arms overall, within each of the four categories defined 
by baseline ECOG performance status (0/1 vs. 2) and smoking history (never vs. 
current/previous), within each sex, and within each study site. 
Genentech, the investigator, and the patient were blinded to treatment assignment.  
Unblinding of treatment assignment prior to final study analysis was permitted only for a 
serious study drug–related toxicity.  All cases of safety unblinding required the approval 


 
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of the Medical Monitor.  After the final analysis, unblinding information was provided to 
all sites with patients receiving study treatment.  Unblinding information for patients who 
had completed study treatment prior to the final analysis was provided upon request. 
If a patient discontinued Tarceva therapy because of unmanageable toxicity, an 
unblinding request could be made to determine the treatment assignment.  Study 
bevacizumab/placebo was discontinued and subsequent therapy provided at the 
discretion of the treating clinician. 
Any toxicities associated or possibly associated with bevacizumab treatment were and 
should be managed according to standard medical practice.  Discontinuation of 
bevacizumab has no immediate therapeutic effect.  Bevacizumab has a terminal half-life 
of 2–3 weeks; therefore, its discontinuation results in slow elimination over several 
months.  There is no available antidote for bevacizumab.  Investigators were allowed to 
hold administration of study drug while waiting for a decision on unblinding to be made. 
Any toxicities associated or possibly associated with Tarceva treatment were and should 
be managed according to standard medical practice.  Erlotinib has a median terminal 
half-life of 36 hours.  There is no available antidote for Tarceva. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation 
a. Bevacizumab and Bevacizumab Placebo 
Bevacizumab is supplied by Genentech, Inc. as a clear to slightly opalescent, sterile 
liquid ready for parenteral administration.  Each 100-mg (25 mg/mL) glass vial contains 
bevacizumab with a vehicle consisting of sodium phosphate, trehalose, polysorbate 20, 
and Sterile Water for Injection, USP.  Vials contain no preservative and are for single 
use only.  For further details, see the Avastin® Investigator Brochure or Package Insert. 
Placebo consisted of vehicle for bevacizumab without the antibody.   
Placebo was supplied by Genentech as a clear to slightly opalescent, sterile liquid ready 
for parenteral administration.  Each glass vial contains sodium phosphate, trehalose, 
polysorbate 20, and SWFI, USP.  Vials contain no preservatives and were for single use 
only.   
Placebo treatment was discontinued as of 15 November 2008 on a case-by-case 
scenario.  All placebo treatment will be discontinued as of the enactment of Protocol 
Amendment 5. 
b. Tarceva 
Tarceva will be supplied by Astellas Pharmaceuticals US on behalf of OSI 
Pharmaceuticals LLC, Inc. and F. Hoffmann-La Roche, Ltd.  The oral tablets are 
conventional, immediate-release tablets containing erlotinib as hydrochloride salt.  In 


 
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addition to the active ingredient (erlotinib), tablets contain lactose (hydrous), 
microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, magnesium 
stearate, and the film coating Opadry® White, which is composed of hypromellose, 
hydroxypropyl cellulose, and titanium dioxide.  Tablets containing 25 mg, 100 mg, and 
150 mg of Tarceva are available.  Erlotinib will be provided in a bottle.  Each bottle 
will contain 30 tablets, a quantity sufficient for 4 consecutive weeks of dosing, with 
overage.  For further details, see the Tarceva® Investigator Brochure or Package Insert 
(see Appendix B). 
4.3.2 
Dosage, Administration, and Storage 
a. Bevacizumab/Placebo 
The dose of bevacizumab in this study continues to be 15 mg/kg administered by IV 
infusion on the first day of each 3-week cycle (± 4 days; the interval between infusions 
must not be < 17 days).  The bevacizumab dose should be based on the patient’s weight 
at screening (within 7 days prior to randomization) and should remain the same 
throughout the study (± 5% dosing variation).  If bevacizumab/placebo administration fell 
outside of the 4-day visit window, for reasons other than toxicity management, the site 
had to obtain a protocol waiver prior to the infusion.  The patient’s schedule was then 
adjusted so that the subsequent bevacizumab/placebo infusion was given 3 weeks after 
the re-scheduled infusion. 
Protocol waivers are no longer required for changes in treatment.  Changes in the 
treatment dose or schedule may be made based upon the investigator’s judgment and 
the institutional guidelines of the site.  Placebo dosing will be discontinued for all patients 
on the Tarceva and placebo arm of the trial without evidence of progression as of the 
enactment of BETA lung trial Amendment 5.   
The initial bevacizumab/placebo dose was delivered over 90 (± 10) minutes as a 
continuous IV infusion on Day 0.  If a patient experienced an infusion-associated 
adverse event, he or she could be pre-medicated for the next study drug infusion; 
however, the infusion time could not be decreased for the subsequent infusion.  If the 
first infusion was tolerated without infusion-associated adverse events, the second 
infusion could be delivered over 60 minutes (± 10 minutes).  If a patient experienced 
infusion-associated adverse events with the 60-minute infusion, all subsequent doses 
were to be given over 90 minutes.  If the 60-minute infusion was well tolerated,  
all subsequent infusions could be delivered over 30 ± 10 minutes.  If a patient 
experienced infusion-associated adverse events with the 30-minute infusion, all 
subsequent doses were to be given over 60 minutes.  If the patient continued to 
experience infusion-associated adverse events with the 90-minute infusion, the patient’s 
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At sites where study treatment continues, upon receipt of the study drug, vials are to be 
refrigerated at 2°C–8°C (36°F–46°F) and should remain refrigerated until use.  DO NOT 
FREEZE.  DO NOT SHAKE. 
VIALS ARE FOR SINGLE USE ONLY.  Vials used for one patient may not be used for 
any other patient. 
The final analysis for Study OSI 3364g was completed in October 2008.  The addition of 
bevacizumab to erlotinib in the study was not associated with an improvement in overall 
survival.  However, bevacizumab when combined with erlotinib doubled PFS and ORR, 
providing clear evidence of clinical activity (see Appendix C).  Patients’ treatment 
assignments have subsequently been unblinded. 
Investigators and their patients have the option to continue active study treatment until 
the time of progression, while continuing to provide long-term data on the safety of the 
bevacizumab and erlotinib combination.  Investigators and patients may also choose to 
discontinue active therapy, given the failure of the study to meet the primary endpoint of 
improved overall survival. 
In cases where the decision is made to continue study treatment, all placebo treatment 
will be discontinued, thus removing the risks and discomforts associated with infusion 
therapy.  All treatment modifications should be made using the investigator’s judgment 
and taking into account the guidance provided by the protocol, the Package Insert, and 
Investigator’s Brochure. 
b. Tarceva 
The dose of Tarceva continues to be 150 mg/day orally.  Tablets should be taken at the 
same time each day with ~200 mL (6−8 ounces) of water on an empty stomach at least 
1 hour before or 2 hours after a meal.  Toxicity due to Tarceva administration may be 
managed by symptomatic treatment, dose interruptions, and/or adjustment of the 
Tarceva dose (see Section 4.3.4 and Table 1). 
Patient compliance in taking the assigned Tarceva daily dose was assessed by standard 
tablet counts.  Bottles or blister packs containing the daily dose of Tarceva for 30 days 
were given to patients on the first day of each 3-week cycle.  Previously distributed 
bottles or blister packs were returned to the clinic and counted; discrepancies were 
resolved with the patient at each clinic visit and documented in the patient’s medical 
chart.   
These drug accountability measures should be continued at sites where patients 
continue to receive study drug. 
Tarceva tablets will be supplied for patients who have not progressed on study treatment 
in white, high-density polyethylene (HDPE) bottles with child-resistant closures or in PVC 


 
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blister packs sealed with aluminum foil.  Bottles and blister packs should be stored at 
temperatures between 15°C and 30°C (59°F and 86°F).   
4.3.3 
Dosage Modification 
Upon enactment of Amendment 6, no dose adjustments will be permitted. Any patient 
requiring a dose modification due to an AE or PD should be terminated from the study 
and treated following the physician’s usual standard of care.  Prior to Amendment 6, 
dose modifications were handled as below. 
a. Bevacizumab/Placebo 
Patients should continue to be assessed clinically for toxicity prior to, during, and after 
each infusion.  If unmanageable toxicity occurs because of bevacizumab/placebo, 
treatment with bevacizumab/placebo should be discontinued.  All placebo treatment will 
be discontinued as of the enactment of Amendment 5. 
Patients have the option to continue on single-agent Tarceva until disease progression 
or unmanageable Tarceva toxicity. 
Infusion Reaction.  Infusion of bevacizumab/placebo should be interrupted for patients 
who develop dyspnea or clinically significant hypotension.  Patients who experience an 
NCI Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0) Grade 
3 or 4 allergic reaction/hypersensitivity, acute respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from bevacizumab/placebo 
treatment. 
The infusion should be slowed to 50% or less or interrupted for patients who experience 
any infusion-associated symptoms not specified above.  When the patient’s symptoms 
have completely resolved, the infusion may be continued at no more than 50% of the 
rate prior to the reaction and increased in 50% increments every 30 minutes if well 
tolerated.  Infusions may be restarted at the full rate during the next cycle.  See 
Section 4.2 for the study drug unblinding procedure. 
b. Tarceva  
Dose reduction or interruption of Tarceva for toxicity may take place at any time during 
the study.  Dose level reductions are presented in Table 1.  If patients do not tolerate the 
second dose reduction, they should be withdrawn from Tarceva treatment and the 
treatment phase of the study and should enter survival follow-up.  If a patient was 
discontinued because of Tarceva toxicity, prior to Amendment 5, an unblinding request 
could be made by the investigator to determine the treatment assignment.  The 
treatment assignments of the patients remaining on trial have been unblinded to their 
clinical team.  Subsequent therapy will be provided at the discretion of the treating 
clinician. 


 
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Table 1 
Tarceva Dose Level Reductions 
Starting Dose 
First Reduction 
Second Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
4.3.4 
Management of Toxicities Related to Study Treatment  
Upon enactment of Amendment 6, no dose adjustments will be permitted. Any patient 
requiring a dose modification due to an AE or PD should be terminated from the study 
and treated following the physician’s usual standard of care.  Prior to Amendment 6, 
toxicities related to study treatment were managed were handled as below. 
Criteria for dose modification and guidelines for the management of toxicities are 
summarized in Table 2 . 
These criteria should be followed for all patients who remain on study treatment after the 
enactment of Amendment 5.  However, all treatment decisions are to be made by the 
treating physician based on his or her clinical judgment and in accordance with 
institutional practice and guidelines. 


 
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Table 2 
Dosage Modification Criteria and Guidelines for Management of 
Study Treatment–Related Toxicities 
NCI CTCAE 
Grade 
Study Drug Dose Modification 
Guideline for Management 
Diarrhea  
 
 
Grade 1 
None. 
Consider loperamide (4 mg at first 
onset, followed by 2 mg every 2–4 
hours until the patient is diarrhea-
free for 12 hours). 
Grade 2 
None. 
(Dose reduction of Tarceva is 
necessary if diarrhea persists over 
48−72 hours despite optimal 
medical management.) 
Loperamide (4 mg at first onset, 
followed by 2 mg every 2–4 hours 
until the patient is diarrhea-free for 
12 hours). 
Grade 3 
Interrupt Tarceva until resolution to 
Grade ≤ 1, and restart at next 
reduced dose.  Continue 
bevacizumab/placebo. 
Per standard of care practices. 
Grade 4 
Discontinue the patient from 
Tarceva and the study treatment 
phase of the study, including 
permanent discontinuation of 
bevacizumab/placebo. 
As listed above. 
Hemorrhage a 
 
 
Grade 1 
pulmonary 
Hold bevacizumab/placebo and 
evaluate source.  Continue Tarceva. 
In patients with hemoptysis, 
consider early use of 
bronchoscopy to identify the site of 
bleeding. 
Grade ≥ 2 
pulmonary 
Discontinue the patient from 
bevacizumab/placebo.  Continue 
Tarceva. 
All Grade 3 hemoptysis adverse 
events should be reported as 
serious adverse events (see 
Section 5.4). 
Grade 2 
(symptomatic), 3, 
4 CNS 
Discontinue the patient from 
bevacizumab/placebo.  Continue 
Tarceva. 
All Grade 2 (symptomatic), 3, and 
4 CNS hemorrhages should be 
reported as serious adverse 
events (see Section 5.4). 
Grade 1, 2  
non-CNS, 
non-pulmonary 
None. 
In patients with bleeding, consider 
a full hemostasis evaluation, which 
may include additional INR, 
bleeding time measurements, and 
platelet aggregation, etc. 
In patients with gastrointestinal 
bleeding, consider stool guaiacs 
and early use of endoscopy or 
other studies to identify the 
location of bleeding. 


 
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Table 2 
Dosage Modification Criteria and Guidelines for Management of 
Study Treatment–Related Toxicities (cont.) 
 
NCI CTCAE 
Grade 
Study Drug Dose Modification 
Guideline for Management 
Hemorrhage 
(cont’d) a 
 
 
Grade 3 
non-CNS, non-
pulmonary 
Patients who are also receiving full-
dose anticoagulation will be 
discontinued from 
bevacizumab/placebo.  Continue 
Tarceva. 
All other patients will have 
bevacizumab/placebo held until all 
of the following criteria are met: 
• The bleeding has resolved and 
hemoglobin is stable. 
• There is no bleeding diathesis 
that would increase the risk of 
therapy. 
• There is no anatomic or 
pathologic condition that 
significantly increases the risk of 
hemorrhage recurrence. 
Patients who experience a repeat 
Grade 3 hemorrhagic event will be 
discontinued from 
bevacizumab/placebo. 
As listed above. 
Grade 4 
non-CNS, non-
pulmonary 
Discontinue the patient from 
bevacizumab/placebo.  Continue 
Tarceva.   
As listed above. 
Hypertension b 
 
 
Grade 3 
Hold bevacizumab/placebo until 
blood pressure is controlled to 
systolic ≤ 150 mmHg and diastolic 
≤ 100 mmHg with standard 
medication.  Continue Tarceva. 
Manage with standard oral 
medications.  Common agents 
given to manage hypertension 
included calcium channel blockers, 
diuretics, and ACE inhibitors. 
Grade 4, or 
RPLS confirmed 
by MRI 
Discontinue the patient from 
bevacizumab/placebo.  Continue 
Tarceva. 
As listed above. 


 
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Table 2 
Dosage Modification Criteria and Guidelines for Management of 
Study Treatment–Related Toxicities (cont.) 
 
NCI CTCAE 
Grade 
Study Drug Dose Modification 
Guideline for Management 
Infusion-related 
adverse events 
 
 
Any grade 
— 
See Section 4.3.3 for the 
management of infusion-related 
events for anaphylaxis precautions.
Pulmonary 
events 
 
 
All grades 
Temporarily interrupt Tarceva 
pending diagnostic evaluation.  If 
the pulmonary adverse event is 
assessed as related to Tarceva, 
discontinue Tarceva and the 
treatment phase of the study. 
Unexplained pulmonary 
symptoms, either new or 
progressive, should be 
aggressively evaluated.   
Rash 
 
 
Tolerable rash 
None. 
Any of the following:  minocycline 
c, topical tetracycline, topical 
clindamycin, topical silver 
sulfadiazine, diphenhydramine, 
oral prednisone (short course) at 
the investigator’s discretion. 
Intolerable rash 
Temporarily interrupt Tarceva.  
Consider temporary or permanent 
dose reduction of Tarceva if rash 
persists or worsens over 10–
14 days.  Continue 
bevacizumab/placebo. 
Manage as described above. 
Grade 4 
Discontinue the patient from 
Tarceva and the treatment phase of 
the study. 
As listed above. 


 
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Table 2 
Dosage Modification Criteria and Guidelines for Management of 
Study Treatment–Related Toxicities (cont.) 
 
NCI CTCAE 
Grade 
Study Drug Dose Modification 
Guideline for Management 
Venous 
thrombosis 
 
 
Grade 3 or 4 
None. 
Patients who require full-dose 
anticoagulation may be treated 
with low-molecular-weight heparin 
or fondaparinux.  Patients 
requiring full-dose anticoagulation 
with warfarin will be discontinued 
from bevacizumab/placebo. d 
Arterial 
thrombosis 
(angina, 
myocardial 
infarction, 
transient 
ischemic attack, 
cerebrovascular 
accident and any 
other arterial 
thromboembolic 
event) 
 
 
Any grade 
Discontinue the patient from 
bevacizumab/placebo.  Continue 
Tarceva. 
Manage per standard of care. 
GI perforation 
 
 
Requiring 
medical or 
surgical therapy 
Discontinue the patient from the 
treatment phase of the study. 
Manage per standard of care. 
Bowel 
obstruction 
 
 
Grade 1 
Continue the patient on study for 
partial obstruction NOT requiring 
medical intervention. 
Manage per standard of care. 
Grade 2 
Hold bevacizumab/placebo for 
partial obstruction requiring medical 
intervention.  The patient may 
restart upon complete resolution.  
Continue Tarceva. 
Manage per standard of care. 


 
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Table 2 
Dosage Modification Criteria and Guidelines for Management of 
Study Treatment–Related Toxicities (cont.) 
 
NCI CTCAE 
Grade 
Study Drug Dose Modification 
Guideline for Management 
Bowel 
obstruction 
(cont.) 
 
 
Grade 3, 4 
Hold bevacizumab/placebo for 
complete obstruction.  If surgery is 
necessary, the patient may restart 
bevacizumab/placebo at least 
28 days following surgery, at the 
investigator’s discretion.  Continue 
Tarceva. 
Manage per standard of care. 
Wound 
dehiscence 
 
 
Requiring 
medical or 
surgical therapy 
Discontinue the patient from the 
treatment phase of the study. 
Manage per standard of care. 
Other (All other 
events 
considered 
related to 
bevacizumab) 
 
 
Grade 3 
Hold bevacizumab until recovery to 
Grade ≤ 1.  Continue Tarceva. 
⎯ 
Grade 4 
Discontinue bevacizumab.  Continue 
Tarceva. 
⎯ 
RPLS = reversible posterior leukoencephalopathy syndrome.  
a For bleeding occurring in patients on anticoagulation with low-molecular-weight heparin or 
fondaparinux, assessment of anti-Factor Xa activity and creatinine clearance is 
recommended. 
b Hypertension will be monitored through routine blood pressure evaluations; any instance of 
hypertension will be recorded as an adverse event.  Patients who develop Grade 3 
hypertension not controlled with medication or Grade 4 hypertension will be discontinued 
from the treatment phase of the study. 
c Recommended dose:  200 mg orally twice daily (loading dose) followed by 100 mg orally 
twice daily for 7−10 days. 
d Patients on Tarceva who require full-dose anticoagulation may not be anticoagulated with 
full-dose warfarin; however, patients with indwelling catheters may receive low-dose warfarin 
for prophylaxis against catheter thrombosis.  In this situation, the patient’s INR should be 
closely followed because of a potential drug−drug interaction between Tarceva and warfarin. 
 


 
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Other serious adverse events or Grade 3 or 4 adverse events deemed by the 
investigator to be related to bevacizumab/placebo or Tarceva should be managed as 
follows:    
If bevacizumab/placebo is the causal drug and the event experienced by the patient is a 
Grade 4 adverse event, the patient should be permanently discontinued from 
bevacizumab/placebo.  For Grade 3 adverse events, the patient may restart 
bevacizumab/placebo at the same dose level if the event has resolved to Grade ≤ 1.  If, 
following re-initiation of bevacizumab/placebo, the adverse event recurs at Grade ≥ 2, 
bevacizumab/placebo should be permanently discontinued.  Patients who discontinue 
bevacizumab have the option of continuing on Tarceva until progressive disease or 
unmanageable toxicity.   
If Tarceva is the causal drug, patients may restart Tarceva at the same dose level or at a 
reduced dose if the event has resolved to Grade ≤ 1.  If, following re-initiation of 
Tarceva, the adverse event recurs at Grade ≥ 2, Tarceva should again be held until the 
event has resolved (Grade ≤ 1).  Tarceva may be restarted at a reduced dose if the 
event has resolved to Grade ≤ 1 after the second interruption.  If the adverse event 
recurs after the patient has had two dose reductions, the patient should be permanently 
discontinued from Tarceva and the treatment phase of the study and should enter 
survival follow-up.   
Dose re-escalation of Tarceva to the next highest level (but never exceeding 
150 mg/day) may be attempted at the discretion of the Principal Investigator if toxicity 
has resolved to Grade ≤ 1 at the reduced dose for ≥ 4 weeks.   
If Tarceva is permanently discontinued, the patient must be discontinued from the 
treatment phase of the study, including permanent discontinuation of 
bevacizumab/placebo.  If a patient is discontinued because of Tarceva toxicity, an 
unblinding request may be made by the investigator to determine the treatment 
assignment.  No unblinding requests will be necessary as of Amendment 5, as all 
patients receiving study treatment will have been unblinded and all placebo treatment 
discontinued.   
Subsequent therapy will be provided at the discretion of the treatment clinician. 
If either drug is held for ≥ 6 weeks, permanent discontinuation from that drug may be 
considered. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Upon enactment of Amendment 6, no information on concomitant therapies will be 
collected.  Prior to Amendment 6, information on concomitant therapies were collected 
as below.  


 
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The following concomitant and excluded therapies are guidelines that should be 
considered and may be followed by all physicians and patients who elect to remain on 
study treatment after the enactment of Amendment 5.  All treatment decisions are to be 
made by the treating physician based upon his or her clinical judgment and in 
accordance with institutional practice and guidelines. 
4.4.1 
Concomitant Therapies and Procedures 
All concomitant medications administered within 14 days preceding the initial study 
treatment administration on this study through the 30-day Post−Study Treatment 
Discontinuation Visit were recorded.  The reason(s) for treatment, dosage, and dates of 
treatment should have been reported to the investigator and recorded as instructed on 
the study-specific Case Report Forms (CRFs). 
• 
Patients should receive full supportive care, including hematopoietic growth factors 
such as Epogen® (epoetin), transfusions of blood and blood products, antibiotics, 
etc., when appropriate. 
• 
Use of anti-tumor therapies is permitted after study treatment discontinuation. 
• 
Use of oral contraceptives or hormone-replacement therapy should be continued. 
• 
Patients who experience infusion-associated temperature elevations to ≥ 38.5°C 
(101.3°F) or other infusion-associated symptoms may be treated symptomatically 
with acetaminophen, diphenhydramine, meperidine,  
or other medications as clinically indicated, including ≤ 48 hours of treatment with 
corticosteroids. 
• 
Patients with indwelling venous catheters may receive prophylaxis against catheter 
thrombosis in accordance with the local standard of care.  Because of a potential 
drug–drug interaction between Tarceva and warfarin, it is suggested that patient 
coagulation parameters be monitored if the patient receives low-dose warfarin. 
• 
Full-dose anticoagulation using low-molecular-weight heparin or fondaparinux is 
permitted, starting either prior to study enrollment or during study participation. 
• 
Concurrent use of anticoagulation and non-steroidal agents are not recommended. 
• 
If patient is undergoing elective surgery, whenever possible at least 56 days should 
elapse after the last bevacizumab/placebo dose before surgery is performed.  Re-
initiation of study drug following surgery requires documented approval from the 
Medical Monitor. 
• 
Prolonged use of systemic corticosteroids for the treatment of skin toxicities is 
discouraged.  Patients who are taking corticosteroids for reasons other than skin 
toxicity at study entry may continue their use.   
• 
Patients receiving prophylactic or low-dose warfarin or its equivalent require close 
INR monitoring due to a potential drug−drug interaction with Tarceva  
• 
Other medication considered necessary for the patient’s safety and well being may 
be given at the discretion of the investigator(s). 
 


 
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Because Tarceva is metabolized via the CYP3A4 pathway, agents known to inhibit or 
induce CYP3A4 function may alter the pharmacokinetics of Tarceva.  Although caution 
and careful monitoring are recommended when use of these compounds is necessary; 
usage does not exclude patient participation in this study. 
4.4.2 
Excluded Therapies 
The following therapies were excluded during the treatment phase of the study:  
• 
Investigational agents  
• 
Anti-neoplastic or anti-tumor agents, including chemotherapy, radiation therapy, 
immunotherapy, and hormonal anti-cancer therapy  
• 
Full-dose anticoagulation with warfarin 
• 
Chronic daily use of aspirin (> 325 mg/day) or other full-dose NSAIDs with 
anti-platelet activity 
• 
Dexamethasone for treatment associated with brain metastases 
 
4.5 
STUDY ASSESSMENTS 
Upon enactment of Amendment 6, data collection will be restricted to spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms, not in the CRF, 
and handled according to instructions in Section 5.4.  Prior to Amendment 6, 
assessments were conducted as below. 
4.5.1 
Screening and Pretreatment Assessments 
Enrollment in the BETA trial has been completed.  Patients should no longer be 
screened for study participation.   
Informed consent was obtained before study-specific screening evaluations were 
performed and should have been documented in the patient’s medical chart.  
After written informed consent was obtained and eligibility was confirmed, the study site 
obtained the patient’s identification number and treatment assignment from the IVRS.  
Patients received their first dose of study treatment on Day 0.  All laboratory evaluations 
were performed by local laboratories. 
a. Within 30 Days prior to Randomization 
• 
Signed informed consent(s) were obtained:  consent to participate in the study, 
consent to participate in optional research blood and tissue sampling for additional 
research, and at selected pharmacokinetic sites, intensive pharmacokinetic blood 
sampling 
• 
Assessments of disease stage according to Tumor/Node/Metastases (TNM) staging 
system for lung cancer 
• 
12-lead electrocardiogram was performed 


 
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• 
Chest X-ray was obtained 
• 
Brain MRI or CT scan was performed 
• 
A radiographic assessment (bidimensional measurement) of all disease sites via 
MRI or CT scan and evaluate using RECIST was performed 
• 
Patients with squamous cell carcinoma, had CT or MRI scans submitted to 
Genentech or its designee for confirmation of eligibility prior to randomization 
• 
Concomitant medications for the 14 days prior to randomization were recorded 
• 
Archival paraffin tissue blocks or unstained slides from resected tumor, core biopsy, 
or fine needle aspirate representative of the patient’s primary cancer were located 
This tissue sample, along with a copy of the surgical pathology report from the 
institution where the original diagnosis was made, was shipped to Genentech or 
its designee following randomization (see Week 0, Day 0 assessment). 
 
b. Within 7 Days prior to Randomization 
• 
Medical history, including demographics and smoking history using the Smoking 
History Worksheet  was recorded 
• 
Scans from patients with squamous cell carcinoma were submitted to Genentech or 
its designee at least 5 business days prior to randomization 
• 
Complete physical examination, including height and weight, were performed 
• 
Blood pressure, pulse, and temperature were recorded 
• 
Patients with evidence of hypertension during study screening were evaluated for 
uncontrolled hypertension in accordance with the JNC 7 guidelines. 
• 
ECOG performance status was recorded 
• 
The following laboratory assessments were performed and evaluated: 
Serum pregnancy test for all females of childbearing potential 
The reason a patient was deemed to be not of childbearing potential in medical 
history was documented for every female patient not provided with a serum 
pregnancy test. 
Hematology tests (CBC with differential, platelet count, and INR) 
Serum chemistry and electrolytes (BUN, creatinine, uric acid, sodium, potassium, 
bicarbonate, chloride, calcium, glucose, LDH, total protein, total bilirubin, AST, 
ALT, alkaline phosphatase, and albumin)  
Urinalysis and urinary protein to creatinine ratio (spot urine) 
Patients had to have a urinary protein to creatinine ratio < 1 to participate in 
the study. 
Screening for proteinuria at ex-U.S. sites was performed with a urine dipstick 
(patients found to have ≥ 3+ proteinuria by dipstick had to undergo 24-hour urine 
collection) 


 
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4.5.2 
Assessments During Treatment 
Patients were treated and assessed according to the plan listed below, before 
Amendment 5.  Changes in the plan may be made after Amendment 5 approval based 
upon the investigator’s clinical judgment and in accordance with institutional standards. 
Patients were scheduled to be evaluated at each treatment cycle (every 3 weeks).  
A window of ± 4 days applied to all visits and all on-study radiographic assessments 
unless otherwise specified (this does not apply to screening assessments).  The interval 
between bevacizumab infusions could not be < 17 days. 
a. Week 0, Day 0 
Prior to Study Drug Administration 
• 
Randomized (may occur up to 5 days prior to Day 0, or on Day 0) 
• 
Medical history reviewed 
• 
Archival paraffin tissue block or unstained slides from resected tumor, core biopsy, 
or fine needle aspirate representative of the patient’s primary cancer, shipped once 
patient was randomized 
This tissue sample, along with a copy of the surgical pathology report from the 
institution where the original diagnosis was made, was shipped to Genentech 
within 30 days following randomization. 
• 
Targeted physical examination performed  
• 
Blood pressure, pulse, and temperature recorded 
• 
The following laboratory assessments were performed on Day 0 only if > 1 week 
has elapsed between screening laboratory tests and Day 0 
Hematology (CBC with differential and platelet count)  
Serum chemistry and electrolytes (BUN, creatinine, uric acid, sodium, potassium, 
bicarbonate, chloride, calcium, glucose, LDH, total protein, total bilirubin, AST, 
ALT, alkaline phosphatase, and albumin) 
Urinalysis and urinary protein to creatinine ratio (spot urine) 
Screening for proteinuria at ex-U.S. sites should be performed with a urine 
dipstick (patients found to have ≥ 3+ proteinuria by dipstick must undergo 
24-hour urine collection) 
See Table 2 for dosing guidelines if results are abnormal. 
• 
Collected optional serum and plasma samples for patients who have agreed to 
participate in additional blood research  
• 
Recorded concomitant medications 
During or following Study Drug Administration 
• 
Administered bevacizumab/placebo by infusion  


 
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• 
Dispensed Tarceva bottle(s)/blister pack(s) and instructed patient regarding the 
administration of Tarceva orally daily for 21 days each cycle 
Patients told to take the first dose of Tarceva in the clinic on Day 0 with ~200 mL 
(6−8 ounces) of water on an empty stomach at least 1 hour before or 2 hours 
after a meal.  All subsequent doses should be taken at the same time each day 
with up to ~200 mL (6−8 ounces) of water at least 1 hour before or 2 hours after 
a meal.   
• 
Recorded adverse events starting on Day 0 
b. Week 3 (Day 21) Visit and Every 3 Weeks Thereafter 
Prior to Study Drug Administration 
• 
Repeated radiologic studies (CT scan, MRI; chest X-ray when indicated 
e.g., abnormality previously noted on chest X-ray only) to evaluate disease 
progression or response every 6 weeks after Day 0, beginning at Week 6 (through 
Week 24, and then every 12 weeks thereafter), and/or at the Study Treatment 
Discontinuation Visit using the same method as that used during the baseline 
assessment. 
Patients with a history of brain metastases underwent head CT scan or MRI 
every 6 weeks after Day 0 (beginning at Week 6) through Week 24 and then 
every 12 weeks thereafter and/or at the Study Treatment Discontinuation Visit 
using the same method as that used during the baseline assessment. 
Performed bidimensional measurements 
Evaluated and documented using RECIST before the next bevacizumab/placebo 
infusion  
Radiologic assessments could be delayed further for documented adverse 
events requiring treatment delay; however, the maximum interval between 
evaluations should not exceed 9 weeks.  Any radiologic assessment completed 
out of this window required a written protocol exception from the Medical Monitor. 
• 
Performed targeted physical examination 
• 
Recorded blood pressure, pulse, and temperature 
• 
Recorded ECOG performance status 
• 
Performed the following laboratory assessments  
Hematology (CBC with differential and platelet count)  
Serum chemistry and electrolytes (BUN, creatinine, uric acid, sodium, potassium, 
bicarbonate, chloride, calcium, glucose, LDH, total protein, total bilirubin, AST, 
ALT, alkaline phosphatase, and albumin):   
every 6 weeks after Day 0, beginning at Week 6 
Urinalysis and urinary protein/creatinine ratio (spot urine:  every 6 weeks after 
Day 0, beginning at Week 6 


 
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Screening for proteinuria at ex-U.S. sites should be performed with a urine 
dipstick (patients found to have ≥ 3+ proteinuria by dipstick must undergo 24-hour 
urine collection) 
See Table 2 for dosing guidelines if results were abnormal. 
• 
For intensive pharmacokinetic analysis patients:  On Days 21, 22, 42, 63, and 84, 
bevacizumab/placebo and erlotinib serial serum concentration determinations were 
collected.  Pharmacokinetic analyses for the BETA trial have been completed.   
• 
Recorded concomitant medications 
• 
Recorded adverse events 
During or following Study Drug Administration  
Sites were made aware of patient treatment assignments in December 2008.  Placebo 
treatment was discontinued for patients randomized to the Tarceva-placebo arm, who 
remained on study treatment.   
The rules below, with the exception of placebo treatment, should be followed until 
Amendment 5 is approved at your site. 
• 
Administer bevacizumab by infusion  
If the bevacizumab infusion falls outside of the 4-day window, the patient’s 
schedule should be adjusted so that the subsequent bevacizumab/placebo 
infusion is given 3 weeks after the re-scheduled infusion. 
• 
Collect previously dispensed Tarceva bottle(s)/blister pack(s) and verify patient 
compliance using a standard tablet count (number of tablets taken divided by the 
number of days since the last visit) 
Reconcile discrepancies with the patient and document compliance and dates 
and reasons for all missed doses in the patient’s medical chart.  Compliance 
≤ 80% when unexplained by symptoms or adverse events suggests a need for 
patient re-education. 
• 
Dispense Tarceva bottle(s)/blister pack(s) and instruct the patient regarding the 
administration of Tarceva orally daily for 21 days each cycle 
• 
Record adverse events 
 
4.5.3 
Study Treatment Discontinuation Visit 
Following termination of the study no further information will be collected upon 
enactment of Amendment 6.  Patients will be followed according to the physician’s 
usual standard of care.  Prior to Amendment 6, the study termination visit and follow-
up assessments were conducted as below. 
Patients may remain in the treatment phase of the study until disease progression or 
until unmanageable toxicity.  The treatment phase is completed when both drugs are 
discontinued.  Patients who discontinue bevacizumab have the option of continuing on 


 
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Tarceva until progressive disease or unmanageable toxicity.  Patients who discontinue 
Tarceva will be discontinued from the treatment phase of the study, including 
discontinuation from bevacizumab.  
A Study Treatment Discontinuation Visit should be scheduled at the completion of the 
treatment phase or at the time of the decision to discontinue treatment.  The following 
evaluations and procedures will be performed at the Study Treatment Discontinuation 
Visit: 
• 
Perform laboratory assessments in keeping with the institutional standard according 
to the investigator’s judgment. 
• 
Collect previously dispensed Tarceva bottle(s)/blister pack(s) and verify patient 
compliance using a standard tablet count (number of tablets taken divided by the 
number of days since the last visit) 
• 
Perform radiologic evaluations if warranted by the clinical situation or in accordance 
with institutional guidelines.  Patients with a history of brain metastases must have a 
CT or MRI of the brain  ± 7 days of the treatment discontinuation visit. 
• 
Perform targeted physical examination as per institutional guidelines 
• 
Record adverse events  
Patients who experience an adverse event at treatment completion or at study 
treatment discontinuation should be followed by the investigator or his or her 
designee to determine the status of the event until the event is resolved, 
determined to be irreversible by the investigator, or until the patient begins an 
alternate form of treatment for their disease (excluding localized radiotherapy). 
• 
Reconcile discrepancies in drug accountability 
• 
Record reason for study treatment discontinuation  
 
4.5.4 
30-Day Post−Study Treatment Discontinuation Visit 
Patients who are discontinued from the treatment phase should return for a visit 
~30 days (28 to 42 days) after the last dose of study treatment for a study assessment.  
Record adverse events for 30 days following the last dose of either drug. 
4.5.5 
Follow-Up Assessments 
Prior to the final analysis, survival follow-up information was collected via telephone calls 
and/or clinic visits every 6 weeks ( ± 2 weeks) until death, loss to follow-up, or study 
termination by Genentech.  Survival follow-up after 30 days after the last dose of study 
treatment is not required for patients as of Amendment 5, as subsequent information will 
not alter the primary results of the trial. 


 
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4.6 
STUDY DRUG DISCONTINUATION 
Reasons for study drug (or treatment phase) discontinuation may include, but are not 
limited to, the following: 
• 
Patient’s request to withdraw from study treatment  
• 
Unwillingness or inability to comply with study requirements 
• 
Clinical need for concomitant or ancillary therapy that is not permitted in the study 
• 
Unrelated intercurrent illness that, in the judgment of the Principal Investigator, will 
affect assessments of clinical status to a significant degree 
• 
Progression of disease 
• 
Unacceptable toxicity 
• 
Completion of the final analysis for the primary endpoint of the trial 
It is the right and duty of the investigator to interrupt the treatment of any patient whose 
health or well-being may be threatened by continuation in this study.  Such patients 
should be withdrawn from the treatment phase of the study, not continued under a 
modified regimen. 
4.7 
STUDY TERMINATION 
Genentech has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• 
Data recording is inaccurate or incomplete 
 
4.8 
STATISTICAL METHODS 
The statistical methods noted below were utilized during the interim and final 
analyses for OSI3364g when appropriate.   Upon enactment of Amendment 6, no 
further analysis will be done. Data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms and will not be 
captured in the CRF. 
OSI3364g was a randomized, placebo-controlled trial designed to evaluate the efficacy 
and safety of bevacizumab in combination with Tarceva relative to Tarceva monotherapy 
in second-line patients with advanced NSCLC. Two interim analyses were conducted 
during the study.  The first was for safety and the second for safety and efficacy.  
Descriptive summaries of continuous data were used to present the group mean, 
standard deviation, median, minimum, maximum, and sample size.  Descriptive 
summaries of discrete data were used to present the number of patients and incidence 
as a frequency and as a percentage. 


 
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4.8.1 
Analysis of the Conduct of the Study 
The number of patients randomized were tabulated by center and by treatment arm.  
Eligibility exceptions and protocol deviations were summarized by treatment arm.  
Patient disposition was tabulated by treatment arm, and reasons for premature 
discontinuation were summarized.  Tarceva and bevacizumab exposure was also 
summarized. 
4.8.2 
Analysis of Treatment Arm Comparability 
Treatment arms were assessed for comparability with respect to demographic and 
baseline characteristics, including age; sex; race; weight; smoking status; histology; 
disease stage; disease measurability; baseline ECOG performance status; number of 
metastatic disease sites; history of treated brain metastases; EGFR expression status by 
IHC; EGFR gene copy number by FISH; and EGFR and Kras mutation status.  The 
baseline value of any variable was defined as the last available value prior to the first 
administration of study treatment. 
4.8.3 
Efficacy Analyses 
To control the overall Type I error rate at the 5% level, the fixed sequence testing 
procedure (Westfall and Krishen 2001) was used to adjust for multiple statistical testing 
of the primary and key secondary efficacy endpoints.  These endpoints were tested in 
the following order: 
• 
Overall survival 
• 
PFS 
• 
Objective response 
• 
Duration of objective response 
 
No adjustment to the α level will be made for the other analyses. 
a. Efficacy Analysis Population 
Analyses of overall survival and PFS included all patients who were randomized.  
For objective response and clinical benefit, only patients with measurable disease at 
baseline were included in the analysis.  For duration of response, only responders were 
included in the analysis.  All analyses were based on the treatment arm to which patients 
were randomized. 
b. Primary Endpoint 
The primary efficacy endpoint was overall survival, defined as the period from the date of 
randomization (as entered in the IVRS) until the date of patient death from any cause.  
All deaths were included, regardless of whether they occur during treatment or following 
treatment discontinuation.  For patients who have not died, survival data were censored 
at the date of last contact.   


 
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The two-sided log-rank test, stratified by the randomization stratification factors, was 
used to perform hypothesis testing for assessing the primary study objective.  The 
randomization stratification factors were ECOG performance status (0/1 vs. 2), smoking 
history (never vs. current/previous), sex (male vs. female), and study site; however, 
because of the large number of study sites in this trial, study sites will not be included in 
any efficacy analyses adjusted for randomization stratification factors.  Levels of the 
stratification factors reported on the CRF were used in the analysis.  A sensitivity 
analysis stratified using levels reported on the IVRS was performed.  Both analyses 
were based on the treatment arm to which the patients have been randomized.   
An interim efficacy analysis was conducted when approximately 67% of the required 
deaths (280 deaths) occurred.  Overall survival was tested at the significance level 
determined using the Lan-DeMets alpha spending function with an O’Brien-Fleming 
boundary so that the overall type I error rate will be maintained at the 0.05 level. 
The DMC recommended that the study continue as planned.  The final efficacy analysis 
was conducted when 418 deaths occurred. 
The unstratified log-rank test was performed as a sensitivity analysis.  The Kaplan-Meier 
methods were used to estimate median overall survival for each treatment arm.  Cox 
proportional hazard models, using two models (with and without stratification by the 
randomization stratification factors), were employed to estimate the hazard ratio (i.e., the 
magnitude of treatment effect and 95% CI).   
c. Secondary Endpoints 
Progression-Free Survival.  PFS was defined as the time from randomization to 
documented disease progression or death from any cause on study treatment, 
whichever occurred earlier.  Disease progression was assessed by the investigator 
according to RECIST.  Death on study treatment was defined as death from any cause 
within 30 days of the last dose of study treatment. 
Data for patients without disease progression or patients who had not died on study 
treatment was censored at the time of the last tumor assessment (or, if no tumor 
assessments were performed after the baseline visit, at the time of randomization plus 
1 day).  Analysis methods were the same as those described for overall survival. 
Objective Response.  Objective response was defined as a complete or partial 
response determined on two consecutive occasions ≥ 4 weeks apart.  Only patients with 
measurable disease at baseline were included in the analysis of the objective response.  
Patients without a post-baseline tumor assessment were considered non-responders. 
An estimate of the ORR and its 95% CI were calculated for each treatment arm.  
The 95% CI for the treatment difference was also calculated.  The Mantel-Haenszel χ2 
test stratified by randomization stratification factors (ECOG performance status  


 
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[0/1 vs. 2], smoking history [never vs. current/previous], and sex) was used to compare 
the treatment groups.  An unadjusted Fisher’s exact test result was also provided. 
Duration of Objective Response.  Among patients with an objective response, duration 
of objective response was defined as the period from the date of initial partial or 
complete response until the date of disease progression or death from any cause on 
study treatment.  Methods for handling censoring and analysis were the same as those 
described for PFS.  Only patients with an objective response were included in the 
analysis of duration of objective response. 
Evaluation of Relationship between Exploratory Markers and Efficacy Outcomes.  
To evaluate the effect of exploratory markers on efficacy outcome, efficacy outcomes 
were summarized for all patients and by treatment arm within each subgroup determined 
by exploratory markers.  Markers considered include the presence or absence of 
somatic gene mutations of the EGFR pathway, EGFR protein expression by IHC, EGFR 
gene copy number by FISH, and other markers relevant for the EGFR pathway.  The 
exploration of markers relevant for the VEGF pathway was considered.  Efficacy 
outcomes considered for this analysis included overall survival, PFS, and ORR.  
Exploratory marker analyses were performed on batched sample sets; results of these 
analyses were not made available to patients or investigators. 
d. Additional Efficacy Analyses 
Effect of Risk Factors.  The Cox proportional hazards model (when appropriate) was 
be used to estimate the effect of risk factors on PFS and duration of survival and to 
evaluate any modifications of treatment effect.  To evaluate the effects of risk factors on 
objective response and to assess modifications of treatment effect, a logistic regression 
model (if appropriate) were applied. 
Clinical Benefit.  Clinical benefit was defined as objective response or stable disease 
maintained for at least 6 weeks.  Only patients with measurable disease at baseline 
were included in the analysis of clinical benefit.  The clinical benefit rate was analyzed as 
described for the ORR. 
4.8.4 
Pharmacokinetic and Pharmacodynamic Analyses 
a. Assessment of the Effect of Bevacizumab on Erlotinib Disposition 
Intensive pharmacokinetic sampling was conducted at selected medical centers to 
evaluate the pharmacokinetic behavior of Tarceva when administered as a single agent 
or when administered in combination with bevacizumab, and to evaluate the 
pharmacokinetic behavior of bevacizumab when administered with Tarceva.  A subset of 
at least 17 patients from each treatment arm were scheduled to undergo intensive 
pharmacokinetic analysis. 


 
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Plasma sampling for erlotinib in both arms was performed at Week 3 (Day 21), when 
erlotinib was at steady state and following the second dose of bevacizumab/placebo .  
Actual doses and sample collection times were used for pharmacokinetic analysis.  The 
disposition of erlotinib in the presence of bevacizumab was compared with the 
pharmacokinetic profile of the erlotinib in the monotherapy arm. 
Erlotinib and OSI-420 Cmax, Tmax, Cmin,ss, AUC0–tau, Cmax,ss, and CL/Fss (erlotinib only) was 
estimated by the non-compartmental approach using a validated software program 
(WinNonlin, version 3.1; Pharsight Corp., Mountain View, CA).  OSI-420 is a primary and 
active metabolite of erlotinib produced by metabolism by the cytochrome P-450 system.  
Drug interactions could result in alterations in either or both erlotinib and OSI-420 
plasma concentrations. 
AUC during the dosing interval for both erlotinib and OSI-420 was calculated using 
standard non-compartmental methods.  A 90% CI for the geometric mean ratio (GMR) of 
the AUC for the Tarceva + bevacizumab and Tarceva + placebo treatment arms was 
calculated for both erlotinib and OSI-420.  Each 90% CI was calculated for the difference 
of the log-transformed AUCs using the t-distribution and then back-transformed to the 
ratio scale. 
In addition, because AAG is a significant covariate in erlotinib clearance, AAG levels 
were drawn on Day 21. 
b. Assessment of the Effect of Erlotinib on Bevacizumab Disposition 
Because there is no arm in which bevacizumab was administered alone (in the absence of 
erlotinib), the assessment of drug interaction on bevacizumab pharmacokinetics was 
different than from above.  Bevacizumab concentrations in the bevacizumab + erlotinib 
arm were compared with historical concentration data used in a population 
pharmacokinetic analysis in cancer patients receiving bevacizumab in Phase I–III studies 
(Report 03-0324-1751 [Population Pharmacokinetics of Bevacizumab:  Structural Model 
Identification, Mean Population Pharmacokinetic Parameter Estimation, and Covariate 
Analysis], submitted as part of the Biologics License Application on 25 September 2003).  
In the population pharmacokinetic analysis, data from eight clinical trials with bevacizumab 
administered by intravenous infusion were included.  A total of 4629 bevacizumab 
concentrations from 491 patients who received bevacizumab doses ranging from 1 to 
20 mg/kg at a dosing frequency ranging from weekly to every 3 weeks were analyzed 
using a nonlinear mixed-effects modeling approach (NONMEM).  This rich dataset from 
the population pharmacokinetic analysis served as a reference for the comparison with the 
new bevacizumab concentration data from this trial.  Specifically, the effect of Tarceva on 
bevacizumab pharmacokinetic disposition was evaluated as follows:  
• 
Compare Cmax and Cmin at Days 21, 42, 63, and 84 in patients from this study with 
historically observed values in patients from the population pharmacokinetic 
database on the same dose schedule of bevacizumab. 


 
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• 
Compare Cmax and Cmin at Days 21, 42, 63, and 84 with the simulated 
concentrations at those times based on the population pharmacokinetic model. 
 
4.8.5 
Safety Analyses 
Upon enactment of Amendment 6, data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms (not in the CRF), 
and handled according to instructions in Section 5.4.  Prior to Amendment 5 safety 
assessments were conducted as below. 
Safety was assessed through summaries of adverse events and laboratory test results.  
Patients who receive any amount of study treatment will be included in the safety 
assessment.  Safety results were summarized by the treatment patients actually 
received for all patients, for patients with squamous cell carcinoma, for patients with 
brain metastases treated prior to enrollment, and for patients receiving full-dose 
anticoagulation with low-molecular-weight heparin or fondaparinux. 
Safety data collected after the final analysis was reviewed and summarized for inclusion 
in the Investigator’s Brochure by Genentech or Genentech’s agent. 
a. Adverse Events 
As clinical data and AEs will no longer be collected in the clinical database, no AEs 
will be recorded on the CRF. 
Verbatim descriptions of treatment-emergent adverse events were mapped to MedDRA 
thesaurus terms and graded according to the NCI CTCAE, Version 3.0.  All adverse 
events, including Grade 3, 4, and 5 events and serious adverse events, were 
summarized by treatment arm and NCI CTCAE grade.  For each patient’s adverse 
events, the maximum severity recorded were used in the summaries. 
b. Laboratory Data  
Clinical laboratory tests will be performed at local laboratories.  Laboratory toxicities 
were defined based on local laboratory normal ranges and NCI CTCAE, Version 3.0.  
Laboratory abnormalities, such as worst toxicity grade and toxicity grade shift from 
baseline, were summarized by treatment arm. 
c. Vital Signs  
Changes in blood pressure over time were summarized by treatment arm. 
4.8.6 
Missing Data 
For overall survival, patients who were lost to follow-up were analyzed as censored 
observations on the date of last contact. 
Details of the analyses of missing data were provided in the Statistical Analysis Plan.  


 
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4.8.7 
Determination of Sample Size 
This was a Phase III study to evaluate the efficacy and safety of bevacizumab in 
combination with Tarceva relative to Tarceva alone in advanced NSCLC. A 33% 
improvement in survival was considered a clinically significant outcome. To calculate the 
number of deaths required in this study, the following assumptions were made: 
• 
Two-sided log-rank test 
• 
83% power at the 5% significance level 
• 
Hazard ratio of bevacizumab + Tarceva versus control (Tarceva alone) of 0.75 
corresponding to a 33% improvement in median overall survival from 8 to 
10.67 months 
• 
Median overall survival for the control arm is hypothesized based on data from 
Study BR.21, taking into account the difference in patient population. 
• 
An interim efficacy analysis will be performed when 67% of the required deaths 
have occurred.  The significance level will be determined using the Lan-DeMets 
alpha spending function with an O’Brien-Fleming boundary. 
• 
Five percent of patients will withdraw consent for survival follow-up or will be lost to 
follow-up. 
With these assumptions, 417 deaths were required for the final analysis.   
4.8.8 
Interim Analyses 
The eligible patient population was expanded to include selected patients with 
squamous cell carcinoma, patients with brain metastases treated prior to enrollment, and 
patients receiving full-dose anticoagulation with low-molecular-weight heparin or 
fondaparinux.  A DMC monitored the safety of these and all other patients on this trial.  
The DMC reviewed safety summaries prepared by an external statistical data 
coordinating center, including monthly serious adverse event reports and thorough 
interim safety reports.  Members of the DMC were external to Genentech and followed a 
charter that outlined their role and responsibilities.  Study personnel remain blinded to 
study results until the formal unblinding took place in October 2008. 
All patients were monitored clinically at 3-week intervals and radiographically at 6-week 
intervals through Week 24, at which point scans were followed at 12-week intervals.  
Patients with a history of brain metastases also underwent head CT scans or MRI scans 
every 6 weeks after Day 0 (beginning at Week 6) through Week 24 and then every 
12 weeks thereafter.  Summaries of collected serious adverse events were reviewed by 
the DMC monthly for all patients, for patients with squamous cell carcinoma, and for 
patients with brain metastases treated prior to enrollment.  
All NCI CTCAE Grade ≥ 3 hemoptysis and symptomatic Grade ≥ 2 CNS hemorrhage 
events were to be reported as serious adverse events.  Grade ≥ 3 hemoptysis events 
were closely monitored for patients with squamous cell carcinoma; enrollment for this 
subpopulation was to be discontinued if the incidence was unacceptable (for the 


 
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stopping guidance, see the DMC charter).  Symptomatic Grade ≥ 2 CNS hemorrhage 
events was closely monitored for patients with brain metastases treated prior to 
enrollment; accrual for this subpopulation was to be stopped if the incidence was 
unacceptable (for the stopping guidance, see the DMC charter).  Symptomatic Grade ≥ 3 
hemorrhage events was closely monitored for patients fully anticoagulated with 
low-molecular-weight heparin or fondaparinux; accrual for this subpopulation was to be 
stopped if the incidence of such events was unacceptable.   
Two interim analyses were conducted.  The first interim analysis was conducted after 
123 patients had been enrolled and followed for at least 2 months.  Only safety data 
were assessed in this analysis.  The DMC reviewed the interim safety report on 10 July 
2006 and recommended that the study continue as planned.  
The second interim analysis was conducted when approximately 67% of the required 
deaths (280 deaths) occurred.  Both safety and overall survival were assessed in this 
analysis.  Formal comparisons between the two treatment arms of the incidence of 
Grade 3−5 and Grade 5 hemoptysis were made.  If the incidence in the Tarceva + 
bevacizumab arm was unacceptable, the study would have been stopped (for the 
stopping guidance, see the DMC charter).  The significance level for the overall survival 
comparison was determined using the Lan-DeMets alpha spending function with an 
O’Brien-Fleming boundary of 0.0124 at 67% event time and 0.0462 at the final analysis.  
The overall survival result was not positive, so the study was continued until 417 deaths 
occurred. 
All summaries/analyses by treatment arm for the DMC review were performed by an 
independent Data Coordinating Center (DCC).  The study team remained blinded to the 
treatment assignment until study unblinding. 
Upon enactment of Amendment 6, data collection will be restricted to the spontaneous 
reporting of serious adverse events via MedWatch FDA 3500 forms and will not be 
captured in the CRF. 
4.9 
DATA QUALITY ASSURANCE 
Genentech supplied CRFs for this study.  The CRO entered data directly into the 
Genentech database via secured access and was responsible for the data management 
of this study, including double data entry and quality checking of the data.  When 
discrepancies were encountered, the CRO sent requests for data clarification to the 
sites. 
Genentech performed oversight of the data management of this study.  Genentech 
produced a Data Quality Plan that describes the quality checking to be performed on the 
data.  Central laboratory data were sent directly to Genentech, using Genentech’s 
standard procedures to handle and process the electronic transfer of the data. 


 
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CRFs and correction documentation were indexed and imaged.  System backups for 
data stored at Genentech and records retention for the study data were consistent with 
Genentech’s standard procedures. 
5. 
ASSESSMENT OF SAFETY 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF. The plan below was utilized prior to the final analysis 
of OSI3364g. 
5.1 
SPECIFICATION OF SAFETY VARIABLES  
Safety assessments consisted of monitoring and recording protocol-defined adverse 
events (AEs) and serious adverse events; measurement of protocol-specified 
hematology, clinical chemistry, and urinalysis variables; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study drug(s). 
Death as a result of disease progression was assessed as an efficacy measure and not 
an AE or SAE. 
5.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with NSCLC that were 
not present prior to the AE reporting period (see Section 5.2.1) 
• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies) 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention 
• 
Preexisting medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period 
• 
Diagnoses and/or symptoms associated with NSCLC should be reported as AEs if 
they worsen or change in character.  Clinical progression of NSCLC should not be 
reported as an AE. 
 


 
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5.1.2 
Serious Adverse Events 
An AE should be classified as an SAE if: 
• 
It results in death (i.e., the AE actually causes or leads to death).  
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death.  It does not include an AE that, had it occurred in a more 
severe form, might have caused death.). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
All AEs that do not meet any of the criteria for serious should be regarded as 
nonserious AEs. 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of a specific AE, e.g., mild (Grade 1), moderate (Grade 2), or severe (Grade 3) 
myocardial infarction (see Section 5.2.2).  “Serious” is a regulatory definition (see 
previous definition) and is based on patient or event outcome or action criteria usually 
associated with events that pose a threat to a patient’s life or functioning.  Seriousness 
(not severity) serves as the guide for defining regulatory reporting obligations from the 
Sponsor to applicable regulatory authorities.  
Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the CRF. 
Only serious AEs will be collected after the enactment of Amendment 5.  The period of 
collection will extend to 30 days after treatment discontinuation. 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF. 
5.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF. The plan below was utilized prior to the final analysis 
of OSI3364g. 


 
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The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in Section 5.1.1, are recorded on the CRF and 
reported to the Sponsor in accordance with protocol instructions.  
Death as a result of disease progression endpoints are only to be assessed as efficacy 
measures and not as AEs or SAEs. 
5.2.1 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported began after informed 
consent was obtained and study treatment was initiated.  It ends 30 days following the 
last administration of study treatment or study discontinuation/termination, whichever is 
earlier.  After this period, investigators should only report SAEs that are attributed to 
prior study treatment. 
SAEs that were observed or reported prior to initiation of study treatment should be 
recorded as SAEs on the CRF if they were associated with protocol-mandated 
interventions (e.g., invasive procedures such as biopsies, medication washout, or no 
treatment run-in). 
5.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation 
timepoints during the study.  All AEs and SAEs whether volunteered by the patient, 
discovered by study personnel during questioning, or detected through physical 
examination, laboratory test, or other means should be recorded in the patient’s medical 
record and on the appropriate AE or SAE CRF page. 
Each recorded AE or SAE should be described by its duration (i.e., start and end dates), 
severity (see Table 3), regulatory seriousness criteria if applicable, suspected 
relationship to the investigational product (see following guidance), and actions taken. 
The AE grading (severity) scale found in the NCI CTCAE, Version 3.0, should be used 
for AE reporting. 


 
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Table 3 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Transient or mild discomfort 
(< 48 hours); no interference with 
the patient’s daily activities; no 
medical intervention/therapy 
required 
2 
Moderate (apply event-specific  
NCI CTCAE grading criteria) 
Mild to moderate interference with 
the patient’s daily activities; no or 
minimal medical 
intervention/therapy required 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening,  
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Extreme limitation in activity; 
significant medical 
intervention/therapy required, 
hospitalization probable 
5 
Death related to AE 
 
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  
Refer to definitions of an SAE (see Section 5.1.2) and Table 2. 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
• 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the investigational product, and the AE cannot be readily 
explained by the patient’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to the 
investigational product; and/or the AE abates or resolves upon discontinuation of 
the investigational product or dose reduction and, if applicable, reappears upon 
re-challenge. 
• 
No 
Evidence exists that the AE has an etiology other than the investigational product 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
administration of the investigational product (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
Note:  The investigator’s assessment of causality for individual AE reports is part of the 
study documentation process.  Regardless of the “Yes” or “No” causality assessment for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 


 
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cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
5.3 
PROCEDURES FOR ELICITING, RECORDING, AND 
REPORTING ADVERSE EVENTS 
5.3.1 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation timepoints should be adopted.  Examples of non-directive questions include:  
“How have you felt since your last clinical visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.2 
Specific Instructions for Recording Adverse Events on the 
Case Report Form 
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the CRF.  Avoid colloquialisms and abbreviations. 
AEs should be recorded either on an AE CRF page (if no serious criteria are met) or 
SAE CRF page, but not both. 
Only one medical concept should be recorded in the event field on the AE or SAE CRF 
page. 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be recorded on the CRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded as an AE or SAE on 
the CRF.  If a diagnosis is subsequently established, it should be reported as follow-up 
information. 
b. Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the CRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF.  For example, 
if a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
recorded separately on the CRF. 


 
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c. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation timepoints.  Such events should only be recorded once on the CRF unless 
their severity increases.  If a persistent AE becomes more severe, it should be recorded 
again on an AE or SAE CRF page.   
A recurrent AE is one that occurs and resolves between patient evaluation timepoints 
and subsequently recurs.  All recurrent AEs should be recorded on an AE or SAE CRF 
page. 
d. Clinical Laboratory Abnormalities 
Individual laboratory abnormalities will generally not be recorded as AEs on the CRF.  
Only clinically significant laboratory abnormalities that result in study withdrawal, meet 
serious criteria, are themselves associated with clinical signs or symptoms, or require 
medical intervention (e.g., low hemoglobin requiring transfusion) will be recorded as AEs 
or SAEs on the CRF. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 × the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the AE or 
SAE CRF page. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the CRF.  If the laboratory 
abnormality can be conveyed as a clinical diagnosis, the diagnosis should be recorded 
as the AE or SAE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, 
seriousness, or etiology changes.  
Only serious AEs will be collected after the initiation of Amendment 5.  The period of 
collection will extend to 30 days after treatment discontinuation.  This will focus the 
safety evaluation of the bevacizumab and Tarceva combination on events of greatest 
clinical significance. 
Upon enactment of Amendment 6, safety data collection will be restricted to the 
spontaneous reporting of serious adverse events via MedWatch FDA 3500 forms and 
will not be captured in the CRF.   


 
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e. Deaths 
For this protocol, mortality was the primary efficacy endpoint.  Deaths that 
occur/occurred during the protocol-specified AE reporting period (see Section 5.2) that 
are/were attributed by the investigator solely to progression of NSCLC should be 
recorded only on the Study Discontinuation CRF page.  All other on-study deaths, 
regardless of attribution, should be recorded on an SAE CRF page and expeditiously 
reported to the Sponsor.  An independent monitoring committee will monitor the 
frequency of death from all causes.  After Amendment 5, this will be performed by 
Genentech or its agent. 
When recording a death on an SAE CRF page, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on 
the SAE CRF page.  If the cause of death is unknown and cannot be ascertained at the 
time of reporting, record “Unexplained Death” on the SAE CRF page. 
During post-study survival follow-up, deaths attributed to progression of NSCLC will be 
recorded only on the Survival and Study Termination CRF pages.  
f. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the Medical and Surgical History CRF page. 
A preexisting medical condition should be re-assessed throughout the trial and recorded 
as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study.  When recording such events on an AE or SAE CRF page, it is 
important to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
g. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. 
If a patient is hospitalized to undergo a medical or surgical procedure as a result of an 
AE, the event responsible for the procedure, not the procedure itself, should be recorded 
as the SAE.  For example, if a patient is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass on the SAE CRF page. 
Hospitalizations for the following reasons will not be recorded as SAEs on the CRF. 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study or 




 
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Investigators will submit written reports of all SAEs, regardless of attribution, to 
Genentech within 24 hours of learning of the events.  For initial SAE reports, 
investigators should record all case details that can be gathered within 24 hours on a 
MedWatch 3500 form.  The completed MedWatch 3500 form and SAE Fax Cover Sheet 
should be faxed immediately upon completion to Genentech’s Drug Safety Department 
at: 
(650) 225-4682 
or  
(650) 225-5288 
Relevant follow-up information should be submitted to Genentech’s Drug Safety as soon 
as it becomes available and/or upon request. 
Note:  All non-U.S. sites were closed prior to the enactment of Amendment 6. 
5.5 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER 
ADVERSE EVENTS 
All SAEs that are encountered during the protocol-specified AE reporting period should 
be followed to their resolutions, or until the investigator assesses them as stable, or the 
patient is lost to follow-up.  Resolution of SAEs (with dates) should be documented via a 
MedWatch FDA 3500 form.   
For some SAEs, the Sponsor or its designee may follow-up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report). 
The safety data collected after the final analysis of OSI3364g will be reviewed on a 
regular basis by Genentech or its agent.  The findings will be recorded in the annual 
Investigator’s Brochure.  If a new safety signal is identified, a safety evaluation following 
Genentech standard operating procedures (SOPs) will be conducted and the data 
reported in keeping with the SOP guidance. 
6. 
INVESTIGATOR REQUIREMENTS 
The requirements listed below were required prior to the final analysis of 
OSI3364g.  These should be continued unless stated otherwise. 


 
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6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with Genentech or 
a Genentech representative:   
• 
Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any subinvestigators must appear on this form.  Investigators must 
also complete all regulatory documentation as required by local and national 
regulations. 
• 
Current curricula vitae of the Principal Investigator and all subinvestigators 
• 
Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the U.S. FDA Form 1572 
• 
Institutional Review Board (IRB) or Ethics Committee (EC) membership list and/or 
Department of Health and Human Services number 
• 
Written documentation of IRB/EC approval of protocol (identified by Genentech 
protocol number or title and date of approval) and Informed Consent Form 
(identified by Genentech protocol number or title and date of approval) 
• 
A copy of the IRB/EC-approved Informed Consent Form 
• 
Written documentation of IRB/EC review and approval of any advertising materials 
to be used for study recruitment, if applicable 
Genentech or its designee must review any proposed deviations from the sample 
Informed Consent Form.  The Genentech Legal Department must review and 
approve any advertising materials. 
• 
Current laboratory certification of the laboratory performing the analysis  
(if other than a Genentech-approved central laboratory), as well as current normal 
laboratory ranges for all laboratory tests 
• 
A signed Clinical Research Agreement 
• 
Certified translations of IRB/EC approval letters, pertinent correspondence, and 
approved Informed Consent Form (when applicable) 
• 
A signed and dated Protocol Acceptance Form 
• 
Other region specific documents, as required 
 
6.2 
STUDY COMPLETION 
Study OSI3364g is considered complete and no further patient data will be collected, except for 
serious adverse event reporting via MedWatch FDA 3500 Forms, (not in the CRF), and will be 
handled according to instructions in Section 5.4. 


 
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The following data and materials are required by Genentech before a study can be 
considered complete or terminated: 
• 
Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period (or the study termination visit after Amendment 
5) 
• 
CRFs (including correction forms) properly completed by appropriate study 
personnel and signed and dated by the investigator 
• 
Completed Drug Accountability Records (IND Retrieval Record [INDRR-1], Drug 
Inventory Log, and Inventory of Returned Clinical Material forms) 
• 
Copies of protocol amendments and IRB/EC approval/notification, if appropriate 
• 
A summary of the study prepared by the Principal Investigator (will accept IRB/EC 
summary close letter) 
• 
All regulatory documents (e.g., curriculum vitae for each Principal Investigator, U.S. 
FDA Form 1572 for each site) 
• 
A signed and dated protocol amendment acceptance form (if applicable) 
• 
Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the U.S. FDA Form 1572 (applicable for 1 year after the 
last patient has completed the study) 
• 
Other region specific documents, as required 
 
6.3 
INFORMED CONSENT 
The Informed Consent Form has been revised to reflect the changes made to the protocol 
under Amendment 6.  Following submission and IRB approval of Amendment 6, only 
those patients who are currently receiving study treatment will be required to be 
reconsented with the amended Informed Consent Form. 
Sample Informed Consent Forms will be provided to each site.  Genentech or its 
designee must review any proposed deviations from the sample Informed Consent 
Form.  The final IRB/EC-approved document must be provided to Genentech for 
regulatory purposes. 
The Informed Consent Form must be signed by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history 
for each patient shall document that informed consent was obtained prior to participation 
in the study.  A copy of the Informed Consent Form must be provided to the patient or 
the patient’s legally authorized representative.  If applicable, it will be provided in a 
certified translation of the local language. 
For patients unable to read or write, the Informed Consent Form should be read to the 
patient by a person other than the patient’s relative/friend or the study staff (e.g., site 
staff not working on this study). 


 
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Signed Informed Consent Form must remain in each patient’s study file and must be 
available for verification by study monitors at any time. 
6.4 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
APPROVAL 
This protocol, the Informed Consent Form, and relevant supporting information must be 
submitted to the IRB/EC for review and must be approved before the study is initiated.  
In addition, any advertising materials must be approved by the IRB/EC.  The study will 
be conducted in accordance with U.S. FDA, applicable national and local health 
authority, and IRB/EC requirements. 
The Principal Investigator is responsible for keeping the IRB/EC apprised of the progress 
of the study and of any changes made to the protocol as deemed appropriate, but in any 
case the IRB/EC must be updated at least once a year.  The Principal Investigator must 
also keep the IRB/EC informed of any significant AEs. 
Investigators are required to promptly notify their respective IRB/EC of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to SAEs that are 
not already identified in the Investigator Brochure and that are considered by the 
investigator to be possibly or probably related to the study drug.  Some IRBs or ECs may 
have other specific adverse event requirements to which investigators are expected to 
adhere.  Investigators must immediately forward to their IRB/EC any written safety report 
or update provided by Genentech (e.g., IND safety report, Investigator Brochure, safety 
amendments and updates, etc.). 
6.5 
STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by Genentech or an authorized Genentech representative to 
inspect study data, patients’ medical records, and CRFs in accordance with current U.S. 
GCPs and the respective local and national government regulations and guidelines (if 
applicable). 
The Principal Investigator will permit authorized representatives of Genentech, the U.S. 
FDA, and the respective national or local health authorities to inspect facilities and 
records relevant to this study. 
Upon enactment of Amendment 6, all necessary study monitoring and site management 
will be performed remotely.  
6.6 
CASE REPORT FORMS 
CRFs will be supplied by Genentech and should be handled in accordance with 
instructions from Genentech. 


 
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All CRFs should be filled out completely by examining personnel or the study 
coordinator.  The CRF should be reviewed, signed, and dated by the investigator. 
All CRFs should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Black ink is required to ensure clarity of reproduced CRF copies.  
When making changes or corrections, cross out the original entry with a single line, and 
initial and date the change.  DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID ON THE ORIGINAL. 
6.7 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification (SDV) to confirm that critical 
protocol data (i.e., source data) transcribed on the CRFs by authorized site personnel 
are accurate, complete, and verifiable from source documents. 
Source documents are where patient data are recorded and documented for the first 
time.  They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at the pharmacy, laboratories, and medico-technical departments involved in a 
clinical trial. 
Source documents that are required to verify the validity and completeness of data 
transcribed on the CRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct 
access to applicable source documents and reports for trial-related monitoring, Sponsor 
audits, and IRB/EC review.  The investigational site must also allow inspection by 
applicable regulatory authorities. 
6.8 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with FDA requirements pertaining to computerized systems used in clinical 
research.  An acceptable computerized data collection system (for clinical research 
purposes) would be one that (1) allows data entry only by authorized individuals; (2) 
prevents ability to delete or alter previously entered data and provides an audit trail for 
such data changes (e.g., modification of file); (3) protects the database from tampering; 
and (4) ensures data preservation. 
In collaboration with the study monitor, Genentech’s Computer Systems Compliance 
group will assess whether electronic records generated from computerized medical 


 
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record systems used at investigational sites can serve as source documents for the 
purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents will need to be maintained to ensure that critical protocol 
data that are transcribed on the CRFs can be verified. 
6.9 
STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be provided by Genentech and 
Astellas Pharmaceuticals.  The recipient will acknowledge receipt of the drug by 
returning the enclosed paperwork that is received with study medication shipments.  
Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site should 
be recorded by using the Drug Inventory Log. 
All partially used or empty containers should be disposed of at the study site according 
to institutional standard operating procedure only after study drug reconciliation has 
been performed and disposal has been authorized by a Genentech representative.   
All forms will be supplied by Genentech. 
6.10 
DISCLOSURE OF DATA 
Patient medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, Genentech, and 
the IRB/EC for each study site, if appropriate. 
6.11 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) and the International Council on 
Harmonisation (ICH) Guideline for Good Clinical Practice (see Section 4.9 of the 
guideline) require that records and documents pertaining to the conduct of this study and 
the distribution of investigational drug, including CRFs,  
consent forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product.  All state and local 


 
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laws for retention of records also apply.  Genentech will notify the Principal Investigator 
of these events. 
No records should be disposed of without the written approval of Genentech. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with those of the relevant 
national and local health authorities.


 
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Oncology Group (ECOG) Trial—E4599 [abstract]. J Clin Oncol 
2005;23:16S(1 Suppl):LBA4. 
Sandler A, Johnson D, Johnson DH, Brahmer J, Schiller JH, Ostland M, Gray R,  
et al.  Retrospective study of clinical and radiographic risk factors 
associated with early-onset, severe pulmonary hemorrhage in bevacizumab 
(Avastin®)-treated patients with NSCLC [abstract]. Proc Am Soc Clin Oncol 
2006; abstract 7068.  
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. 
Eastern Cooperative Oncology Group. Comparison of four chemotherapy 
regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 
346:92–8. 


 
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Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. 
Prospective randomized trial of docetaxel versus best supportive care in 
patients with non-small-cell lung cancer previously treated with 
platinum-based chemotherapy. J Clin Oncol 2000;18:2095–103. 
Shepherd FA, Pereira J, Ciuleanu TE, Tan EH, Hirsh V, Thongprasert S, et al.  A 
randomized placebo-controlled trial of erlotinib in patients with advanced 
non-small cell lung cancer (NSCLC) following failure of 1st-line or 2nd-line 
chemotherapy:  a National Cancer Institute of Canada Clinical Trials Group 
(NCIC CTG) trial [abstract]. Proc Am Soc Clin Oncol 2004; abstract 7022. 
Sweeney CJ, Sandler AB. Treatment of advanced (stages III and IV) non–small 
cell lung cancer. Curr Probl Cancer 1998;22:85–132. 
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. 
Guidance for industry: in vivo drug metabolism/drug interaction 
studies⎯study design, data analysis, and recommendations for dosing and 
labeling, November 1999.  
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures. J Stat Planning Inference 2001;99:25–40. 
 


 
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Appendix A  
Study Flowchart 
Study Period 
Screening
Treatment 
Survival Follow-Up
Week
0 
3 
6 
9 
12 
Day
–30 
0 
21 
42 
63 
84 
Every 
3 Weeks 
Every 
6 Weeks 
Study Treatment 
Discontinuation 
Visit a 
Every 6 Weeks 
after Study 
Treatment 
Discontinuation 
Written informed consent(s) 
x  
 
 
 
 
 
 
 
 
 
Medical history 
x  
x 
 
 
 
 
 
 
 
 
Demographics 
x  
 
 
 
 
 
 
 
 
 
Assess disease stage using TNM 
x 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
x 
 
 
 
 
 
 
 
 
 
Chest X-ray  
x 
 
 
 
 
 
 
 
 
 
Brain MRI or CT scan  
x 
 
 
 
 
 
 
 
x b 
 
Tumor assessments CT/MRI  
x 
 
 
 
 
 
 
 
 
 
Archival tissue sample c 
x 
 
 
 
 
 
 
 
 
 
Complete physical examination 
x  
 
 
 
 
 
 
 
 
 
Height and weight 
x  
 
 
 
 
 
 
 
 
 
Blood pressure, pulse, and 
temperature 
x  
 
 
 
 
 
 
 
 
 
ECOG performance status 
x  
 
 
 
 
 
 
 
 
 
Serum pregnancy test  
x  
 
 
 
 
 
 
 
 
 
CBC, differential, and platelet count 
x  
 
 
 
 
 
 
 
 
 
INR 
x  
 
 
 
 
 
 
 
 
 
Serum chemistry and electrolytes  
x  
 
 
 
 
 
 
 
 
 
Urinalysis, protein to creatinine ratio  
x  
 
 
 
 
 
 
 
 
 
Bevacizumab administration  
 
x 
x 
x 
x 
x 
x 
 
 
 
Dispense/collect Tarceva d 
 
 
 
 
 
 
x 
 
x 
 
Concomitant medications  
x  
 
 
 
 
 
 
 
 
 
Adverse events e 
 
 
 
 
 
 
x 
 
x 
 


Appendix A  
Study Flowchart (cont’d) 
Bevacizumab and Erlotinib—Genentech, Inc. 
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a A Study Treatment Discontinuation Visit should be scheduled at the completion of the treatment phase or at the decision to discontinue 
treatment.  Another visit should be scheduled for ∼30 days (28−42 days) after the end of study treatment to assess adverse events. 
b Brain MRI or CT scan for patients with a history of brain metastases. 
c An archival paraffin tissue block or unstained slides (preferably 10 or more) from tumor resection, core biopsy, or fine needle aspirate. 
d Dispense Tarceva and collect Tarceva bottles dispensed at previous visit, if applicable; verify patient compliance.  Tarceva tablets should be 
taken at the same time each day with ∼200 mL (6−8 ounces) of water on an empty stomach at least 1 hour before or 2 hours after a meal. 
e Serious adverse events will be recorded starting on Day 0 and for 30 days following the last dose of study treatment (or the decision to 
discontinue study treatment). 
 


 
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Appendix B  
Tarceva® Package Insert 
 


 
Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
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Appendix B  
Tarceva® Package Insert (cont.) 
Bevacizumab and Erlotinib—Genentech, Inc. 
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Appendix B  
Tarceva® Package Insert (cont.) 
Bevacizumab and Erlotinib—Genentech, Inc. 
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Appendix C  
Final Study Results 
Final Study Results 
A Phase III, multicenter, placebo-controlled, double-blind, randomized, clinical trial to 
evaluate the efficacy of bevacizumab (Avastin®) in combination with erlotinib (Tarceva®) 
compared with erlotinib alone for treatment of advanced non−small cell lung cancer 
(NSCLC) after failure of standard first-line chemotherapy (BETA).   
Authors:  J Hainsworth1, M Lin2, P O’Connor2, and R Herbst3 for the BETA Lung 
Investigators (1 Sarah Cannon Research Institute, Nashville TN, 2 Genentech, Inc., San 
Francisco, CA, 3 MD Anderson Cancer Center, Houston TX) 
Background:  Bevacizumab (B) with chemotherapy and erlotinib (E) monotherapy have 
demonstrated a survival benefit in the treatment of patients (pts) with advanced NSCLC 
(Sandler et al. NEJM 2006; Shepherd et al. NEJM 2005).  Randomized Phase II data 
supported the hypothesis that combining B + E might improve efficacy, with acceptable 
safety (Herbst et al. JCO 2007).   
Methods:  Patients with advanced NSCLC who progressed during or after first-line 
therapy were enrolled.  The primary endpoint of the trial was overall survival (OS).  
Secondary endpoints included PFS and ORR.  Eligible patients were B appropriate, 
including a group with treated brain metastases, squamous cell disease at low risk for 
bleeding, and those requiring anticoagulation.  Previous anti-angiogenisis or epidermal 
growth factor receptor (EGFR) targeted therapy was not allowed.  Patients were 
randomized (1:1) to B + E or E + placebo (P).  E dosing was 150 mg daily.  B/P dosing 
was 15 mg/kg intravenous every 3 weeks.  Responses were assessed every 6 weeks 
until Week 24 and every 12 weeks thereafter.  Treatment continued until disease 
progression or unacceptable toxicity.   
Results:  636 patients were enrolled from June 2005 to April 2008.  The final analysis 
was conducted after 418 deaths were recorded.  Median OS was 9.3 mos (B + E) vs. 
9.2 months (E+P), p = 0.75, HR=0.97(95% CI: 0.80 -1.18).  Median PFS was 3.4 mos 
(B+E) vs. 1.7 mos (E+P), p<0.0001; HR = 0.62 (95%CI: 0.52-0.75).  ORR was 12.6% 
(B+E) vs.6.2% (E+P), p=0.006.  The safety profile for B+E was consistent with known 
profiles for B and E and will be described further at presentation.  Conclusions:  The 
addition of B to E in the BETA lung study was not associated with an improvement 
overall survival.  However, B + E doubled PFS and ORR, providing clear evidence of 
clinical activity. 


 
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Appendix D  
MedWatch Form FDA 3500 
 


Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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Appendix D  
MedWatch Form FDA 3500 (cont’d) 
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SAP_001.pdf: 
 
Official Title: A Phase III, Multicenter, Placebo-Controlled, Double-Blind, 
Randomized Clinical Trial to Evaluate the Efficacy of Bevacizumab in 
Combination With Tarceva® (Erlotinib) Compared With Tarceva Alone 
for Treatment of Advanced Non−Small Cell Lung Cancer (NSCLC) 
After Failure of Standard First-Line Chemotherapy 
NCT Number: NCT00130728 
Document Date: SAP Version A1: 6-December-2006 
 
 


CONFIDENTIAL 
 
This is a Genentech, Inc.  document that contains confidential information.  Nothing herein is to be 
disclosed without written consent from Genentech, Inc. 
 
Statistical Analysis Plan:  Bevacizumab and TARCEVA—Genentech, Inc. 
OSI3364g-A1 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, MULTICENTER, 
PLACEBO-CONTROLLED, DOUBLE-BLIND, 
RANDOMIZED CLINICAL TRIAL TO EVALUATE 
THE EFFICACY OF BEVACIZUMAB IN 
COMBINATION WITH TARCEVA (ERLOTINIB) 
COMPARED WITH TARCEVA ALONE FOR 
TREATMENT OF ADVANCED NON−SMALL CELL 
LUNG CANCER (NSCLC) AFTER FAILURE OF 
STANDARD FIRST-LINE CHEMOTHERAPY 
PROTOCOL NUMBER: 
OSI3364g 
STUDY DRUG: 
Bevacizumab 
Tarceva (Erlotinib) 
IND NUMBER: 
BB-IND 7023 
SPONSOR: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080-4990  U.S.A. 
PLAN PREPARED BY: 
, Ph.D. 
, M.S. 
RECORDS RETENTION: 
Genentech Central Records 
DATE FINAL: 
11 July 2005 
DATE AMENDED: 
6 December 2006 
 
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AMENDMENT SUMMARY TO THE OSI3364g 
STATISTICAL ANALYSIS PLAN 
6 December 2006 AMENDMENT 
 
 
RATIONALE 
The OSI3364g Statistical Analysis Plan has been amended to reflect changes to the 
study design made in the protocol amendments.  The major changes are as follows: 
• 
An interim efficacy analysis has been incorporated into the study design.  
The details of the interim efficacy analysis are now included. 
• 
The study has been amended to include study sites from other countries. Region 
of study sites (United States vs. the rest of the world) is added as one of the 
factors to be assessed for potential differences in treatment effect in the 
exploratory efficacy analysis. 
• 
The inclusion criteria have been expanded to allow patients with peripheral 
squamous cell carcinoma, patients with treated brain metastasis prior to 
enrollment, and patients requiring therapeutic anticoagulation with low molecular 
weight heparins or fondaparinux to be enrolled.  Therefore, additional 
summaries of adverse events are added for these subgroups of patients. 
• 
Potential sensitivity analyses are planned for overall survival if substantial 
treatment crossover to bevacizumab-class agents is observed.  
Additional editorial changes have been made to improve clarity and consistency.   
All significant new information appears in italics.  This amendment represents 
cumulative changes to the original Statistical Analysis Plan. 
 
Page   42


TABLE OF CONTENTS 
 
 
Page 
Statistical Analysis Plan:  Bevacizumab and TARCEVA—Genentech, Inc. 
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1. 
PROTOCOL SYNOPSIS...................................................................................4 
2. 
RANDOMIZATION ISSUES ..............................................................................4 
3. 
STATISTICAL METHODS.................................................................................4 
3.1 
Analysis of Study Conduct......................................................................5 
3.2 
Analysis of Treatment Group Comparability ...........................................5 
3.3 
Efficacy Analyses....................................................................................6 
3.3.1 
Primary Efficacy Endpoint .........................................................6 
3.3.2 
Secondary Efficacy Endpoints...................................................7 
3.3.3 
Exploratory Efficacy Endpoints..................................................9 
3.4 
Pharmacokinetic Analyses....................................................................11 
3.4.1 
Assessment of the Effect of Bevacizumab on 
Erlotinib Disposition.................................................................12 
3.4.2 
Assessment of the Effect of Erlotinib on 
Bevacizumab Disposition ........................................................13 
3.5. 
Safety Analyses....................................................................................14 
3.5.1 
Adverse Events.......................................................................15 
3.5.2 
Laboratory Data ......................................................................15 
3.5.3 
Vital Signs ...............................................................................15 
3.6 
Missing Data.........................................................................................16 
3.7 
Interim Analyses ...................................................................................16 
4. 
DETERMINATION OF SAMPLE SIZE ............................................................17 
5. 
TABLE OF CONTENTS OF PLANNED TABLES, 
LISTINGS, AND GRAPHS ..............................................................................18 
6. 
REFERENCES................................................................................................21 
 
APPENDICES 
Appendix A: Protocol Synopsis for Study OSI3364g   
(Amendment 4, 30 November 2006) 
Appendix B: Study Flowcharts for Study OSI3364g  
(Amendment 4, 30 November 2006) 
Appendix C: Hierarchical Dynamic Randomization Scheme 
 
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1. 
PROTOCOL SYNOPSIS 
The protocol synopsis for Study OSI3364g (Amendment 4, 30 November 2006) is in 
Appendix A.  For additional details, see the study flowcharts in Appendix B. 
 
2. 
RANDOMIZATION ISSUES 
Patients will be randomized to receive either Tarceva + placebo or 
Tarceva + bevacizumab using an interactive voice response system (IVRS) after 
written informed consent has been obtained and eligibility has been established.  
Patients may be randomized up to 5 days prior to study treatment initiation.  
A hierarchical dynamic randomization scheme will be used to ensure 
approximately equal sample sizes for the two treatment arms overall, within each 
of the four categories defined by baseline ECOG performance status (0/1 vs. 2) 
and smoking history (never vs. current/previous), within each sex (male vs. 
female), and within each study site.  The detailed randomization scheme is 
provided in Appendix C. 
The IVRS vendor, ClinPhone Inc. (Nottingham, UK), will develop the program to 
implement the hierarchical dynamic randomization.  A Genentech study 
statistician and the independent Data Coordinating Center (DCC), 
Statistics Collaborative, Inc. (Washington, DC), will review the simulated 
randomization log and results prior to the activation of the IVRS.  In addition, 
the DCC will check the treatment assignment every month during the study to 
ensure randomization is carried out correctly.   
 
3. 
STATISTICAL METHODS 
This study is a randomized, placebo-controlled, double-blind, parallel-group trial 
designed to evaluate the efficacy and safety of bevacizumab in combination with 
Tarceva relative to Tarceva monotherapy in second-line patients with advanced 
non−small cell lung cancer (NSCLC).  An interim efficacy analysis will be performed 
after approximately 280 deaths (67% of the total 417 deaths required for the final 
analysis) have been observed.  If the interim analysis result is positive (i.e., crosses 
the O’Brien-Fleming boundary; see Section 3.7), the study will be unblinded.  
Otherwise, this study will be unblinded for analysis when the total number of required 
events (417 deaths; see Section 4) has been reached.  A data cutoff date will be 
determined when this number of events has occurred.  The clinical database will 
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be thoroughly cleaned and frozen, the treatment assignment will be unblinded, 
analyses will be performed, and a clinical study report will be prepared. 
Descriptive summaries of continuous data will present the group mean, standard 
deviation (SD), median, minimum, maximum, and sample size.  Descriptive 
summaries of discrete data will present the number of patients as a frequency 
and as a percentage. 
 
3.1 
ANALYSIS OF STUDY CONDUCT 
The number of patients who are randomized will be tabulated by center and by 
treatment arm.  Eligibility exceptions and protocol deviations will be summarized by 
treatment arm.  Patient disposition will be tabulated by treatment arm, and reasons 
for premature study discontinuation will be summarized by treatment arm.   
Tarceva and bevacizumab exposure and treatment compliance will be 
summarized by treatment arm.  Treatment compliance will be measured by dose 
intensity, which is defined as the total cumulative dose received divided by 
the total expected cumulative dose from the first to the last dose.   
 
3.2 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Treatment arms will be assessed for comparability with respect to demographic 
and baseline characteristics, including age; sex; race/ethnicity; weight; smoking 
status; histology; disease measurability; baseline ECOG performance status; 
number of disease sites; history of treated brain metastases; epidermal growth factor 
receptor (EGFR) expression status by immunohistochemistry (IHC); EGFR gene 
copy number by fluorescent in situ hybridization (FISH); and EGFR and K-ras 
mutation status.  No formal tests of hypotheses will be performed.  The baseline 
value of any variable will be defined as the last available value prior to the first 
administration of study treatment. 
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3.3 
EFFICACY ANALYSES 
Unless otherwise specified, efficacy analyses will include all patients who are 
randomized and will be based on the treatment arm to which the patients have 
been randomized.  For objective response and clinical benefit, only patients with 
measurable disease at baseline will be included in the analysis.  For duration of 
response, only responders will be included in the analysis. 
To manage the overall type I error rate at the 5% level, the fixed sequence 
testing procedure (Westfall and Krishen 2001) will be used to adjust for multiple 
statistical testing of the primary and key secondary efficacy endpoints.  
These endpoints will be tested in the following order: 
• 
Overall survival 
• 
Progression-free survival (PFS) 
• 
Objective response 
• 
Duration of objective response 
The treatment difference in the primary endpoint (overall survival) will be tested 
at the two-sided 5% overall significance level using the O’Brian Fleming 
boundary (see Section 3.7).  If this test result is positive at either the interim or 
the final analysis, the treatment difference in PFS will be tested at the 5% 
significance level.  Only if the treatment effect on PFS is positive, the difference 
in objective response between the two treatment groups will be tested at the 5% 
level, and so on.  If any test result is not positive, testing of the subsequent 
endpoints will not occur. 
No adjustment to the α level will be made for the other analyses. 
 
3.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is overall survival, defined as the time from 
the date of randomization (as entered into the IVRS) until the date of patient 
death from any cause.  All deaths will be included, regardless of whether they 
occur during treatment or following treatment discontinuation.  For patients who 
have not died, survival data will be censored at the date of last contact.   
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The two-sided log-rank test, stratified by the randomization stratification factors 
except study site, will be used to perform hypothesis testing for assessing 
the primary study objective at the 5% significance level.  The randomization 
stratification factors are ECOG performance status (0/1 vs. 2), smoking history 
(never vs. current/previous), sex (male vs. female), and study site; however, 
because of the large number of study sites in this trial, study site will not be 
included in any efficacy analyses adjusted for randomization stratification factors.  
The stratification values reported on the Case Report Form (CRF) will be used in 
the analysis.  If > 5% of patients have discrepancies in stratification factors 
between the CRF and the IVRS, a sensitivity analysis stratified by values 
reported on the IVRS will be performed.  Both analyses will be based on 
the treatment arm to which the patients have been randomized. 
The Kaplan-Meier method will be used to estimate the median overall survival for 
each treatment arm.  Cox proportional hazard models, using two models 
(with and without stratification by the randomization stratification factors), will be 
used to estimate the hazard ratio (i.e., the magnitude of treatment effect and 
95% confidence interval [CI]). 
 
3.3.2 
Secondary Efficacy Endpoints 
a. Progression-Free Survival (PFS) 
PFS is defined as the time from randomization to documented disease 
progression or death on study treatment, whichever occurs earlier.  
Disease progression will be assessed by the investigator according to the 
Response Evaluation Criteria in Solid Tumors (RECIST).  Patients with a global 
deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression will also be considered to have 
disease progression (i.e., clinical progression will also be considered as an event 
“per RECIST”).  Death on study treatment is defined as death from any cause 
within 30 days of the last dose of study treatment. 
Data for patients without disease progression and for patients who have not died 
on study treatment will be censored at the time of the last tumor assessment 
(or, if no tumor assessments were performed after the baseline visit, at the time 
of randomization).  Analysis methods are the same as those described for overall 
survival. 
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b. Objective Response 
Objective response is defined as a partial or complete response determined on 
two consecutive occasions ≥ 4 weeks apart.  Only patients with measurable 
disease at baseline will be included in the analysis of objective response.  
Patients without a post-baseline tumor assessment will be considered 
non-responders. 
An estimate of the objective response rate and its 95% CI will be calculated for 
each treatment arm.  The 95% CI for the treatment difference will also be 
calculated.  The Mantel-Haenszel χ2 test stratified by randomization stratification 
factors (ECOG performance status [0/1 vs. 2], smoking history [never vs. 
current/previous], and sex [male vs. female]) will be used to compare 
the treatment difference.  An unadjusted Pearson χ2 test result will also be 
provided as a sensitivity analysis. 
c. Duration of Objective Response 
Only patients with an objective response will be included in the analysis of 
duration of objective response.  Duration of objective response is defined as 
the period from the date of the initial partial or complete response until the date of 
disease progression or death on study treatment from any cause.  Methods for 
handling censoring and analysis are the same as described for overall survival 
and PFS.   
d. Evaluation of the Relationship between Exploratory Markers and 
Efficacy Outcomes 
To evaluate the effect of exploratory markers on efficacy outcome, efficacy 
outcomes will be summarized by treatment arm within each subgroup determined 
by exploratory markers.  Patients with missing or unevaluable marker status will be 
excluded from all analyses described in this section.  Efficacy outcomes considered for 
this analysis will include overall survival, PFS, and objective response rate.  
The Cox proportional hazard model will be used to evaluate the difference in 
treatment effect on overall survival and PFS across subgroups defined by a 
biomarker by testing the interaction effect of treatment and the biomarker.  
The biomarker will be treated as the stratification factor in the Cox model to allow for 
different underlying baseline hazard functions between the two subgroups defined by 
the biomarker when testing the treatment by biomarker interaction.  The logistic 
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regression model will be used to evaluate the difference in treatment effect on objective 
response rate across subgroups defined by a biomarker by testing the interaction effect of 
treatment and the biomarker.  In addition, the Cox model or logistic regression model 
will be used to assess the clinical benefit in each subset defined by 
the biomarkers.  The analyses described in this section will not be stratified by 
randomization stratification factors unless substantial imbalances are observed because 
of an anticipated small sample size in some subsets. 
Markers to be considered include EGFR expression by IHC using the Dako 
EGFR PharmDx immunohistochemistry kit, EGFR gene copy number by 
fluorescence in situ hybridization (FISH) using the Vysis LSI EGFR 
SpectrumOrange/CEP 7 SpectrumGreen kit, and the presence or absence of 
somatic gene mutations of the EGFR pathway by DNA sequencing.  A positive 
EGFR expression by IHC will be defined as having ≥ 10% of tumor cells staining 
for EGFR.  A high copy number of the EGFR gene will be defined as high 
polysomy (greater than four gene copies in > 40% of cells) or amplification 
(gene/chromosome > 2, or > 15 gene copies in > 10% of cells).  The EGFR gene 
will be considered wild type if no mutations are detected in exons 18−21. 
Other markers relevant for the EGFR or VEGF pathway may also be explored.   
 
3.3.3 
Exploratory Efficacy Endpoints 
a. Effect of Risk Factors 
The effects of demographic and baseline characteristics on treatment 
comparisons for overall survival, PFS, and response rate will be examined as 
exploratory analyses.  It is expected that many of the subgroups defined by these 
factors will be small and will not have adequate power to detect a treatment 
difference.   
The risk factors to be considered include the following: 
• 
Sex:  male, female  
• 
Baseline ECOG performance score:  0−1, 2 
• 
Sex by baseline ECOG performance score strata 
• 
Smoking history:  never smoked, smokers 
• 
Age group:   < 65 years,  ≥ 65 years 
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• 
Race/ethnicity 
• 
Best response to prior therapy:  CR/PR (complete response/partial 
response), SD  (stable disease), PD (progressive disease) 
• 
Histology:  adenocarcinoma, adenocarcinoma with BAC (bronchioloalveola 
carcinoma) or BAC-like features 
• 
Time from initial NSCLC diagnosis to randomization:  < 6, 6−12, > 12 months  
• 
Region of study sites:  sites in the United States, sites in the rest of the world 
For overall survival and PFS, the Kaplan-Meier estimated median time will be 
summarized by treatment arm for each of the subgroups defined above along 
with a hazard ratio (treatment:control) estimated by unstratified Cox regression 
displayed on a Forest plot (Lewis and Clarke 2001).  The difference in treatment 
effect across subgroups will be assessed using Cox regression to test 
the interaction effect between treatment and each of the above factors 
separately.  The risk factor will be treated as the stratification factor in the Cox model to 
allow for different underlying baseline hazard functions among the subgroups defined by 
the risk factor when testing the treatment by factor interaction.  In addition, the overall 
treatment difference with adjustment for each factor will be evaluated using Cox 
regression with risk factor and the randomization stratification factors as covariates 
in the model. 
For objective response, the response rate will be summarized by treatment arm 
for each of the subgroups defined above along with the odds ratio 
(treatment:control) estimated by logistic regression displayed on a Forest plot.  
The difference in treatment effect across subgroups will be assessed using 
logistic regression by testing the interaction effect between treatment and each of 
the above factors separately.  In addition, the overall treatment difference with 
adjustment for each factor will be evaluated using logistic regression with 
adjustment for the factor and the randomization stratification factors.   
b. Clinical Benefit 
Clinical benefit will be defined as objective response or stable disease 
maintained for at least 6 weeks from the start of treatment.  Only patients with 
measurable disease at baseline will be included in the analysis of clinical benefit.  
The clinical benefit rate will be analyzed as described for the objective response 
rate. 
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c. Sensitivity Analysis 
Patients can receive any subsequent treatments during survival follow-up after the end of 
study treatment to warrant best supportive care.  Consequently, the potential survival 
benefit of the treatment relative to control may be obscured by the potential benefit 
patients receive from subsequent treatments.  For example, treatment effects may be 
masked if a substantial proportion of patients receive bevacizumab or agents in the same 
class as one of the subsequent treatments (i.e., crossover to bevacizumab-class).  
To address this issue, sensitivity analyses of overall survival will be performed if 
substantial crossover is observed. 
The analyses may include but not limited to the following: 
1. Patients receiving bevacizumab-class agents in the subsequent treatments will be 
censored at the initial time of receiving the first subsequent bevacizumab-class agent.  
Analysis methods are otherwise the same as those described for overall survival in 
Section 3.3.1. 
2. Overall survival analysis will be performed in patients who did not receive any 
bevacizumab-class agents in subsequent treatments.  Analysis methods are the same 
as those described for overall survival in Section 3.3.1. 
 
3.4 
PHARMACOKINETIC ANALYSES  
The purpose of this pharmacokinetic study is to characterize the pharmacokinetic 
behavior of erlotinib and bevacizumab in a subset of patients with previously 
treated advanced NSCLC.  
Intensive pharmacokinetic sampling will be conducted at selected study sites to 
evaluate the drug−drug interaction in pharmacokinetics between erlotinib and 
bevacizumab.  To evaluate the effect of bevacizumab on erlotinib 
pharmacokinetics in the two treatment arms (Tarceva vs. Tarceva + bevacizumab), 
a subset of 17 evaluable patients will be needed.  A patient will be considered 
evaluable for erlotinib pharmacokinetic analysis if he or she has a full profile of 
erlotinib (i.e., he or she has sufficient samples to determine the pharmacokinetic 
outcome measures).  In addition, to evaluate the effect of erlotinib on 
bevacizumab pharmacokinetics, peak and trough concentrations will be obtained 
from those patients participating in the intensive pharmacokinetic study, and the 
concentration levels will be compared with historical concentration data.  
Subjects who received bevacizumab and had at least one peak or one trough 
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concentration at any one of the sampling timepoints (Days 21, 42, 63, and 84) will 
be included in this analysis.   
Pharmacokinetic analyses will be performed separately for bevacizumab and 
erlotinib.   
 
3.4.1 
Assessment of the Effect of Bevacizumab on Erlotinib Disposition 
Plasma sampling for erlotinib in both arms will be performed at Week 3, 
when erlotinib is at steady state, and following the second dose of bevacizumab 
or placebo.  Samples will be drawn at the following timepoints:  Day 21, 
pre−Tarceva dose and 2, 4, 6, 8, 10, and 12 hours post−Tarceva dose; Day 22, 
pre−Tarceva dose.  In addition, because α-1-acid glycoprotein (AAG) is 
a significant covariate in erlotinib clearance, samples for AAG levels will be 
drawn on Day 21 pre−Tarceva dose.  Actual doses and sample collection times 
will be used in the pharmacokinetic analysis.   
The plasma concentrations of erlotinib and its O-demethylated metabolite 
(OSI-420) versus actual time for each subject will be presented graphically in 
the raw and log10-transformed scale, respectively.  OSI-420 is the primary and 
active metabolite of erlotinib produced by metabolism by the cytochrome P-450 
system.  The mean (+ standard error of mean [SEM]) plasma erlotinib and 
OSI-420 concentrations versus scheduled time will also be presented graphically 
by treatment.  Note that concentrations below the limit of quantification will be 
imputed using one-half the limit of quantification in all summaries and analyses. 
Erlotinib and OSI-420 maximum concentration (Cmax), time at which 
the maximum concentration was achieved (tmax), maximum concentration at 
steady state (Cmax, ss), area under the erlotinib time−concentration curve 
(AUC0−τ), minimum concentration at steady state (Cmin, ss), and apparent 
clearance (CL/F) (erlotinib only) for each treatment group will be estimated by 
the non-compartmental approach using a validated software program 
(WinNonlin, Version 5.5.1, Pharsight Corp., Mountain View, CA).  The AUCs will 
be calculated using the linear trapezoidal rule up to the time at which the 
maximum concentration was achieved (tmax) and using the log trapezoidal rule 
after tmax.  AUC0−τ will be calculated from the time of dosing (0 hour) to the last 
measurable concentration (Cτ). 
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Descriptive statistics, including mean, SD, median, range, and geometric mean 
for each pharmacokinetic parameter, will be tabulated by treatment group.   
Only patients who have estimates of AUC0−τ and Cmax will be included in 
the assessment of drug interaction of bevacizumab with erlotinib.  The drug−drug 
interaction will be evaluated by calculating the 90% CIs of the ratios of AUC0−τ 
and Cmax between the two treatment arms.  The analysis of variance (ANOVA) 
approach will be used to obtain the least squares (LS) means and standard 
errors (SE) of AUC0−τ and Cmax in natural log scale.  The ratio of AUC0−τ and Cmax 
between the two treatment groups will be estimated by taking the anti-log of 
the difference in the LS mean between the two arms.  The 90% CI will be 
obtained by taking the anti-log of the 90% CI for the mean difference in log scale.  
That is, the 90% CI is the anti-log of 
LS meanT – LS meanTA ± t.95[df] • SE(LS meanT – LS meanTA), 
where 
LS meanT and LS meanTA are the LS mean for the Tarceva alone and 
Tarceva + bevacizumab arms (log scale), respectively, 
t.95[df] is the 95th percentile of the Student t-distribution with degrees of 
freedom for overall error from the ANOVA model, and 
SE(LS meanT – LS meanTA) is the SE of the contrast term for 
the difference in LS means. 
 
3.4.2 
Assessment of the Effect of Erlotinib on Bevacizumab Disposition 
Because there is no arm in which bevacizumab is administered alone 
(in the absence of erlotinib), the assessment of the effect of erlotinib on 
bevacizumab pharmacokinetics will be different from the approach described 
above.  The effect of erlotinib on bevacizumab will be assessed for all patients 
who have received bevacizumab and have had at least one peak or one trough 
concentration at any one of the sampling timepoints (Days 21, 42, 63, and 84).   
Bevacizumab concentrations in the Tarceva + bevacizumab arm will be 
compared with historical concentration data used in a population 
pharmacokinetic analysis in cancer patients receiving bevacizumab in Phase I–III 
studies (Report 03-0324-1751 [Population Pharmacokinetics of Bevacizumab:  
Structural Model Identification, Mean Population Pharmacokinetic Parameter 
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Estimation, and Covariate Analysis], submitted as part of the bevacizumab 
Biologics License Application on 25 September 2003).  Specifically, the effect of 
erlotinib on bevacizumab pharmacokinetic disposition will be evaluated as 
follows:  
• 
Cmax and Cmin at Days 21, 42, 63, and 84 in patients from this study will be 
compared with historically observed values in patients from the population 
pharmacokinetic database on the same dose and schedule of bevacizumab.  
• 
The mean and SD of Cmax and Cmin at Days 21, 42, 63, and 84 in patients 
from this study will be calculated and compared with historical data from patients 
from the population pharmacokinetic database who were given 15 mg/kg 
bevacizumab every 3 weeks.  The individual Cmax and Cmin versus actual time 
for each patient and the mean (SEM) concentrations versus scheduled time 
for the data from this study and the historical data will be presented 
graphically.  
• 
Cmax and Cmin at Days 21, 42, 63, and 84 will be compared with simulated 
concentrations at those timepoints based on the population pharmacokinetic 
model from Report 03-0324-1751. 
• 
First, 500 patients will be drawn with replacement from the bevacizumab 
population pharmacokinetic database.  The simulated Cmax and Cmin at 
Days 21, 42, 63, and 84 for these 500 patients following administration of 
15 mg/kg bevacizumab every 3 weeks will be obtained based on 
the population pharmacokinetic model from Report 03-0324-1751, 
with the random and residual effects simulated from the normal distribution.   
Then, the mean and SD of the predicted Cmax and Cmin at each timepoint for 
these 500 patients will be calculated and informally compared with 
the observed concentration data from this study.  No formal statistical 
comparisons will be made. 
 
3.5. 
SAFETY ANALYSES 
Adverse events, laboratory test results, and changes in blood pressure will be 
summarized by treatment arm.  Patients who receive any amount of study 
treatment will be included in the safety analyses.  Safety results will be 
summarized based on the treatment that patients actually receive. 
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3.5.1 
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events will be mapped to 
Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms and 
graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 3.0. 
The incidence in patients of the following events will be summarized for each 
treatment group by system organ class and preferred term.  For each patient’s 
adverse events, the maximum severity recorded will be used in the summary. 
• 
All adverse events 
• 
Grade 3–4 and Grade 5 adverse events 
• 
All deaths 
• 
Serious adverse events 
• 
Adverse events leading to discontinuation of study drug 
• 
Adverse events by subgroup:  incidence of all adverse events summarized 
by age at baseline (< 65, ≥ 65 years old), sex (male, female), and 
race/ethnicity 
• 
Adverse events in a special population:  the incidence of all adverse events 
in patients with squamous cell carcinoma, patients with treated brain 
metastases prior to enrollment, and patients requiring low molecular weight 
anticoagulant 
 
3.5.2 
Laboratory Data  
Clinical laboratory tests will be performed at local laboratories.  Laboratory 
toxicities will be defined based on local laboratory normal ranges and 
the NCI CTCAE, Version 3.0.  For each laboratory parameter, the toxicity grade 
at baseline and the worst toxicity grade during the treatment phase will be 
summarized by treatment group.  The worst toxicity grade shift from baseline for 
white blood count, absolute neutrophil count, platelet count, and SGOT and 
SGPT levels will be summarized by treatment arm. 
 
3.5.3 
Vital Signs  
Blood pressure will be measured at baseline and every 3 weeks during the study 
treatment phase.  Changes in blood pressure over time will be summarized 
graphically and in tabular format by treatment arm. 
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Statistical Analysis Plan:  Bevacizumab and TARCEVA—Genentech, Inc. 
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3.6 
MISSING DATA 
For overall survival, patients who are lost to follow-up will be treated as censored 
on the date of last contact. 
For PFS, patients who do not have disease progression and who have not died 
on study treatment will be treated as censored at the time of the last tumor 
assessment (or, if no tumor assessments were performed after the baseline visit, 
at the time of randomization). 
For objective response and clinical benefit, patients without a post-baseline 
tumor assessment will be considered non-responders. 
For duration of objective response, patients who do not have disease 
progression and who have not died on study treatment will be treated as 
censored at the time of the last tumor assessment. 
 
3.7 
INTERIM ANALYSES 
A Data Monitoring Committee (DMC) will monitor safety and will meet periodically 
to review safety summaries prepared by the external statistical DCC.  
The detailed interim safety analysis plan and the role and responsibilities of 
the DMC members are described in the separate Charter for the Data Monitoring 
Committee.  Members of the DMC will be external to Genentech and will follow 
the charter.  Study personnel will remain blinded to study results until final study 
unblinding.   
An interim efficacy analysis is planned and will be performed by the DCC after 
approximately 280 deaths (67% of the total required deaths for final analysis) have been 
observed.  The overall survival will be tested at the significance level determined using 
the Lan-DeMets α-spending function with an O’Brien-Fleming boundary of 0.0124 at 
67% event time and 0.0462 at the final analysis, so that the overall type I error rate will 
be maintained at the 0.05 level.  The two-sided log-rank test, stratified by 
the randomization stratification factors except study site, will be used to perform 
hypothesis testing for assessing the primary study objective.  If the overall survival result 
is positive, the study will be unblinded and the primary analysis will be performed.  
Otherwise, the study will continue until 417 deaths have occurred. 
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4. 
DETERMINATION OF SAMPLE SIZE 
This is a Phase III study to evaluate the efficacy and safety of bevacizumab in 
combination with Tarceva relative to Tarceva alone in advanced NSCLC.  
A 33% improvement in median survival is considered a clinically significant 
outcome.  To calculate the number of deaths required for this study, the following 
assumptions were made: 
• 
Two-sided log-rank test 
• 
83% power at the 5% significance level 
• 
Hazard ratio of bevacizumab + Tarceva versus control (Tarceva alone) of 
0.75 corresponding to a 33% improvement in median overall survival from 8 
to 10.67 months 
• 
An interim efficacy analysis will be performed when 67% of the required deaths for 
final analysis have occurred.  The significance level will be determined using 
the Lan-DeMets α-spending function with an O’Brien-Fleming boundary. 
• 
Five percent of patients will withdraw consent for survival follow-up or will be lost 
to follow-up. 
Median overall survival for the control arm is hypothesized based on data from 
Study BR.21, taking into account the difference in patient population. 
With these assumptions, 417 deaths are required.  Assuming an accrual rate of 
20 patients per month, 650 patients enrolled over 35 months (accounting for 
staggered accrual) and followed for an additional 2 months will provide 417 deaths. 
For the subpopulation undergoing intensive pharmacokinetic analysis, 
17 evaluable patients will be needed in each treatment arm.  A patient will be 
considered evaluable for pharmacokinetic analysis if he or she has a full profile of 
erlotinib samples and at least two bevacizumab samples.  This sample size is 
estimated to obtain 81% power for evaluating the equivalence of AUC between 
the two treatment arms with an equivalence limit of 0.67−1.5, assuming that 
the true mean log (natural log) of the AUCs of the two treatment arms is identical, 
that the AUC interpatient coefficient of variation is ~40% (based on the estimates 
from Report 034-0143-1219:  Population Pharmacokinetics of Tarceva), and that 
data will be analyzed in the natural log scale using two one-sided t-tests for 
differences in mean AUC at the 5% significance level for each test.  Additional 
patients may need to be added to obtain 34 evaluable patients. 
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5. 
TABLE OF CONTENTS OF PLANNED TABLES, LISTINGS, AND GRAPHS 
Study Population and Disposition Data 
Table 14.1/1: 
Enrollment by Investigator (Randomized Patients) 
Table 14.1/2: 
Patient Status and Reasons for Study Discontinuation 
(Randomized Patients) 
Table 14.1/3: 
Reasons for Discontinuation of Treatment Phase (Randomized 
Patients) 
Table 14.1/4: 
Reasons for Early Discontinuation of Bevacizumab/Placebo 
(Treated Patients) 
Table 14.1/5.1 
Patient Eligibility:  Description of Inclusion and Exclusion Criteria 
Table 14.1/5.2 
Patient Eligibility: Inclusion and Exclusion Criteria Not Met 
(Randomized Patients) 
Table 14.1/6 
Number and Percentage of Patients Using Concomitant Medications 
on Study Treatment (Treated Patients) 
 
Efficacy and Pharmacokinetic Data 
Table 14.2/1: 
Demographics and Baseline Characteristics (Randomized Patients) 
Table 14.2/2: 
Patient Compliance with Study Treatment (Treated Patients) 
Table 14.2/3: 
Duration of Study Treatment (Treated Patients) 
Table 14.2/4: 
Overall Survival (Randomized Patients) 
Table 14.2/5: 
Progression-Free Survival (Randomized Patients) 
Table 14.2/6: 
Objective Response (Patients with Measurable Disease at Baseline) 
Table 14.2/7: 
Duration of Objective Response (Patients with an Objective Response) 
Table 14.2/8: 
Overall Survival by Biomarker (Randomized Patients) 
Table 14.2/9: 
Progression-Free Survival by Biomarker (Randomized Patients) 
Table 14.2/10: 
Objective Response by Biomarker (Patients with Measurable Disease at 
Baseline) 
Table 14.2/11: 
Overall Survival by Risk-Factor Subgroup (Randomized Patients) 
Table 14.2/12: 
Progression-Free Survival by Risk-Factor Subgroup (Randomized 
Patients) 
Table 14.2/13: 
Objective Response by Risk-Factor Subgroup (Patients with 
Measurable Disease at Baseline) 
Table 14.2/14: 
Overall Survival Adjusted for Risk Factors (Randomized Patients) 
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Table 14.2/15: 
Progression-Free Survival Adjusted for Risk Factors (Randomized 
Patients) 
Table 14.2/16: 
Objective Response Adjusted for Risk Factors (Patients with 
Measurable Disease at Baseline 
Table 14.2/17: 
Summary of Erlotinib Pharmacokinetic Parameters (Erlotinib 
Pharmacokinetic Evaluable Patients) 
Table 14.2/18: 
Erlotinib AUC0−τ and Cmax (Patients with  
Estimable Erlotinib AUC0−τ and Cmax) 
Table 14.2/19: 
Comparison of Observed Cmax and Cmin from the Bevacizumab + Tarceva 
Study with Historical  
Data from Population Pharmacokinetic Dataset  
Table 14.2/20: 
Comparison of Observed Cmax and Cmin from the Bevacizumab + Tarceva 
Study with Simulated Concentrations based on the Population 
Pharmacokinetic Model  
Table 14.2/21: 
Comparison of Individual Pharmacokinetic Parameters in 
the Bevacizumab + Tarceva Study versus Other Studies in the 
Population Pharmacokinetic Analysis 
Table 14.2/22: 
Population Pharmacokinetic Estimates with and without the 
Bevacizumab + Tarceva Data 
 
Figure 14.2/1: 
Overall Survival Curves (Randomized Patients) 
Figure 14.2/2: 
Progression-Free Survival Curves (Randomized Patients) 
Figure 14.2/3: 
Duration of Objective Response Curves (Patients with an Objective 
Response) 
Figure 14.2/4: 
Erlotinib Concentrations by Patient (Erlotinib Pharmacokinetic 
Evaluable Patients) 
Figure 14.2/5: 
Erlotinib Concentrations (in Log10 Scale) by Patient (Erlotinib 
Pharmacokinetic Evaluable Patients) 
Figure 14.2/6: 
Mean (SE) Erlotinib Concentrations by Treatment (Erlotinib 
Pharmacokinetic Evaluable Patients) 
Figure 14.2/7: 
OSI-420 Concentrations by Patient (Erlotinib Pharmacokinetic 
Evaluable Patients) 
Figure 14.2/8: 
OSI-420 Concentrations (in Log10 Scale) by Patient (Erlotinib 
Pharmacokinetic Evaluable Patients) 
Figure 14.2/9: 
Mean (SE) OSI-420 Concentrations by Treatment (Erlotinib 
Pharmacokinetic Evaluable Patients) 
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Safety Data 
Table 14.3/1: 
Administration of Bevacizumab/Placebo (Treated Patients) 
Table 14.3/2: 
Administration of Tarceva (Treated Patients) 
Table 14.3/3: 
All Deaths (Treated Patients) 
Table 14.3/4: 
All Adverse Events (Treated Patients) 
Table 14.3/5: 
Adverse Events at NCI CTCAE Grade 3 to 4 and Grade 5 (Treated 
Patients) 
Table 14.3/6: 
Serious Adverse Events (Treated Patients) 
Table 14.3/7: 
Adverse Events Leading to Discontinuation of Bevacizumab or Placebo 
(Treated Patients) 
Table 14.3/8: 
Adverse Events Leading to Discontinuation of Tarceva (Treated 
Patients) 
Table 14.3/9: 
Adverse Events by Age at Baseline (Treated Patients) 
Table 14.3/10: 
Adverse Events by Sex (Treated Patients) 
Table 14.3/11: 
Adverse Events by Race (Treated Patients) 
Table 14.3/12: 
Adverse Events in Patients with Squamous Cell Carcinoma (Treated 
Patients) 
Table 14.3/13: 
Adverse Events in Patients with Treated Brain Metastases (Treated 
Patients) 
Table 14.3/14: 
Adverse Events in Patients Requiring Anticoagulant (Treated Patients) 
Table 14.3/15: 
Selected Adverse Events (Treated Patients) 
Table 14.3/16: 
Baseline Laboratory Abnormalities by Highest NCI-CTC Grade 
(Treated Patients) 
Table 14.3/17: 
Post-Baseline Laboratory Abnormalities by Highest NCI-CTC Grade 
(Treated Patients) 
Table 14.3/18: 
NCI-CTC Grade Changes in Selected Laboratory Parameters from 
Baseline (Treated Patients) 
Table 14.3/19: 
Change in Blood Pressure over Time (Mean and SE) (Treated Patients) 
 
Figure 14.3/1: 
Change in Blood Pressure over Time (Mean and SE) (Treated Patients) 
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6. 
REFERENCES 
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479−80.  
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures. J Stat Planning Inference 2001;99:25−40. 
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