`
`OSI EX. 2004 - 0001
`OSI EX. 2004 - 0001
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGEFOR:
`
`APPLICATION NUMBER
`
`21-743
`
`Statistical Review(s)
`
`OSI EXHIBIT 2004
`OSI EXHIBIT 2004
`APOTEX V. OSI
`APOTEX V. OSI
`IPR2016-01284
`IPR2016-01284
`
`

`

`
`
`OSI EX. 2004 - 0002
`OSI EX. 2004 - 0002
`
`
`
`U.S. Department of Kealth and Human Services
`Food and Drug Administration
`Center for Drug Evaluation Research
`Office of Pharmacoepidemiotogy and Statistical Science
`Office of Biostatistics
`
`STATISTICAL REVIEW AND EVALUATION
`
`CLINICAL STUDIES
`ADDENDUM 1
`
`NDA /Serial Number:
`
`21-743 /NO00
`
`Drug Name:
`
`Applicant:
`
`Indication(s):
`
`Date(s):
`
`Tarceva™(erlotinib hydrochloride, OSI-774)
`
`OSI Pharmaceuticals
`
`Metastatic Non-smail Cell Lung Cancer
`
`Submission Date: July 30, 2004
`
`PDUFADate: January 30, 2005
`Review Date: November 1, 2004
`
`Review Priority:
`
`Priority
`
`Biometrics Division:
`
`Division of Biometrics I (HFD-710)
`
`Statistical Reviewers:
`
`Rajeshwari Sridhara, Ph.D.
`
`Concurring Reviewer:
`
`Yeh-Fong Chen, Ph.D.
`Kooros Mahjoob, Ph.D., Acting Director
`
`Medical Division:
`Clinical Team:
`
`Project Manager:
`
`Oncology Drug Products (HFD-150)
`
`Martin Cohen, M.D. & John Johnson, M.D.
`
`Mz. Paul Zimmerman
`
`Keywords:
`
`Superiority, log-rank test, Cox regression, QoL
`
`1
`
`
`
`

`

`
`
`OSI EX. 2004 - 0003
`OSI EX. 2004 - 0003
`
`In this addendum additional exploratory analyses with respect to smoking history
`in the Study BR.21 are presented. These analyses do not change the conclusions
`and recommendations of the review.
`
`The following table showsthe baseline characteristics in patients with smoking
`history and without smokinghistory.
`
`Table 1; Demographics and Baseline Characteristics of Patients by Smoking
`History
`
`
`
`=358
`
`=18
`
`Non-smokers
`
`N=49
`
`
`
`£/S
`
`tntofertrlun
`
`
`
`
`
`
`
`
`
`= 78
`57.7%
`™
`2.5%
`2 (4.8%
`4.8%
`10 (5.4%
`11 3.1%
`Race: Biack
`
`
`292 (81.6%)|153 (81.8% 62.5% 26 (61.9%
`
`5 (24.0%
`|Others|195.3%)|84.3%)|9 (8.7%
`6 (53.9%
`
`|61-69yrs|129.36.0%)|56(29.9%)|24 (23.1%
`>= 70
`24 (23.1%
`18 (17.3%)
`EGFRStatus:
`positive
`
`58 (16.2%)
`
`35 (18.7%)
`
`12 (28.6%)
`
`negative
`
`Unknown
`Histology: Adeno
`
`MN
`
`.
`
`)
`
`163 (45.5%
`
`80 (42.8%
`
`76 (73.1%
`
`33 (78.6%
`
`8 (2.2%
`32 (8.9%
`33 (9.2%
`
`2 (1.1%
`20 (10.7%
`18 (9.6%
`
`2 (1.9%
`5 (4.8%
`10 (9.6%
`
`0 (0.0%
`2 (4.8%
`3 (7.1%
`
`‘Unknown 247 (69.0%)|120(64.2%)|67 (64.4%) 25 (59.5%)
`
`
`
`squamous 122 (34.1%)|67 (35.8%) 11 (7.5%) 4 (9.5%)
`
`
`
`
`
`
`
`
`
`
`5%)|_30(28.8%)_|
`
`114 (31.8%)|59(31.5% 30 (28.8% 17 (40.5%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`39 (92.9%
`
`

`

`
`
`OSI EX. 2004 - 0004
`OSI EX. 2004 - 0004
`
`Reviewer's Comments:
`
`|. The patients characteristics appear to be balanced betweenthe treatment
`arms within the subgroup of patients with smoking history (except for age
`group), and within the subgroup of patients with no smoking history
`(except for EGFR positive status, performancestatus and response to prior
`therapy).
`2. There is however a difference between the subgroups with respectto the
`distribution of gender, race and histology.
`3. Results from analyses adjusting for imbalances within each of the two
`subgroups were similar to the unadjusted analyses:
`Smoking Group: HR = 0.865, 95% CI: 0.713, 1.050 Unadjusted analysis;
`HR= 0.866, 95% CI: 0,713, 1.052 Adjusted for age group analysis.
`Non-smoking Group: HR = 0.422, 95% CI: 0.278, 0.640 Unadjusted
`analysis;
`HR = 0.422, 95% CI: 0.296, 0.645 Adjusted for performancestatus,
`response to prior therapy and EGFRstatus.
`
`Further analyses of difference between patients with smoking history versus no
`smoking history in each of the treatment arms are presented below.
`
`Table 2: Survival Analyses Results in Tarceva Treated Patients
`
`Known Population
`
`
`
`
`
`
`Med.Survivalin
`
`
`4.7, 6.5
`months (95% CI
`Hazard Ratio = Smokers / Non-smokers;
`
`N=358
`
`N=104
`
`12.3
`
`10.6, 16.1
`“Unadjusted, log-rank test.
`
`95% C
`1.860
`(1.418,2.441)
`
`< 0.0001
`
`
`
`
`Table 3: Survival Analyses Results in Placebo Treated Patients
`
`# of Deaths|iso|8 0.989 0.9532
`
`P-value
`
`
`
`
`Smoking History
`Smokers
`Non-smokers
`| Hazard Ratio
`Known Population
`N=187
`N=42
`95% C
`
`
`
`7
`Med.Survivalin
`.
`5.6
`(0.691, 1.417)
`4.6
`
`
`
`
`3.9, 6.2
`3.5, 8.0
`months (95% CI
`i Hazard Ratio = Smokers / Non-smokers;
`a Unadjusted, log-rank test.
`
`Reviewer 's comment:
`
`The non-smokers appear to benefit more from Tarceva compared to smokers.
`
`
`
`
`
`

`

`OSI EX. 2004 - 0005
`OSI EX. 2004 - 0005
`
`
`This is a representation of an electronic record that was signed electronically and
`this pageis the manifestation of the electronic signature.
`
`
`
`aaaaaASeaShrnSSSPSSOePP aharmhP-S- P-O- ia.
`
`Rajeshwari Sridhara
`11/1/04 10:43:09 AM
`BIOMETRICS
`
`
`
`

`

`
`
`OSI EX. 2004 - 0006
`OSI EX. 2004 - 0006
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation Research
`Office of Pharmacoepidemiology and Statistical Science
`Office of Biostatistics
`
`STATISTICAL REVIEW AND EVALUATION
`CLINICAL STUDIES
`
`NDA/Serial Number:
`
`21-743 /NO00
`
`Drug Name:
`
`Applicant:
`
`Indication(s):
`
`Date(s):
`
`Tarceva™ (erlotinib hydrochloride, OSI-774)
`
`OSI Pharmaceuticals
`
`Metastatic Non-small Cell Lung Cancer
`
`Submission Date: July 30, 2004
`
`PDUFADate: January 30, 2005
`
`Review Completion Date: October 1, 2004
`
`Review Priority:
`
`Priority
`
`Biometrics Division:
`
`Division of Biometrics I (HFD-710)
`
`Statistical Reviewers:
`
`Rajeshwari Sridhara, Ph.D.
`
`Concurring Reviewer:
`
`Kooros Mahjoob, Ph.D., Acting Director
`
`Yeh-Fong Chen, Ph.D.
`
`Medical Division:
`
`Clinical Team:
`
`Oncology Drug Products (HFD-150)
`
`Martin Cohen, M.D. & John Johnson, M.D.
`
`Project Manager:
`
`Mr. Paul Zimmerman
`
`Keywords:
`
`Superiority, log-rank test, Cox regression, QoL
`
`

`

`
`
`OSI EX. 2004 - 0007
`OSI EX. 2004 - 0007
`
`Table of Contents
`
`2
`
`3
`
`2.1
`2.1.1
`2.1.2
`2.2
`
`3.1
`3.1.1
`BALL
`3.1.1.2
`3.1.1.3
`3.1.1.4
`3.1.1.5
`3.1.1.6
`3.1.1.7.
`
`1 Executive Summary..........cscccsssssssssessscccscsesssssecessesssssssssssssssssesenscssssssenenssncsnes 3
`1.1
`Conclusions and Recommendations..........c.cssescessesersscssesccesees 3
`1.2
`Brief Overview of Clinical Studies.................sscsscssseesereeess 3
`1.3
`Statistical Issues and Findings..............csccensscsssescessscstsstesassseee 3
`Tntroduction..............c.ccscsssesssscoseseesssennscsnsecsersecessesssssceeterssseenssvens
`OVEIrVIEW «..........cssescresceerscnasencessonensonsnsenensensosensscaaeaascsseneseasaensseses
`Background«00.02... cececcececcesceneescesecseeeeceeteceeceececeenenscseeesesesensenseaes 5
`Statistical Issuesoo...scscsesessscesessssssseesessnsseeesvesseesesseseneseneesees 5
`Data Sources.......scccsscsssscssssssccsesssesssssssessecsscssssseacasssanssscseacsassces O
`Statistical Evaluation.........cccccccscsecesssecccsecccsscessessseccecsssceeseoees O
`Evaluation of Efficacy...........cscssscssccscsscsesssecsssececcsssesscsascceeascees 6
`Study BR.21 occ. sscsssssesserseessseversecsaceecsosseesacsserssenseasesseeseesatsnees 7
`Study Design... cceeeeeesccscesacscenecseeaesscsssssscasersssseesane D
`Study Objectives ...........ccesssecenseessesssseeessesseesseneceeseseseeseeeaneas 8
`Efficacy Endpoint...............:sccscesssccssesseeessesssccsseceseesssesacsceetansness 8
`Sample Size Considerations«0.0...seeeneseesenceeeseeoeeeeeteneatenees 9
`Interim Analysis...cccssescessssecessecsssseseseersesseeessnssssnesneassneess 9
`Efficacy Analysis Methods .00.......ccssccsscsssssscseessscersrssesssnreneneasess 9
`Sponsor’s Results and Statistical Reviewer’s Findings/
`Comment ..0......eecesseeeceesneesecseescenceeseccesaseseessnesesaeseesesseasersaeeass 11
`3.1.1.7.1 Baseline Characteristics........0...ccsccccsssssstessnessrnssssersnessnterees 11
`3.1.1.7.2 Primary Efficacy Analyses.00...........ccscccsessssssseseseesesseeesseneas 12
`3.1.1.7.3 Exploratory Survival Analyses ..2..0..00......:.csscsesesssseereseneenees 16
`3.1.1.7.4 Secondary Efficacy Analyses...........ccscsssscsessesssssenseeseseess 25
`3.1.1.7.4.1
`Progression-free Survival ...0.....0....ccccccsscsessecseneccecnenees 25
`3.1.1.7.4.2 Objective Response Rate............ccccscssesessssesseseseseseesseeees 26
`3.1.1.7.4.3 Quality of Life Endpoints...ee cceeeeeeeceeeees 28
`Study A248-1007..........usccscssssssecseseecsessssssnsesesesnsseereseeaceeacaesees 33
`Studies OSI2298g and BOL6411 ou...seeeceseeeeseeeeteeeesereenenes 34
`Evaluation of Safety.........cccccscsssssscsssscecsessseeaseessvsssensesenssensereas 35
`
`3.1.2
`3.1.3
`3.2
`
`4
`
`Findings inSpecial/SubgroupPopann35
`Gender, Race amd Age ..........-..-cssssosssssvensenssessessssesessssesatacsesass 35
`4.1
`Other Special/Subgroup Populations...sssecsessessetessessecsscesuseesssses 3O
`4.2
`Summary and Conclusions...........cc1.-csssssssssceceseseoneenensensensensens OO
`Statistical Issues and CollectiveEvidence...ssassacsuceesseseeccsesseuces 38
`5.1
`Conclusions and Recommendations..........ccssssscsssssssrsseseseeess 39
`5.2
`APPENDICES........oscssoscsecscecsescesescecensosessssevnasassassasacsassasscsasscsasaacussssussesscessseases 40
`Appendix 1: Measurement Schedule (Excerpt from Sponsor protocol) ... 40
`Appendix 2: Response Criteria (Excerpt from Sponsor’s Protocol)......... 41
`Appendix 3: QoL Variables (excerpt from Sponsor'sStatistical Analysis
`Appendix 4: QoL Questionnaire (Excerpt from sponsor”s'sprotocol)saseeees 44
`
`5
`
`PHAM)? ...scesscossssscsscsssssssssssrscscsscentorsersessens
`
`svssecsenssesssesserses 42
`
`

`

`
`
`OSI EX. 2004 - 0008
`OSI EX. 2004 - 0008
`
`Appendix 5: Evaluation of Baseline Prognostic Factors — Univariate
`ANALYSES.....cccsscsssssssesccessescseacssccssssvessssscossccsecssacssossnecsecssesecssese AD
`
`RS THI
`
`ts,
`
`

`

`
`
`OSI EX. 2004 - 0009
`OSI EX. 2004 - 0009
`
`1 Executive Summary
`
`1.1. Conclusions and Recommendations
`
`In this reviewer's opinion the study results from a single, randomized, multicenter,
`double-blinded, placebo-controlled phaseIII trial support the claim of efficacy
`based on overall survival of Tarceva™ (erlotinib hydrochloride) for patients with
`locally advanced or metastatic non-small cell lung cancer after failure of at least
`one prior chemotherapy regimen.
`
`1.2 Brief Overview of Clinical Studies
`
`This submission consists of results of one phaseIII, randomized, placebo-
`controlled, double-blinded clinicaltrial (registration trial BR.21, referred as
`BR.21 here after) comparing OSI-774 (Tarceva™,referred as erlotinib here after)
`versus placebo in patients with incurable stage IITB/TV non-smallcell lung cancer
`(NSCLC) who havefailed standard therapy for advanced or metastatic disease.
`The sponsorhas also provided supportive efficacy data from a phaseII, single
`arm study (A248-1007) of erlotinib following failure of platinum based
`combination chemotherapyin patients with advanced NSCLC. In addition the
`sponsorhas also submitted results of two phase ILL, randomized, double-blinded,
`multicenter trials (Study OSI2298¢g and Study BO16411) oferlotinib plus
`chemotherapy (carboplatin + paclitaxel, and cisplatin + gemcitabine, respectively)
`vs. chemotherapy alonein patients with advanced (stage IIIB/'V) NSCLC who
`had not received prior chemotherapy. The addition of erlotinib to chemotherapy
`in both the studies did not demonstrate additional benefit with respect to overall
`survival compared to chemotherapy alone.
`
`Study BR.21 was a phaseIII, comparative international study conducted in 731
`patients from 86 study centers in 17 countries. Patients > 18 years old with
`histologically or cytologically confirmed diagnosis of incurable stage ITIB/IV
`NSCLCwhohavereceived at least one but no more than twoprior regimens of
`which at least one had to be combination chemotherapy(if > 70 years old), who
`had ECOGperformancestatus of 0 to 3, had adequate renal and hepatic functions
`were randomized in 2:1 ratio to receive either erlotinib (150 mgtablets orally) or
`placebo. In this study, patients werestratified at randomization by center, number
`of prior regimens, prior platinum therapy, best response to prior therapy, and
`ECOGperformancestatus.
`
`1.3
`
`Statistical Issues and Findings
`
`This NDA submission is to support administration oferlotinib in patients with
`advanced or metastatic NSCLC who havefailed at least one prior chemotherapy.
`
`

`

`
`
`OSI EX. 2004 - 0010
`OSI EX. 2004 - 0010
`
`In this NDA submission, study BR.21 is the only randomized pivotal study
`conductedto establish efficacy. This study enrolled a total of 731 patients with
`488 patients who receivederlotinib and 243 patients who received placebo. The
`primary efficacy endpoint ofthis study was survival. The applicanthas submitted
`this application claiming efficacy based on overall survival. There was a
`statistically significant difference between the two treatment arms with respect to
`overall survival in the ITT population (log-rank test, P-value = 0.002,stratified
`log-rank test, P-value= < 0.0001).
`
`-
`
`Statistical Issues:
`
`1. The primary analysis of the primary endpoint overall survival was based
`on stratified tog-rank test including randomizationstratification factors
`and EGFRstatus. In 67% ofthe patients EGFR status was not evaluated.
`An adjusted analysis including these 67% patients with missing data on
`EGFRstatus is questionable.
`2. The results of exploratory analyses in the subgroups suggest a significant
`survival benefit due to erlotinib in the EGFR positive patients and suggest
`no survival benefit in the EGFR negative population.
`
`Findings:
`
`The protocol specified primary analysis was stratified log-rank test in the intent-
`to-treat (ITT) population to compare overall survival between the two treatment
`arms. This study demonstrates efficacy based on overall survivalas presented in
`the following Table A.
`
`Table A: Primary Efficacy of Overall Survival Analysis in the ITT
`Population
`
`ITT Population
`
`Placebo
`N=243
`
`
`
`Tarceva
`N=488
`
`Hazard Ratio
`(95% Cl)
`
`
`
`0.764
`(0.645, 0.905)
`
`# of Deaths
`6.7
`4.7
`Med. Survival in
`
`
`
`5.5, 7.8
`4.1, 6.3
`mouths (95%C
`Hazard Ratio = Tarceva / Placebo;*Unadjusted, log-rank test, adjusted (for
`randomization stratification factors) analysis p-value < 0.0001
`
`
`
`
`
`
`
`
`
`P-value
`
`0.0018
`
`
`
`
`
`

`

`OSI EX. 2004 - 0011
`OSI EX. 2004 - 0011
`
`2
`
`Introduction
`
`2.1 Overview
`
`Lung cancer is a commondisease in U.S. Currently the treatments approved for
`the first line therapy of non-smallcell lung cancer (NSCLC)Stage IIIB/IV
`patients are paclitaxel/cisplatin, gemcitabine/cisplatin, and vinorelbine + cisplatin.
`Approvedtreatments for the second line therapy ofNSCLCStageIIIB/IV patients
`are docetaxel (approval based on demonstration of survival benefit over best
`supportive care) and alimta (accelerated approval based on responserate). Iressa
`was granted accelerated approval for the third line setting of NSCLC Stage
`IIIB/TV patients based on observed responserate.
`
`
`
`2.1.1 Background
`
`Epidermal growth factor receptor (EGFR)andits ligands are overexpressed or
`involved in autocrine growth loops in a number oftumortypes, including
`NSCLC. EGFRis considered an important prognostic indicator in patients with
`epithelial malignancies. Increased EGFR expressionis correlated with aggressive
`morphology, poor outcome in NSCLC,and poor response to therapy. ‘Erlotinib
`acts through direct and reversible inhibition of the EGFR tyrosine kinase, andit
`inhibits the EGF-dependentproliferation ofcells at nanomolar concentrations and
`blocks cell cycle progression at the GI phase.
`
`In this application the sponsor has submitted results of 4 studies in NSCLC
`patients and 5 studies in other tumor types. Study BR.21 is submitted as the
`registration study.
`
`2.1.2 Statistical Issues
`
`1. The primary analysis of the primary endpointoverall survival was based
`on stratified log-rank test including randomization stratification factors
`and EGFRstatus. In 67% of the patients EGFR status was not evaluated.
`An adjusted analysis including these 67% patients with missing data on
`EGFRstatus is questionable.
`2. The results of exploratory analyses in the subgroups suggesta significant
`survival benefit due to erlotinib in the EGFR positive patients and suggest
`no survival benefit in the EGFR negative population.
`
`
`
`

`

`
`
`OSI EX. 2004 - 0012
`OSI EX. 2004 - 0012
`
`2.2 Data Sources
`
`Data and reports used for review are from the electronic submission received on
`$/12/04, 6/22/04 and 7/29/64 The network paths are:
`\\Cdsesub 1\N21743\N_000\2004-05-12\clinstat\lung,
`\\Cdsesub1\N21743\N_000\2004-06-22\crt\datasets\BR21 ,
`\Cdsesub1\N21743\N_000\2004-06-22\clinstat\lung\BR21 ,
`\Cdsesub1\N21743\N_000\2004-07-29\clinstat\lung\ise , and
`\Cdsesub1\N21743\N_000\2004-09-17 .
`
`3. Statistical Evaluation
`
`3.1 Evaluation of Efficacy
`
`The sponsor has submitted efficacy results from the following 4 studies conducted
`in NSCLCpatients:
`
`(a) The registration Study BR.21 was a multicenter, international, double-blinded,
`randomized, phaseIII trial of erlotinib 150 mg tablet/day versus placebo
`tablet/day (matched to erlotinib in color, shape, size and packaging) for locally
`advanced or metastatic NSLC patients who had failed at least one but no more
`than two prior chemotherapy regimen. Thetrial treatment was continued until
`disease progression or unacceptabletoxicity. First patient was entered in this
`Study BR.21 on November 1, 2001 and thelast patient was entered on January
`31, 2003. The data cut-off date for this application was January 30, 2004. A
`detailed statistical evaluation of efficacy evidence of this study is presented in
`section 3.1.1 of this review.
`
`(b) Study A248-1007 was a multicenter, open-label, phase I single arm trial of
`erlotinib 150 mg tablet/day following failure of platinum based combination
`chemotherapy in EGFR-positive patients with advanced NSCLC.Thetrial
`treatment was taken until disease progression, or unmanageable toxicity. First
`patient was entered in this Study A248-1007 on January 25, 2000 andthe last
`patient was entered on February 14, 2001. The data cut-off date for this
`application was January 27, 2003. Resuits from Study A248-1007 were submitted
`as supportive evidence to Study BR.21. A summary ofthe efficacy findings of
`this study is presented in section 3.1.2 ofthis review.
`
`(c) Study OSI2298g was a randomized, double-blinded, multicenter, Phase II
`comparative trial of erlotinib in combination with chemotherapy (paclitaxel and
`carboplatin) versus chemotherapyalonein patients with advanced (stage IIIB or
`IV) NSCLC whohavenot received prior chemotherapy. This study was initiated
`
`
`
`
`
`

`

`
`
`OSI EX. 2004 - 0013
`OSI EX. 2004 - 0013
`
`on July 18, 2001 and completed on July 11, 2003. A summary ofthe efficacy
`findings of this study is presented in section 3.1.3 of this review.
`
`(d) Study BO16411 was a randomized, double-blinded, placebo-controlled,
`multicenter, Phase HII comparative trial of erlotinib in combination with
`chemotherapy (gemcitabline and cisplatin) versus chemotherapy alonein patients
`with advanced (stage IIIB or IV) NSCLC whohavenotreceived prior
`chemotherapy. A summary of the efficacy findings of this study is presented in
`section 3.1.3 ofthis review.
`
`3.1.1 Study BR.21
`
`3.1.1.1 Study Design
`
`Study BR.21 was a phaseIII, randomized, placebo-controlled, double-blinded
`clinical trial comparing erlotinib to placebo. Patients > 18 years old with
`histologically or cytologically confirmed diagnosis of incurable stage II[B/IV
`NSCLC whohavereceived at least one but no more than two prior regimens of
`whichat least one had to be combination chemotherapy (if > 70 years old), who
`had ECOGperformancestatus of 0 to 3, had adequate renal and hepatic functions
`were randomized in 2:1 ratio to receive either erlotinib (150 mg/day tablets orally)
`or placebo (“150 mg”/day tablets matchedto erlotinib in color, shape, size and
`packaging). In this study, patients were stratified at randomization by center,
`number of prior regimens,prior platinum therapy, best response to prior therapy,
`and ECOG performancestatus. Patients were treated until documented
`progressive disease or until developmentofintolerable toxicity. Dose escalation
`was not pennitted. The prescribed dose was self-administered, taken in the
`morning with up to 200 mL of waterat least 1 hour before or 2 hours after
`ingesting any food or other medications.
`
`Efficacy was evaluated by periodic assessments (Appendix 1) of survival and
`QoL scores. Tumor measurements were evaluated every 8 weeks. Safety was
`assessed every 4 weeks.
`
`49
`oo, . .
`-
`td formerly C__
`generated randomization codes and managed the C
`- interactive voice
`response system ([VRS). The IVRS minimized potential imbalances between
`treatment arms, based on the abovestated 5 stratification factors using a dynamic
`minimization technique. Therapy began within 2 working daysafter
`randomization and patients were considered on treatment until study drug was
`discontinued.
`
`

`

`
`
`OSI EX. 2004 - 0014
`OSI EX. 2004 - 0014
`
`3.1.1.2 Study Objectives
`
`The primary objective of this study was to compare overall survival between the
`two treatment arms (erlotinib vs. placebo).
`
`The secondary objectives included comparison of (1) progression-free survival
`(PFS), (2) response rates (RR), (3) response duration, (4) nature, severity, and
`frequency of toxicities, and (5) quality of life (QoL) as measured by the European
`Organization for the Research and Treatment of Cancer (EORTC)quality oflife
`questionnaires QLQ-C30 and the lung cancer module QLQ-LC13. The objectives
`also includedto correlate the expression of tissue EGFRlevels (at diagnosis) with
`outcomes and response to treatment, and to measure and correlate trough levels of
`erlotinib with clinical responses and /or adverse events.
`
`3.1.1.3 Efficacy Endpoints
`
`Primary Efficacy Endpointof this study was survival (OS) defined as the time
`from the date of randomization to the date of death from any cause. Survival time
`was censored at the date of last post-therapy follow-up visit for patients who were
`still alive.
`
`Secondary Efficacy Endpoints included:
`(1) PFS defined as the length of time from randomizationto the first observation
`of disease progression or death due to any cause.
`(2) Objective response, determined using RECIST criteria (Appendix 2).
`(3) Duration of response was measured from the time measurementcriteria for
`CR/PR werefirst met until the first date that recurrent or progressive disease or
`death was cbjectively documented.
`(4) QoL, assessed by the EORTC QLQ-30 and QLQ-LC13, with the emphasis on
`the three pre-specified symptoms (cough, dyspnea, and pain) (Appendix 3).
`
`Reviewer's Commenst:
`
`1. All patients who had measurable lesions and whohad atleast one
`objective tumor assessmentafter baseline were considered as evaluable for
`response.
`2. All patients who had completed quality of life assessments were evaluable
`for QoL.
`3. The protocol does not specifically emphasize on the three QoL symptoms,
`cough, dyspnea and pain. These were added as pre-specified symptoms in
`the statistical analysis plan and study report.
`
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`3.1.1.4 Sample Size Considerations
`
`The study was planned to enroll 700 patients. With this sample size, the study
`was powered to detect a 33% increase in overall survival time (median survival of
`4 months to 5.3 months, hazard ratio (HR)of 1.33) in the erlotinib arm compared
`to placebo arm with 90% power and maintaining a family-wise two-sided type I
`error rate of 0.05. The final analysis was planned to be conducted when 582
`deaths were observed.
`
`Reviewer’s Comments:
`
`1.
`
`In the original protocol (dated September 10, 2001) the sample size was
`determined to be 330 patients with the planned final survival analysis
`when 256 deaths occurred. This calculation was based on detecting a 50%
`improvementin survival for erlotinib (6 months vs. 4 months, HR = 1.5)
`with 90% powerusing two-sided 5% level of significance. The sample
`size was amended (amendmentdated August 29, 2002) to be 700 patients
`in order to detect a 33% improvement instead of 50% improvement. It
`was stated that because of the lack of demonstrable benefit in adding
`Iressa to standard chemotherapy for NSCLCin thefirst line setting as
`reported by AstraZenecain their press release dated August 19, 2002, and
`the rapid accrual to study BR.21, that it was decided to increase the
`sample size to be able to detect a smaller but clinically relevant
`improvementin survival.
`2. The actual number ofpatients entered on this study was 731 patients.
`
`3.1.1.5 Interim Analysis
`
`Nointerim analysis was plannedforthis study.
`
`3.1.1.6 Efficacy Analysis Methods
`
`The primary efficacy analysis was to compare overall survival time using log-
`rank test stratified by all stratification factors except center plus patient’s EGFR
`status (positive/mutated vs. unknown vs. negative) at baselinein all the
`randomized patients (ITT population). Kaplan-Meier curves were to be used to
`display the survival curves and 95% confidence intervals for the median survival
`computed using the method of Brookmeyer and Crowley. In addition, the effect
`of study center and other potential prognostic factors on overall survival was
`planned to be assessed using Cox regression. Additional supporting analysis was
`to include Kaplan-Meierestimation.
`
`Progression-free survival (PFS) was specified as one of the secondary endpoints.
`PFS was defined as the time from randomization to the first observation of
`
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`OSI EX. 2004 - 0016
`OSI EX. 2004 - 0016
`
`disease progression or death due to any cause. A patient who stopped treatment
`with study drug and went on to receive alternative therapy for NSCLC,priorto
`documentation of disease progression, was planned io be censored on the date
`alternative therapy began. Same methods as used in overall survival analysis
`were to be employed to analyze PFS data.
`
`The secondary endpoint of response rate was planned to be estimated as the
`proportion of patients evaluable for response who metthe criteria of complete or
`partial response. A Cochran-Mantel-Haenzel test was to be used to compare the
`tumor response rate between the two treatment arms adjustingall stratification
`factors, except center plus patient’s EGFR status. Duration of response was
`planned to be analyzed using similar methods as described for overall survival.
`
`The EORTC QLQC30 (Appendix 4) that was used in this study is a self-
`administered cancer specific questionnaire with multi-dimensional scales. It
`consists of both multi-item scales and single item measures, including five
`functioning domains, a global quality of life domain, three symptom domains and
`six single items. For each domain orsingle item measure a linear transformation
`was to be applied to standardize the raw score to range between 0 and 100. The
`QLQ-LC13 (Appendix 5) ung cancer module which wasaiso used in this study
`includes questions assessing lung cancer-associated symptoms (cough,
`haemoptysis, dyspnea, andsite-specific pain), treatment-related side effects (sore
`mouth, dysphagia, peripheral neuropathy and alopecia) and pain medication. The
`protocol specified that the questionnaires would be scored as described in QLQ-
`C30 manual, and analyzed accordingly. The protocol specified that the method of
`analysis of variance for repeated measures was planned to be used for domains
`represented by aggregate scores. Questionnaires for patients had to be completed
`at baseline and every 4 weeks while on study drug. A final questionnaire had to be
`completed within 2 weeks of progressive disease, or it would be considered
`completed at the 4-weekvisit after the end of treatmentif it had not already been
`completed within 2 weeks of progressive disease.
`
`In thestatistical analysis plan it was specified that the primary endpoints in the
`quality oflife analysis were defined as the time from randomization to
`deterioration in the following three QoL symptoms: cough (Question 1 in QLQ-
`LC13), dyspnea (Question 8 in QLQ-C30) and pain (Questions | and 19 in QLQ-
`C30). Patients were considered as deteriorated for a given symptom iftheir
`change of score from the baseline on the domain/single item defining this
`symptom was 10 points or higherat any time-point after the baseline assessment.
`It was stated in the statistical analysis plan that the value of 10 points on a 100
`scale was chosenas previous studies had indicated that a 10% change of highest
`possible score are perceivedas clinically significant.
`
`10
`
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`Thestatistical analysis plan stated that for each symptom, ali patients who had a
`baseline andat least one ofthe follow-up QoL assessments for the symptom
`would be included in the time to deterioration analysis. Patients would be
`censored at the time of the last QoL questionnaire completion if they had not
`deteriorated before that. Unstratified log-rank test would be used as the primary
`method to compare the time to deterioration in each symptom between the two
`treatment arms. The Hochberg procedure was planned to be used to adjust the p-
`values of the log-rank tests for these three comparisons.
`
`Reviewer's Comment:
`
`The primary endpoints and the method of QoL analysis was specified differently
`in the statistical analysis plan which wasfinalized on June 11, 2003, afterall
`patients had been entered on the study. Giventhat this was a secondary endpoint
`and the analysis plan was finalized after the completion of accrualto the study
`(last patient entered on January 31, 2003) analysis of QoL data can only be
`considered as exploratory.
`
`3.1.1.7 Sponsor’s Results and Statistical Reviewer’s Findings/ Comments
`
`In the BR.21 study, a total 731 patients with advanced or metastatic NSCLC were
`entered into the study across 86 study sites, 27 in Canada, 1 in US and 58
`internationally (rest of the world). The overall survival efficacy analysis
`submitted in this NDA was based on 488patients in erlotinib treatment arm and
`243 patients in placebo arm. A total of 7 patients were declared as lost to follow-
`up (4 patients in the erlotinib arm and3 patients in the placebo arm). The sponsor
`has reported some discrepancies between the data provided bythe center to obtain
`randomization and the actual baseline data. Of note, response to prior
`chemotherapy at baseline was better than was reported at randomization for 26
`patients (5%) in the erlotinib arm andfor 9 patients (4%)in the placebo arm, and
`it was worse for 57 patients (12%) and 22 patients (9%) in the erlotinib and
`placebo armsrespectively.
`
`3.1.1.7.1 Baseline Characteristics
`
`The baseline Characteristics of the overail population are presented in Table 1.
`
`Reviewer's Comment:
`
`In the overall patient population the baseline characteristics appear to be balanced
`between the two treatment arms.
`
`
`
`ll
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`Table i: Demographics and Baseline Characteristics of Patients
`
`
`
`Placebo(N= 243
`173 (35.5%
`83 (34.2%
`
`
` |MaleCTC815 (64.5%
`160 (65.8%
`12 (4.9%
`
`Race: Black
`
`18 (3.7%0
`
`|61-69yss—_—|166 (34.0% 69 (28.4%0
`
`
`97 (19.9%
`43 (17.7%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`78 32.1%
`
`162 (33.2%
`
`80 (32.9%
`
`312 (63.9%
`Baseline PS,prior response, prior number of therapy,prior platinum treatment
`were stratification factors at baseline (characteristics in blue; using data variables
`alaecog,alabrsp, alareg and alaplat in patient.xptdata set).
`
`3.1.1.7.2 Primary Efficacy Analyses
`
`Primary efficacy analysis was overall survival analysis using stratified log-rank
`test. At the time of this analysis presented in this NDAa total of 587 deaths were
`observed (final analysis planned with 582 deaths). Theresults of the survival
`analysis based on ITT population using unadjusted log-rank test are presented in
`
`12
`
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`

`
`
`OSI EX. 2004 - 0019
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`
`Table 2 (same as reported by the sponsor). The results of the stratified log-rank
`test, primary analysis as specified in the protocol, were similar to the unadjusted
`analysis (adjusted p-value < 0.0001). The results of adjusted analysis using Cox
`regression as specified in the protocol are presented in Table 3. The Kaplan-
`Meier curves ofthe overali survival in the ITT population are illustrated in Figure
`1.
`
`Table 2: Primary Efficacy of Overall Survival Analysis in the ITT
`Population
`
`ITT Population
`
`Placebo
`N=243
`
`Tarceva
`N=488
`
`Hazard Ratio
`
`P-value
`
`(95% CIT) # of Deaths
`
`6.7
`4.7
`5.5, 7.8
`4.1,6.3
`months (95% C
`“Unadjusted, log-rank test, adjusted (for
`Hazard Ratio = Tarceva / Placebo;
`randomization stratification factors) analysis p-value < 0.0001
`
`0.764
`(0.645, 0.905)
`
`0.0018
`
`Figure 1: Kaplan-Meier Survival Curves in the ITT Population
`
`Proportion
`
`Surviving
`
`—
`go
`ioeeet
`“tee -
`(0 = placebo and 1 = erlotinib)
`
`13
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`

`OSI EX. 2004 - 0020 OSI EX. 2004 - 0020
`
`
`
`Table 3: Cox Regression Analysis in the ITT Population Adjusting for
`Randomized Stratification Factors and Baseline EGFR Status (Protocol
`Specified Analysis)
`
`0.915
`1.356
`
`0.752, 1.113
`1.104, 1.666
`
`0.3725
`0.0037
`
`
`
`
`
`HazardRatio|_95% C.l.
`
`Treatment (Tarceva vs Placebo
`,
`0.726
`0.612, 0.861
`0.0002
`