asco 2010 confidential do not distribute randomized, open-label, phase 3 study of panitumumab (pmab)...

ASCO 2010ASCO 2010CONFIDENTIALCONFIDENTIAL

DO NOT DISTRIBUTEDO NOT DISTRIBUTE

Randomized, open-label, phase 3 study of panitumumab Randomized, open-label, phase 3 study of panitumumab (pmab) with FOLFIRI vs FOLFIRI alone as 2nd‑line treatment (pmab) with FOLFIRI vs FOLFIRI alone as 2nd‑line treatment

(tx) in patients (pts) with metastatic colorectal cancer (tx) in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy by skin toxicity (ST)(mCRC): Efficacy by skin toxicity (ST)

Timothy Price,Timothy Price,11 Alberto Sobrero, Alberto Sobrero,22 Gregory Wilson, Gregory Wilson,33 Eric Van Eric Van Cutsem,Cutsem,44 Birute Aleknaviciene, Birute Aleknaviciene,55 Alberto Zaniboni, Alberto Zaniboni,66 Jörg Thomas Jörg Thomas

Hartmann,Hartmann,77 Ying Tian, Ying Tian,88 Jennifer Gansert, Jennifer Gansert,88 Marc Peeters Marc Peeters99

11Queen Elizabeth Hospital, Woodville, Australia; Queen Elizabeth Hospital, Woodville, Australia; 22Ospedale San Martino, Genova, Italy; Ospedale San Martino, Genova, Italy; 33Christie Hospital, Manchester, United Kingdom; Christie Hospital, Manchester, United Kingdom; 44University Hospital Gasthuisberg, Leuven, University Hospital Gasthuisberg, Leuven,

Belgium; Belgium; 55Vilniaus Universiteto Onkologijos Institutas, Vilnius, Lithuania; Vilniaus Universiteto Onkologijos Institutas, Vilnius, Lithuania; 66Casa di Cura Casa di Cura Poliambulanza, Brescia, Italy; Poliambulanza, Brescia, Italy; 77Universitätsklinikum Kiel, Kiel, Germany; Universitätsklinikum Kiel, Kiel, Germany; 88Amgen Inc., Amgen Inc.,

Thousand Oaks, California, USA; Thousand Oaks, California, USA; 99University Hospital Ghent, Ghent, BelgiumUniversity Hospital Ghent, Ghent, Belgium



IntroductionIntroduction• Panitumumab, a fully human monoclonal antibody targeting the EGFR, is approved for use Panitumumab, a fully human monoclonal antibody targeting the EGFR, is approved for use

as monotherapy for chemorefractory as monotherapy for chemorefractory mCRCmCRC1,21,2 in patients with wild-type (WT) in patients with wild-type (WT) KRASKRAS tumors tumors22

• Study 20050181 is an open-label, randomized, global, phase 3 trial investigating the Study 20050181 is an open-label, randomized, global, phase 3 trial investigating the addition of panitumumab to FOLFIRI chemotherapy as 2addition of panitumumab to FOLFIRI chemotherapy as 2ndnd‑line treatment (tx) for patients ‑line treatment (tx) for patients with mCRC by with mCRC by KRASKRAS mutational status mutational status– Originally designed to compare the tx effect in the all randomized population, the study Originally designed to compare the tx effect in the all randomized population, the study

was amended to focus on hypothesis testing in the WT was amended to focus on hypothesis testing in the WT KRASKRAS subset subset

• Primary findings were previously presentedPrimary findings were previously presented33

• Skin-related toxicities are the most common adverse events associated with EGFR Skin-related toxicities are the most common adverse events associated with EGFR inhibitorsinhibitors

• The occurrence of grade 2 or higher skin toxicity (ST) has been associated with efficacy in The occurrence of grade 2 or higher skin toxicity (ST) has been associated with efficacy in the monotherapy settingthe monotherapy setting44

• Here we present the results from the primary analysis and efficacy and patient-reported Here we present the results from the primary analysis and efficacy and patient-reported outcome (PRO) results by ST severityoutcome (PRO) results by ST severity



Study Schema and StratificationStudy Schema and Stratification

Tx Arm 1:Tx Arm 1:

Panitumumab Panitumumab 6.0 mg/kg Q2W + 6.0 mg/kg Q2W +

FOLFIRI Q2WFOLFIRI Q2W

EENNRROOLLLLMMEENNTT

EENND D OOF F TTRREEAATTMMEENNTT

LLOONNGGTTEERRMMFFOOLLLLOOWWUUPP

PRO assessments PRO assessments every 4 weeksevery 4 weeks

Disease Disease assessments every assessments every

8 weeks8 weeks

Tx Arm 2:Tx Arm 2:

FOLFIRI Q2WFOLFIRI Q2WStudy Study 20050181 20050181 CountriesCountries

United United StatesStates

RussiaRussiaJapanJapan

FranceFranceBelgiumBelgiumThe NetherlandsThe NetherlandsGermanyGermanySwitzerlandSwitzerlandAustriaAustriaItalyItalyCzech RepublicCzech RepublicSlovakiaSlovakiaPolandPolandLithuaniaLithuania

AustraliaAustralia

Enrollment Target:Enrollment Target:1100 patients1100 patients

Randomization stratification:Randomization stratification:• ECOG score: 0-1 vs. 2ECOG score: 0-1 vs. 2• Prior oxaliplatin exposure for mCRCPrior oxaliplatin exposure for mCRC• Prior bevacizumab exposure for mCRCPrior bevacizumab exposure for mCRC

SSCCRREEEENNIINNGG

UkraineUkraineRomaniaRomaniaBulgariaBulgariaUnited KingdomUnited KingdomIrelandIrelandPortugalPortugalSpainSpainNorwayNorwaySwedenSwedenFinlandFinland



Objectives and Endpoints for Primary AnalysisObjectives and Endpoints for Primary Analysis• Primary objectives:Primary objectives:

– To assess the effect of panitumumab on progression-free To assess the effect of panitumumab on progression-free survival (PFS) and overall survival (OS) by survival (PFS) and overall survival (OS) by KRASKRAS mutational mutational status*status*

• Co-Primary endpoints (independently tested):Co-Primary endpoints (independently tested):– PFS (by blinded central radiology review)PFS (by blinded central radiology review)– OSOS

• Other key endpoints:Other key endpoints:– Objective response rate (ORR)Objective response rate (ORR)– Time to progression (TTP)Time to progression (TTP)– Duration of response (DOR)Duration of response (DOR)– Safety Safety – PROPRO

**KRASKRAS status was determined by blinded, independent central testing status was determined by blinded, independent central testing



• To evaluate efficacy by worst grade ST (0-1 vs 2-4) according to tumor To evaluate efficacy by worst grade ST (0-1 vs 2-4) according to tumor KRASKRAS status in panitumumab-treated patients status in panitumumab-treated patients

• PFSPFS• OSOS• ORRORR

– To minimize lead-time bias and under-reporting of ST because of early To minimize lead-time bias and under-reporting of ST because of early tx discontinuation, a landmark approach was used that limits the tx discontinuation, a landmark approach was used that limits the analysis to patients with a PFS time of at least 28 days (when >50% of analysis to patients with a PFS time of at least 28 days (when >50% of patients had worst grade ST severity)patients had worst grade ST severity)

• To evaluate PRO by worst grade ST (0-1 vs 2-4) in patients with WT or To evaluate PRO by worst grade ST (0-1 vs 2-4) in patients with WT or mutant (MT) mutant (MT) KRASKRAS tumors tumors – EQ-5D health state index (HSI)EQ-5D health state index (HSI)– EQ-5D overall health rating (OHR)EQ-5D overall health rating (OHR)

• Analyses by ST were ad hoc and not pre-specifiedAnalyses by ST were ad hoc and not pre-specified

Objectives for Efficacy and PRO Objectives for Efficacy and PRO Analyses by STAnalyses by ST



Key Eligibility CriteriaKey Eligibility Criteria• Metastatic adenocarcinoma of the colon or rectumMetastatic adenocarcinoma of the colon or rectum• Documented disease progression ≤ 6 months after only 1 Documented disease progression ≤ 6 months after only 1

prior fluoropyrimidine-based therapy for mCRCprior fluoropyrimidine-based therapy for mCRC• No prior EGFR inhibitor therapyNo prior EGFR inhibitor therapy• No prior irinotecan No prior irinotecan • Measurable diseaseMeasurable disease• Paraffin-embedded tumor tissue available for central Paraffin-embedded tumor tissue available for central

biomarker testingbiomarker testing• ECOG performance status of 0 – 2 ECOG performance status of 0 – 2 • Adequate hematologic, renal, and hepatic functionAdequate hematologic, renal, and hepatic function• Signed informed consentSigned informed consent



Statistical Considerations for Efficacy and Statistical Considerations for Efficacy and PRO Analyses by STPRO Analyses by ST

• ST was defined as any tx emergent adverse event indicative of a skin disorder and represents a ST was defined as any tx emergent adverse event indicative of a skin disorder and represents a composite category of adverse event terms including but not limited to rash, dermatitis composite category of adverse event terms including but not limited to rash, dermatitis acneiform, pruritus, dry skin, skin fissures, and erythemaacneiform, pruritus, dry skin, skin fissures, and erythema

• Retrospective ad-hoc analyses were performed to determine the effect of ST on efficacy and Retrospective ad-hoc analyses were performed to determine the effect of ST on efficacy and quality-of-life endpointsquality-of-life endpoints

– PFS (central review) and OSPFS (central review) and OS• A stratified Cox proportional hazards model was used to examine the relationship A stratified Cox proportional hazards model was used to examine the relationship

between worst grade ST severity (grade 2 - 4 : grade 0 - 1) and time to eventbetween worst grade ST severity (grade 2 - 4 : grade 0 - 1) and time to event– ORR (central review)ORR (central review)

• The ORR by worst grade ST and the common odds ratio for ORR between worst grade The ORR by worst grade ST and the common odds ratio for ORR between worst grade ST (grade 2 - 4 : grade 0 - 1) stratified by randomization factors was providedST (grade 2 - 4 : grade 0 - 1) stratified by randomization factors was provided

– PROPRO• The primary analyses of the PRO endpoints were performed with the PRO data The primary analyses of the PRO endpoints were performed with the PRO data

collected every 4 weeks from baseline to the discontinuation of second-line txcollected every 4 weeks from baseline to the discontinuation of second-line tx• A linear mixed model was applied to analyze the changes from baseline PRO score A linear mixed model was applied to analyze the changes from baseline PRO score

with unstructured covariance and fixed covariates of worst skin toxicity, baseline with unstructured covariance and fixed covariates of worst skin toxicity, baseline PRO, study stratification variables (ECOG and prior oxaliplatin or prior bevacizumab) PRO, study stratification variables (ECOG and prior oxaliplatin or prior bevacizumab) and a random patient effectand a random patient effect

• In all PRO assessments, a higher score indicates a better health statusIn all PRO assessments, a higher score indicates a better health status



Results: Results: KRASKRAS Ascertainment AscertainmentPanitumumabPanitumumab

+ FOLFIRI+ FOLFIRI FOLFIRIFOLFIRI TotalTotal

Patients randomized - n Patients randomized - n 591591 595595 11861186

Patients included in Patients included in KRASKRAS analysis - n (%) analysis - n (%) 541 (92)541 (92) 542 (91)542 (91) 1083 (91)1083 (91)

WT WT KRASKRAS, %, % 5656 5454 5555

MT MT KRASKRAS, %, % 4444 4646 4545

KRASKRAS tumor status was determined using the DxS kit (Manchester, UK) that tumor status was determined using the DxS kit (Manchester, UK) that detects the 7 most common detects the 7 most common KRASKRAS mutations in codons 12 and 13 mutations in codons 12 and 13



Demographics and Disease Characteristics for Demographics and Disease Characteristics for Primary AnalysisPrimary Analysis

WT WT KRASKRASaa (n = 597) (n = 597) MT MT KRASKRASaa (n = 486) (n = 486)

Panitumumab Panitumumab + FOLFIRI+ FOLFIRI(n = 303)(n = 303)

FOLFIRIFOLFIRI(n = 294)(n = 294)



Sex – men - n (%)Sex – men - n (%) 188 (62)188 (62) 191 (65)191 (65) 133 (56)133 (56) 148 (60)148 (60)Age – years, median (min, max)Age – years, median (min, max) 60 (28, 84)60 (28, 84) 61 (29, 86)61 (29, 86) 61 (29, 83)61 (29, 83) 64 (29, 86)64 (29, 86)Race, white – n (%)Race, white – n (%) 294 (97)294 (97) 278 (95)278 (95) 226 (95)226 (95) 238 (96)238 (96)ECOG performance status – n (%)ECOG performance status – n (%)

0-10-1 288 (95)288 (95) 273 (93)273 (93) 224 (94)224 (94) 233 (94)233 (94)22 15 (5)15 (5) 21 (7)21 (7)bb 14 (6)14 (6) 15 (6)15 (6)

Primary tumor type – n (%)Primary tumor type – n (%)

Colon cancerColon cancer 187 (62)187 (62) 189 (64)189 (64) 156 (66)156 (66) 164 (66)164 (66)Rectal cancerRectal cancer 116 (38)116 (38) 105 (36)105 (36) 82 (34)82 (34) 84 (34)84 (34)

Sites of metastatic disease:Sites of metastatic disease:

Liver onlyLiver only 51 (12)51 (12) 59 (20)59 (20) 37 (16)37 (16) 35 (14)35 (14)Liver + otherLiver + other 220 (73)220 (73) 189 (64)189 (64) 166 (70)166 (70) 172 (69)172 (69)Other onlyOther only 47 (16)47 (16) 44 (15)44 (15) 34 (14)34 (14) 39 (16)39 (16)Missing or unknownMissing or unknown 0 (0)0 (0) 2 (<1)2 (<1) 1 (<1)1 (<1) 2 (<1)2 (<1)

Prior oxaliplatin therapyPrior oxaliplatin therapy 204 (67)204 (67) 191 (65)191 (65) 164 (69)164 (69) 169 (68)169 (68)Prior bevacizumab therapyPrior bevacizumab therapy 55 (18)55 (18) 60 (20)60 (20) 45 (19)45 (19) 43 (17)43 (17)aaDemographics and disease characteristics were similarly distributed between treatment arms in Demographics and disease characteristics were similarly distributed between treatment arms in the WT/MT KRAS Analysis Sets the WT/MT KRAS Analysis Sets

bbIncluded 1 patient with ECOG 3Included 1 patient with ECOG 3



201816141210864200.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gres

sion

-free

Pro

babl

ility

Months

PFS by PFS by KRASKRAS Mutation Status Mutation Status(Central Review)(Central Review)

HR = 0.73 (95% CI: 0.59, 0.90)HR = 0.73 (95% CI: 0.59, 0.90)Log-rank p-value = 0.004Log-rank p-value = 0.004

EventsEventsn (%) n (%)

Median Median (95% CI) (95% CI) monthsmonths

Panitumumab + Panitumumab + FOLFIRIFOLFIRI

178/ 303 (59)178/ 303 (59) 5.9 (5.5 - 6.7)5.9 (5.5 - 6.7)

FOLFIRIFOLFIRI 203/ 294 (69)203/ 294 (69) 3.9 (3.7 - 5.3)3.9 (3.7 - 5.3)

WT WT KRASKRAS MT MT KRASKRAS

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months0 2 4 6 8 10 12 14 16 18 20

Pro

gres

sion

-free

Pro

babl

ility





162/ 238 (68) 162/ 238 (68) 5.0 (3.8 - 5.6) 5.0 (3.8 - 5.6)

FOLFIRIFOLFIRI 161/ 248 (65) 161/ 248 (65) 4.9 (3.6 - 5.6) 4.9 (3.6 - 5.6)



0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Sur

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bilit

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1.0

20181614121086420

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0.8

0.9

Months323028262422 34

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0.0

OS by OS by KRASKRAS Mutation Status Mutation Status







200/ 303 (66) 200/ 303 (66) 14.5 (13.0 - 16.0)14.5 (13.0 - 16.0)

FOLFIRIFOLFIRI 207/ 294 (70) 207/ 294 (70) 12.5 (11.2 - 14.2) 12.5 (11.2 - 14.2)




181/ 238 (76) 181/ 238 (76) 11.8 (10.4 - 13.3)11.8 (10.4 - 13.3)

FOLFIRIFOLFIRI 193/ 248 (78) 193/ 248 (78) 11.1 (10.3 - 12.4)11.1 (10.3 - 12.4)



Objective Response by Objective Response by KRASKRAS Status Status (Central Review)(Central Review)

WT WT KRASKRAS MT MT KRASKRASPanitumumab Panitumumab

+ FOLFIRI+ FOLFIRI(n = 297)(n = 297)




Objective response rate, %Objective response rate, %(95% CI)(95% CI)1,21,2

3535(30 – 41)(30 – 41)

1010(7 – 14)(7 – 14)

1313(9 – 18)(9 – 18)

1414(10 – 19)(10 – 19)

Complete responseComplete response 00 00 00 00

Partial responsePartial response 3535 1010 1313 1414

Stable diseaseStable disease 3939 5555 5555 4949

Progressive diseaseProgressive disease 1818 2626 2222 272711For WT For WT KRASKRAS subset: p < 0.001(descriptive); exact test of odds ratio stratified by randomization subset: p < 0.001(descriptive); exact test of odds ratio stratified by randomization factorsfactors

22For MT For MT KRASKRAS subset: p = 1.0 (descriptive); exact test of odds ratio stratified by randomization subset: p = 1.0 (descriptive); exact test of odds ratio stratified by randomization factorsfactorsAll responses were confirmed no earlier than 28 days after the response criteria were first metAll responses were confirmed no earlier than 28 days after the response criteria were first met



Grade 3/4 Adverse Events of InterestGrade 3/4 Adverse Events of InterestPrimary AnalysisPrimary Analysis

1MedDRA = Medical Dictionary for Regulatory Activities2There was one grade 5 adverse event of diarrhea in the WT KRAS panitumumab + FOLFIRI group3There were 2 grade 5 adverse events of pulmonary embolism in the MT KRAS FOLFIRI group4Included cases in which primary cause of death was reported to be disease progression; only 1 panitumumab-related fatal adverse event was reported: ileus

WT WT KRASKRAS(n = 596)(n = 596)

MT MT KRASKRAS(n = 483)(n = 483)

Adverse Event by MedDRAAdverse Event by MedDRA11– %– %Panitumumab Panitumumab

+ FOLFIRI+ FOLFIRI(n = 302)(n = 302) FOLFIRI FOLFIRI

(n = 294)(n = 294)

Panitumumab Panitumumab + FOLFIRI+ FOLFIRI(n = 237)(n = 237) FOLFIRIFOLFIRI

(n = 246)(n = 246)Patients with any event Patients with any event 7373 5252 6464 5050Skin toxicitySkin toxicity 3737 22 3232 11NeutropeniaNeutropenia 2020 2323 1414 1717DiarrheaDiarrhea22 1414 99 1414 1111StomatitisStomatitis 88 33 99 44Pulmonary embolismPulmonary embolism33 55 22 33 22DehydrationDehydration 33 22 33 22HypomagnesemiaHypomagnesemia 33 <1<1 55 00ParonychiaParonychia 33 <1<1 33 00Febrile neutropeniaFebrile neutropenia 22 33 11 33Infusion-related reaction Infusion-related reaction (panitumumab)(panitumumab) <1<1 -- 00 --

Fatal adverse eventsFatal adverse events44 - % - % 4 4 66 77 55



Distribution of Worst Grade ST Over the Distribution of Worst Grade ST Over the Treatment PeriodTreatment Period

WT KRASWT KRAS MT KRASMT KRASWorst Worst

Grade 0-1Grade 0-1aaWorst Worst

Grade 2-4Grade 2-4Worst Worst

Grade 0-1Grade 0-1aaWorst Worst

Grade 2-4Grade 2-4

Patients - n (%)Patients - n (%) 90 (30)90 (30) 212 (70)212 (70) 75 (32)75 (32) 162 (68)162 (68)Time to worst grade – Time to worst grade – median (days)median (days) 1313 34.534.5 1111 2828

aaTime to worst grade only included patients with worst grade 1Time to worst grade only included patients with worst grade 1



Duration of Panitumumab ExposureDuration of Panitumumab Exposure

WT KRASWT KRAS MT KRASMT KRASWorst Worst




Grade 2-4Grade 2-4Duration of panitumumab Duration of panitumumab treatment – median (weeks)treatment – median (weeks) 12.912.9 2525 10.610.6 22.722.7



Demographics and Disease Characteristics Demographics and Disease Characteristics by Worst ST Gradeby Worst ST Grade

WT WT KRASKRAS Panitumumab + Panitumumab + FOLFIRIFOLFIRI

MT MT KRASKRAS Panitumumab + Panitumumab + FOLFIRIFOLFIRI

Worst ST Worst ST Grade 0 - 1Grade 0 - 1

(n = 90)(n = 90)

Worst ST Worst ST Grade 2 - 4 Grade 2 - 4

(n = 212)(n = 212)

Worst ST Worst ST Grade 0 - 1Grade 0 - 1

(n = 75)(n = 75)

Worst ST Worst ST Grade 2 - 4 Grade 2 - 4

(n = 162)(n = 162)Sex – men - n (%)Sex – men - n (%) 49 (54)49 (54) 138 (65)138 (65) 38 (51)38 (51) 95 (59)95 (59)Age – years, median (min, max)Age – years, median (min, max) 62.5 (29, 82)62.5 (29, 82) 59 (28, 84)59 (28, 84) 60 (29, 83)60 (29, 83) 61 (31, 81)61 (31, 81)Race, white – n (%)Race, white – n (%) 88 (98)88 (98) 205 (97)205 (97) 72 (96)72 (96) 153 (94)153 (94)ECOG performance status – n (%)ECOG performance status – n (%)

0 - 10 - 1 85 (94)85 (94) 203 (96)203 (96) 65 (87)65 (87) 158 (98)158 (98)22 5 (6)5 (6) 9 (4)9 (4) 10 (13)10 (13) 4 (2)4 (2)

Primary tumor type – n (%)Primary tumor type – n (%)

Colon cancerColon cancer 58 (64)58 (64) 128 (60)128 (60) 45 (60)45 (60) 110 (68)110 (68)Rectal cancerRectal cancer 32 (36)32 (36) 84 (40)84 (40) 30 (40)30 (40) 52 (32)52 (32)

Sites of metastatic disease:Sites of metastatic disease:

Liver onlyLiver only 12 (13)12 (13) 39 (18)39 (18) 10 (13)10 (13) 27 (17)27 (17)Liver + otherLiver + other 66 (73)66 (73) 139 (66)139 (66) 60 (80)60 (80) 106 (65)106 (65)Other onlyOther only 12 (13)12 (13) 34 (16)34 (16) 5 (7)5 (7) 28 (17)28 (17)



Prog

ress

ion-

free

Surv

ival

Prob

abili

ty

0.00.10.20.30.40.50.60.70.80.91.0

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 Prog

ress

ion-

free

Surv

ival

Prob

abili

ty

0.00.10.20.30.40.50.60.70.80.91.0

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26

PFS (Central Assessment) by ST SeverityPFS (Central Assessment) by ST SeverityKRAS KRAS Safety Set, Panitumumab*Safety Set, Panitumumab*


HR (Gr 2-4:0-1) = 0.460 (95% CI: 0.340, 0.623)HR (Gr 2-4:0-1) = 0.460 (95% CI: 0.340, 0.623)Log-rank p-value <0.0001Log-rank p-value <0.0001

HR (Gr 2-4:0-1) = 0.592 (95% CI: 0.447, 0.786)HR (Gr 2-4:0-1) = 0.592 (95% CI: 0.447, 0.786)Log-rank p-value = 0.0003Log-rank p-value = 0.0003



Grade 2-4Grade 2-4 172 / 208 (83) 172 / 208 (83) 7.4 (6.1 – 8.3)7.4 (6.1 – 8.3)

Grade 0-1Grade 0-1 74 / 84 (88) 74 / 84 (88) 4.5 (3.7 – 6.3) 4.5 (3.7 – 6.3)



Grade 2-4Grade 2-4 152 / 160 (95) 152 / 160 (95) 6.0 (5.5 – 7.4)6.0 (5.5 – 7.4)

Grade 0-1Grade 0-1 68 / 70 (97) 68 / 70 (97) 2.8 (2.0 – 3.7)2.8 (2.0 – 3.7)

*Landmark analysis among patients with a PFS time ≥ 28 days*Landmark analysis among patients with a PFS time ≥ 28 days



OS by ST SeverityOS by ST SeverityKRAS KRAS Safety Set, Panitumumab*Safety Set, Panitumumab*


Surv

ival

Prob

abili

ty

0.00.10.20.30.40.50.60.70.80.91.0

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Surv

ival

Prob

abili

ty

0.00.10.20.30.40.50.60.70.80.91.0

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

HR (Gr 2-4:0-1) = 0.408 (95% CI: 0.294, 0.564)HR (Gr 2-4:0-1) = 0.408 (95% CI: 0.294, 0.564)Log-rank p-value <0.0001Log-rank p-value <0.0001

HR (Gr 2-4:0-1) = 0.415 (95% CI: 0.302, 0.572)HR (Gr 2-4:0-1) = 0.415 (95% CI: 0.302, 0.572) Log-rank p-value <0.0001Log-rank p-value <0.0001


Median Median (95% CI) months(95% CI) months

Grade 2-4Grade 2-4 130 / 208 (63) 130 / 208 (63) 16.5 (14.7 – 19.5)16.5 (14.7 – 19.5)

Grade 0-1Grade 0-1 66 / 84 (79) 66 / 84 (79) 9.0 (6.7 – 12.2) 9.0 (6.7 – 12.2)



Grade 2-4Grade 2-4 116 / 160 (73) 116 / 160 (73) 13.7 (12.5 – 15.0)13.7 (12.5 – 15.0)

Grade 0-1Grade 0-1 61 / 70 (87) 61 / 70 (87) 7.3 (5.3 – 8.6)7.3 (5.3 – 8.6)

*Landmark analysis among patients with a PFS time ≥ 28 days*Landmark analysis among patients with a PFS time ≥ 28 days



All treatedGrade 0-1Grade 2-4

37

24

42

14 13 14

Res

pons

eR

ate

(%)

0

10

20

30

40

50

60

70

80

90

100

Wild-type Mutant

n = 286 n = 84 n = 202 n = 224 n = 70 n = 154

ORR (Central) by ST SeverityORR (Central) by ST SeverityKRAS KRAS Safety & Central Tumor Response Set*Safety & Central Tumor Response Set*

*Landmark analysis among patients with a PFS time *Landmark analysis among patients with a PFS time ≥ 28 days≥ 28 days

aaAssociation between severity and objective response rate over study period (ORR) (Odds ratio Grade 2-4 vs. 0-1, adjusted for Association between severity and objective response rate over study period (ORR) (Odds ratio Grade 2-4 vs. 0-1, adjusted for stratification factors)stratification factors)

p = 0.003a

Odds ratio (95% CI) = 2.46 (1.31, 4.61)

p = 1.000a

Odds ratio (95% CI) = 1.03 (0.42, 2.72)

PanitumumabPanitumumab



Number of pts that Completed the EQ-5D HSI by Number of pts that Completed the EQ-5D HSI by KRASKRAS and and Worst ST (Panitumumab Arm Only)Worst ST (Panitumumab Arm Only)

WT WT KRASKRAS MT MT KRASKRASNumber of pts at Number of pts at each timepoint - neach timepoint - n

ST Grade 0 – 1ST Grade 0 – 1 ST Grade 2 – 4ST Grade 2 – 4 ST Grade 0 – 1ST Grade 0 – 1 ST Grade 2 – 4ST Grade 2 – 4

BaselineBaseline 7373 195195 5656 149149Week 4Week 4 6969 174174 5555 139139Week 8Week 8 5959 174174 4747 137137Week 12Week 12 4242 144144 3434 109109Week 16Week 16 3838 144144 2727 111111Week 20Week 20 2929 124124 2020 8787Week 24Week 24 2424 113113 1818 6969Week 28Week 28 2020 7878 1313 5050Week 32Week 32 1818 7575 99 4646Week 36Week 36 1515 6060 33 3030Week 40Week 40 1010 4545 33 2323

• Overall compliance for the EQ-5D Health State Index was 65% for patients with WT Overall compliance for the EQ-5D Health State Index was 65% for patients with WT KRASKRAS and 66% for patients with MT and 66% for patients with MT KRASKRAS



Number of pts that Completed the EQ-5D OHR by Number of pts that Completed the EQ-5D OHR by KRASKRAS and and Worst ST (Panitumumab Arm Only)Worst ST (Panitumumab Arm Only)

WT WT KRASKRAS MT MT KRASKRASNumber of pts at Number of pts at each timepoint - neach timepoint - n

ST Grade 0 – 1ST Grade 0 – 1 ST Grade 2 – 4ST Grade 2 – 4 ST Grade 0 – 1ST Grade 0 – 1 ST Grade 2 – 4ST Grade 2 – 4

BaselineBaseline 7272 191191 5959 150150Week 4Week 4 6767 170170 5555 137137Week 8Week 8 5959 172172 4848 138138Week 12Week 12 4343 142142 3333 109109Week 16Week 16 3838 143143 2727 112112Week 20Week 20 2929 122122 2020 8686Week 24Week 24 2424 113113 1818 7070Week 28Week 28 2020 7777 1313 5050Week 32Week 32 1818 7575 99 4545Week 36Week 36 1515 5959 33 3030Week 40Week 40 1111 4545 22 2222

• Overall compliance for the EQ-5D Overall Health Rating was 64% for patients with WT Overall compliance for the EQ-5D Overall Health Rating was 64% for patients with WT KRASKRAS and 65% for patients with MT and 65% for patients with MT KRASKRAS



Least Square Mean Difference in HSI Least Square Mean Difference in HSI Between ST Grade 0-1 vs 2-4Between ST Grade 0-1 vs 2-4


Cha

nge

From

Bas

elin

e

-0.60

-0.50

-0.40

-0.30

-0.20

-0.10

-0.00

0.10

0.20

0.30

PRO Analysis Week

0 4 8 12 16 20 24 28 32 36 40

Worst Grade ST 0-1Worst Grade ST 2-4

Cha

nge

From

Bas

elin

e

-0.25

-0.20

-0.15

-0.10

-0.05

-0.00

0.05

0.10

PRO Analysis Week

0 4 8 12 16 20 24 28 32 36 40


Overall Difference (Gr 0-1 minus 2-4) between two Overall Difference (Gr 0-1 minus 2-4) between two groups: - 0.035 (95% CI: - 0.088, 0.017)groups: - 0.035 (95% CI: - 0.088, 0.017) Vertical lines = 95% CIVertical lines = 95% CI

Overall Difference (Gr 0-1 minus 2-4) between two Overall Difference (Gr 0-1 minus 2-4) between two groups: 0.009 (95% CI: - 0.051, 0.069)groups: 0.009 (95% CI: - 0.051, 0.069) Vertical lines = 95% CIVertical lines = 95% CI



Least Square Mean Difference in OHR Least Square Mean Difference in OHR Between ST Grade 0-1 vs 2-4Between ST Grade 0-1 vs 2-4


Cha

nge

From

Bas

elin

e

-20.00

-15.00

-10.00

-5.00

0.00

5.00

10.00

15.00

PRO Analysis Week

0 4 8 12 16 20 24 28 32 36 40


Cha

nge

From

Bas

elin

e

-10.00

-8.00

-6.00

-4.00

-2.00

0.00

2.00

4.00

6.00

PRO Analysis Week

0 4 8 12 16 20 24 28 32 36 40


Overall Difference (Gr 0-1 minus 2-4) between two Overall Difference (Gr 0-1 minus 2-4) between two groups: - 0.676 (95% CI: - 4.555, 3.203)groups: - 0.676 (95% CI: - 4.555, 3.203) Vertical lines = 95% CIVertical lines = 95% CI

Overall Difference (Gr 0-1 minus 2-4) between two Overall Difference (Gr 0-1 minus 2-4) between two groups: 3.259 (95% CI: - 2.373, 8.892)groups: 3.259 (95% CI: - 2.373, 8.892) Vertical lines = 95% CIVertical lines = 95% CI



Conclusions Conclusions • This large, randomized trial prospectively analyzed by This large, randomized trial prospectively analyzed by KRAS KRAS status as a predictive status as a predictive

biomarker for EGFR treatment in 2biomarker for EGFR treatment in 2ndnd-line mCRC -line mCRC • As previously reported, in patients with WT As previously reported, in patients with WT KRAS KRAS tumors, panitumumab significantly tumors, panitumumab significantly

improved PFS when added to FOLFIRI (median 5.9 vs 3.9 mo; HR = 0.73, p = 0.004)improved PFS when added to FOLFIRI (median 5.9 vs 3.9 mo; HR = 0.73, p = 0.004)– A trend towards improved overall survival (but not statistically significant) was A trend towards improved overall survival (but not statistically significant) was

observed in patients with WT observed in patients with WT KRASKRAS tumors with panitumumab + FOLFIRI (median tumors with panitumumab + FOLFIRI (median 14.5 vs 12.5 mo; HR = 0.85, p = 0.12)14.5 vs 12.5 mo; HR = 0.85, p = 0.12)

– Response rate was improved in patients with WT Response rate was improved in patients with WT KRASKRAS tumors with tumors with panitumumab + FOLFIRI (35% vs 10%)panitumumab + FOLFIRI (35% vs 10%)

– Panitumumab was tolerable when administered with FOLFIRIPanitumumab was tolerable when administered with FOLFIRI• ST grade 2-4 was associated with longer PFS and OS vs ST grade 0-1, regardless of ST grade 2-4 was associated with longer PFS and OS vs ST grade 0-1, regardless of

KRASKRAS tumor status tumor status– This nonrandomized analysis may be confounded by duration of panitumumab This nonrandomized analysis may be confounded by duration of panitumumab

exposure and time on studyexposure and time on study– A definitive conclusion cannot be reached with this exploratory analysisA definitive conclusion cannot be reached with this exploratory analysis

• ST grade 2-4 was associated with increased ORR vs ST grade 0-1 only in pts with WT ST grade 2-4 was associated with increased ORR vs ST grade 0-1 only in pts with WT KRASKRAS tumors tumors

• When panitumumab is administered in combination with FOLFIRI, there is no overall When panitumumab is administered in combination with FOLFIRI, there is no overall difference in PRO between pts with WT or MT difference in PRO between pts with WT or MT KRASKRAS experiencing ST grade 2-4 vs ST experiencing ST grade 2-4 vs ST grade 0-1grade 0-1



ReferencesReferences1.1. VectibixVectibix®® Prescribing Information, Amgen Inc. Thousand Oaks, CA; 2009 Prescribing Information, Amgen Inc. Thousand Oaks, CA; 20092.2. Amgen Europe B.V. VectibixAmgen Europe B.V. Vectibix®® Summary of Product Characteristics. 2009 Summary of Product Characteristics. 20093.3. Peeters et al: Randomized phase 3 study of panitumumab with FOLFIRI vs Peeters et al: Randomized phase 3 study of panitumumab with FOLFIRI vs

FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC) colorectal cancer (mCRC) Eur J Cancer SupplEur J Cancer Suppl 7:10, 2009 7:10, 2009

4.4. Van Cutsem E, et al: Open-Label Phase III Trial of Panitumumab Plus Best Van Cutsem E, et al: Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer. Chemotherapy-Refractory Metastatic Colorectal Cancer. J Clin OncolJ Clin Oncol 25:1658-1664, 200725:1658-1664, 2007

asco 2010 confidential do not distribute randomized, open-label, phase 3 study of panitumumab (pmab)...

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