Panitumumab Efficacy and Panitumumab Efficacy and Patient-Reported Outcomes in Patient-Reported Outcomes in

Metastatic ColorectalMetastatic ColorectalCancer Patients With Wild-Type Cancer Patients With Wild-Type

KRASKRAS Tumor Status Tumor Status

Rafael G. Amado, MD;Rafael G. Amado, MD;11 Michael Wolf, MS; Michael Wolf, MS;11 Dan Freeman, PhD; Dan Freeman, PhD;11 Marc Peeters, MD, PhD;Marc Peeters, MD, PhD;22 Eric Van Cutsem, MD, PhD; Eric Van Cutsem, MD, PhD;33

Salvatore Siena, MD;Salvatore Siena, MD;44 Sid Suggs, PhD; Sid Suggs, PhD;11 Giovanna Devercelli, PhD; Giovanna Devercelli, PhD;11

Michael Woolley, PhD;Michael Woolley, PhD;11 and David Chang, PhD and David Chang, PhD11

11Amgen Inc., Thousand Oaks, CA, USA; Amgen Inc., Thousand Oaks, CA, USA; 22Ghent University Hospital, Ghent, Belgium;Ghent University Hospital, Ghent, Belgium;

33University Hospital Gasthuisberg, Leuven, Belgium; University Hospital Gasthuisberg, Leuven, Belgium; 44Ospedale Niguarda Ca’Granda, Milan, ItalyOspedale Niguarda Ca’Granda, Milan, Italy

This study was funded by Amgen Inc.

DisclosuresDisclosures

• This study was sponsored by Amgen Inc.This study was sponsored by Amgen Inc.• R.G. Amado, M. Wolf, D. Freeman, S. Suggs, S. Patterson, D. Chang, R.G. Amado, M. Wolf, D. Freeman, S. Suggs, S. Patterson, D. Chang,

T. Juan, M. Reiner, and R. Radinsky are Amgen employees and own T. Juan, M. Reiner, and R. Radinsky are Amgen employees and own Amgen Inc. stock. Amgen Inc. stock.

• M. Peeters, Amgen advisory board and Amgen honoraria; E. Van M. Peeters, Amgen advisory board and Amgen honoraria; E. Van Cutsem, Amgen advisory board and Amgen honoraria; N.J. Meropol, Cutsem, Amgen advisory board and Amgen honoraria; N.J. Meropol, consultant for Amgen, Genentech, and Imclone; J. Berlin, advisory consultant for Amgen, Genentech, and Imclone; J. Berlin, advisory boards for Amgen, BMS, and Imclone. boards for Amgen, BMS, and Imclone.

• Panitumumab, a fully human monoclonal antibody directed against Panitumumab, a fully human monoclonal antibody directed against EGFr, has demonstrated efficacy as monotherapy in patients with EGFr, has demonstrated efficacy as monotherapy in patients with metastatic colorectal cancer (mCRC).metastatic colorectal cancer (mCRC).1, 21, 2

• Recent studies have suggested that the mutational status of the Recent studies have suggested that the mutational status of the KRASKRAS gene in tumors of patients with mCRC may impact response to anti-gene in tumors of patients with mCRC may impact response to anti-EGFr therapies.EGFr therapies.33

• A phase 3, randomized controlled trial demonstrated that panitumumab A phase 3, randomized controlled trial demonstrated that panitumumab was well tolerated and significantly improved progression-free survival was well tolerated and significantly improved progression-free survival compared with best supportive care alone, in refractory mCRC patients.compared with best supportive care alone, in refractory mCRC patients.22

• Using tumor samples from that study,Using tumor samples from that study, we correlatedwe correlated KRAS KRAS status with status with clinical and patient-reported outcomes.clinical and patient-reported outcomes.

IntroductionIntroduction

1 Vectibix™ Prescribing Information; Amgen Inc. Thousand Oaks CA, 20072 Van Cutsem E, et al. J Clin Oncol 2007;25:1658–1664.3 Benvenuti S, et al. Cancer Res. 2007;67:2643–2648.

Randomization stratification• ECOG score (0-1 vs. 2)• Geographic region (Western EU vs. Central & Eastern EU vs. Rest of World)

1:1

Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC

BSC PD Follow-up

RANDOMIZE

Optional Panitumumab

Crossover Study

Hypothesis: There would be a larger treatment effect in patients with wild-type KRAS compared to patients with mutant KRAS

KRASKRAS Analysis of a Phase 3, Randomized, Controlled Trial Comparing Analysis of a Phase 3, Randomized, Controlled Trial Comparing Panitumumab vs BSC in Colorectal CancerPanitumumab vs BSC in Colorectal Cancer

Van Cutsem E et al. J Clin Oncol 2007;25:1658–1664.

Objectives and Analysis MethodologyObjectives and Analysis Methodology

Primary Objective

• To assess whether the effect of panitumumab on PFS was significantly greater in patients with wild-type KRAS compared with mutant KRAS

Secondary Objectives

• To assess whether panitumumab improves PFS compared with BSC alone in patients with wild-type KRAS

• To assess whether panitumumab improves overall survival (OS) compared with BSC alone in patients with wild-type KRAS

Compare PFS in wild-type KRAS

subset

Test for a PFS effect among all

randomized patients at a 5% level

Test for quantitative PFS effect interaction,

i.e., wild-type effect > mutant

p ≤ 0.05 p > 0.05

p ≤ 0.05 p > 0.05

Compare OR & OS in wild-type KRAS subset STOP

STOP

Assay Used to Detect Assay Used to Detect KRASKRAS Mutational Status Mutational Status

• DNA was isolated from fixed tumor samplesDNA was isolated from fixed tumor samples

• Mutant Mutant KRASKRAS was detected using a was detected using a KRASKRAS mutation kit (DxS Ltd, mutation kit (DxS Ltd, Manchester, UK) that used allele-specific, real-time PCRManchester, UK) that used allele-specific, real-time PCR

– The kit can detect approximately 1% of mutant DNA in a The kit can detect approximately 1% of mutant DNA in a background of wild-type genomic DNAbackground of wild-type genomic DNA

– The test identifies 7 somatic mutations in codons 12 and 13The test identifies 7 somatic mutations in codons 12 and 13

• Gly 12 AspGly 12 Asp

• Gly 12 AlaGly 12 Ala

• Gly 12 ValGly 12 Val

• Gly 12 SerGly 12 Ser

• Gly 12 Arg• Gly 12 Cys• Gly 13 Asp

Patient DispositionPatient Disposition

rpr t oln = 90

ScreenedN = 1,040

RandomizedN = 463

Randomized to panitumumab + BSC

N = 231

Randomized to BSC alone

N = 232

Excluded from KRAS analyses(missing or unevaluable)

N = 36

KRAS mutant N = 84

WT KRASN = 124

KRAS mutant N = 100

WT KRASN = 119

Received P’mab in

X-over protocolN = 77

Received P’mab in

X-over protocolN = 90

BSC = Best supportive care; WT = wild-type

PFS by PFS by KRASKRAS Status and Treatment Status and Treatment

Mutant KRAS WT KRAS

• The relative effect of panitumumab versus BSC was significantly greater in patients with WT versus mutant KRAS.• The quantitative-interaction test comparing the magnitude of the relative treatment effect on PFS

between WT and mutant KRAS was statistically significant (p < 0.0001).• PFS was significantly greater for panitumumab treatment compared with BSC in the WT KRAS

group (stratified log-rank test p < 0.0001).

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pmab + BSC

Weeks

78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 191 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2

84100

76/84(90) 7.4 9.995/100(95) 7.3 10.2

Events/N (%)Median (Wks)

Mean

0

1

2

3

4

5

6

7

8

9

0

Pmab + BSCBSC AloneBSC Alone

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Patients at RiskPatients at Risk

78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 191 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2

84100

76/84(90) 7.4 9.995/100(95) 7.3 10.2

Pmab + BSCBSC AlonePmab + BSCBSC Alone

(Wks)

HR = 0.99 (95% CI: 0.73–1.36) HR = 0.45 (95% CI: 0.34–0.59)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Weeks

36 38 40 42 44 46 48 50 52

7 7 6 5 510 9 9 6 6 6 5 4 3 3 2 2 2 2 1

124

Stratified log-rank test, p < 0.0001

119 112106 80 69 63 58 50 45 44 44 33 25 21 20 17 13 13 13 10119 109 91 81 38 20 15 15 14 11 6

115/124 (93) 12.3 19.0114/119 (96) 7.3 9.3

Pmab + BSCBSC Alone

Events/N (%)Median (Wks)

Mean (Wks)

Pro

port

ion

Eve

nt-f

ree

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

PFS – Interval Censored (Sensitivity Analysis) PFS – Interval Censored (Sensitivity Analysis) by by KRASKRAS Status and Treatment Status and Treatment

Mutant KRAS WT KRAS

76/84 (90) 895/100 (95) 8

Pmab + BSCBSC Alone

Events/N (%)Median (Wks)

Pro

por

tion

Eve

nt-F

ree

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

Pro

por

tion

Eve

nt-F

ree

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

115/124 (93) 16114/119 (96) 8

Pmab + BSCBSC Alone

Events/N (%)Median (Wks)

Weeks Weeks

HR=0.49 (95% CI: 0.37-0.65) HR=1.07 (95% CI: 0.77-1.48)

Maximum Percent Decrease in Target Lesions Maximum Percent Decrease in Target Lesions Final Analysis, Final Analysis, KRASKRAS Evaluable Group Evaluable Group

16014012010080604020%

Cha

nge

-20-40-60-80

0

PR (0%) SD (12%) PD (70%)

Mutant

Patient

Pmab+ BSC

16014012010080604020%

Cha

nge

-20-40-60-80

0

PR (17%) SD (34%) PD (36%)

Wild-Type

Patient

16014012010080604020

% C

hang

e

-20-40-60-80

0

PR (0%) SD (8%) PD (60%)

Patient

BSCAlone

16014012010080604020

% C

hang

e

-20-40-60-80

0

PR (0%) SD (12%) PD (75%)

Patient

BSC = Best supportive care; Pmab = panitumumab

Overall Survival by Overall Survival by KRAS KRAS Status and Status and TreatmentTreatment

124 92 58 35 18 9 3 2 1119 82 54 28 18 10 5 1 084 51 21 10 6 3 3 1 0100 55 30 18 11 3 0 0 0

Pmab WT, NBSC WT, N

Pmab Mutant, NBSC Mutant, N

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al P

rob

abili

ty

Pmab, Wild-type 107 / 124 (86)

110 / 119 (92)

8.1

7.6

Events / N (%)Median

In Months

BSC, Wild-type

Wild-type vs. Mutant(treatment arms combined)

Pmab, Mutant

BSC, Mutant

79 / 84 (94)

95 / 100 (95)

4.9

4.4

HR = 0.67 (95% CI: 0.55–0.82)adjusted for treatment and randomization factors (ECOG, region)

Treatment Difference (95% CI) for Treatment Difference (95% CI) for FACT/NCCN Colorectal Cancer Symptom FACT/NCCN Colorectal Cancer Symptom

Index (FCSI)Index (FCSI)Mutant KRAS WT KRAS

Panitumumab - BCSImputed - LVCF

-16.00

-12.00

-8.00

-4.00

0.00

4.00

8.00

12.00

16.00

20.00

Week4 8 12 16

FC

SI

Dif

fere

nce

-16.00

-12.00

-8.00

-4.00

0.00

4.00

8.00

12.00

16.00

20.00

Week4 8 12 16

Panitumumab - BCSImputed - LVCF

MCID= -4.0

Treatment Difference (95% CI) for Treatment Difference (95% CI) for EORTC-QLQ-C30 Global Health StatusEORTC-QLQ-C30 Global Health Status

Mutant KRAS WT KRAS

EO

RT

C G

lob

al H

ealt

h

-16.00 -14.00 -12.00 -10.00 -8.00 -6.00 -4.00 -2.00 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00

Week4 8 12 16

Week

-16.00 -14.00 -12.00 -10.00 -8.00 -6.00 -4.00 -2.00 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00

4 8 12 16

Panitumumab - BCSImputed - LVCF Panitumumab - BCSImputed - LVCF

MCID = -7.07

PFS by Minimum Post-Baseline mDLQI Score, PFS by Minimum Post-Baseline mDLQI Score, Panitumumab Landmark Safety SetPanitumumab Landmark Safety Setaa

aExcludes patients with progression-free survival < 28 days. By mDLQI scores, dichotomization of PFS for degree of being bothered was explored using all possible cut points of mDLQI (based on the effect size from a Cox model) to find the maximum difference by mDLQI score.

Mutant KRAS WT KRAS

Weeks from Randomization

≤ 66.667> 66.667

Median (Wks)Events / N (%)

84 / 90 (93)

18 / 18 (100)

22.4

7.4

10 20 30 40 50 60 70 80 90 1000

Pro

po

rtio

n E

ve

nt-

Fre

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization

0 10 20 30 40 50 60 70 80 90

Events / N (%)Median (Wks)

52 / 54 (96)

18 / 18 (100)

7.6

7.4≤ 66.667> 66.667

ConclusionsConclusions

• In patients with chemotherapy-refractory mCRC, the clinical In patients with chemotherapy-refractory mCRC, the clinical efficacy of panitumumab monotherapy appears to be efficacy of panitumumab monotherapy appears to be restricted to patients with WT KRAS tumorsrestricted to patients with WT KRAS tumors

• Results of QOL analyses by KRAS status are consistent Results of QOL analyses by KRAS status are consistent with clinical outcomeswith clinical outcomes

• KRAS genotyping of tumors should be strongly considered KRAS genotyping of tumors should be strongly considered in patients with mCRC being treated with panitumumab in patients with mCRC being treated with panitumumab monotherapymonotherapy

• Ongoing studies in 1st and 2nd lines will prospectively Ongoing studies in 1st and 2nd lines will prospectively examine the effect of panitumumab in combination with examine the effect of panitumumab in combination with chemotherapy in patients with WT and mutant KRAS tumorschemotherapy in patients with WT and mutant KRAS tumors

AcknowledgmentsAcknowledgments

• We thank the patients and their families for study We thank the patients and their families for study participation, investigators and study personnelparticipation, investigators and study personnel