Panitumumab Efficacy and Patient-Reported Outcomes in Metastatic Colorectal
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Panitumumab Efficacy and Patient-Reported Outcomes in Metastatic Colorectal Cancer Patients With Wild-Type KRAS Tumor Status.

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This study was funded by Amgen Inc.

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This study was funded by amgen inc

Panitumumab Efficacy and Patient-Reported Outcomes in Metastatic ColorectalCancer Patients With Wild-Type KRAS Tumor Status

Rafael G. Amado, MD;1 Michael Wolf, MS;1 Dan Freeman, PhD;1Marc Peeters, MD, PhD;2 Eric Van Cutsem, MD, PhD;3Salvatore Siena, MD;4 Sid Suggs, PhD;1 Giovanna Devercelli, PhD;1Michael Woolley, PhD;1 and David Chang, PhD1

1Amgen Inc., Thousand Oaks, CA, USA; 2Ghent University Hospital, Ghent, Belgium;3University Hospital Gasthuisberg, Leuven, Belgium; 4Ospedale Niguarda Ca’Granda, Milan, Italy

This study was funded by Amgen Inc.


Disclosures

Disclosures

  • This study was sponsored by Amgen Inc.

  • 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 Amgen Inc. stock.

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


Introduction

Introduction

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

  • Recent studies have suggested that the mutational status of the KRAS gene in tumors of patients with mCRC may impact response to anti-EGFr therapies.3

  • A phase 3, randomized controlled trial demonstrated that panitumumab was well tolerated and significantly improved progression-free survival compared with best supportive care alone, in refractory mCRC patients.2

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

1 Vectibix™ Prescribing Information; Amgen Inc. Thousand Oaks CA, 2007

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

3 Benvenuti S, et al. Cancer Res. 2007;67:2643–2648.


This study was funded by amgen inc

R

A

N

D

O

M

I

Z

E

PanitumumabPD Follow-up

6.0 mg/kg Q2W

+ BSC

BSCPD Follow-up

Optional Panitumumab Crossover Study

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

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

1:1

  • Randomization stratification

  • ECOG score (0-1 vs. 2)

  • Geographic region (Western EU vs. Central & Eastern EU vs. Rest of World)

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


Objectives and analysis methodology

Objectives 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

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

Compare PFS in wild-type KRAS subset

STOP

p ≤ 0.05

p > 0.05

Compare OR & OS in wild-type KRAS subset

STOP


Assay used to detect kras mutational status

DNA was isolated from fixed tumor samples

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

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

The test identifies 7 somatic mutations in codons 12 and 13

Gly 12 Asp

Gly 12 Ala

Gly 12 Val

Gly 12 Ser

Assay Used to Detect KRAS Mutational Status

  • Gly 12 Arg

  • Gly 12 Cys

  • Gly 13 Asp


Patient disposition

Patient Disposition

Screened

N = 1,040

Randomized

N = 463

Randomized to

BSC alone

N = 232

Randomized to

panitumumab + BSC

N = 231

Excluded from KRAS analyses

(missing or unevaluable)

N = 36

KRAS mutant

N = 84

KRAS mutant

N = 100

WT KRAS

N = 124

WT KRAS

N = 119

Received

P’mab in

X-over protocol

N = 77

Received

P’mab in

X-over protocol

N = 90

r

p

r

t

o

l

n

=

9

0

BSC = Best supportive care; WT = wild-type


Pfs by kras status and treatment

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HR = 0.45 (95% CI: 0.34–0.59)

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PFS by KRAS 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).


Pfs interval censored sensitivity analysis by kras status and treatment

P

P

m

m

ab

ab

+

+

BS

BS

C

C

BS

BS

C

C

A

A

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

Mutant KRAS

WT KRAS

M

e

d

ian

M

e

d

ian

E

v

e

n

t

s

/N

(

%

)

(

W

ks)

E

v

e

n

t

s

/N

(

%

)

(

W

ks)

76/84

(

90)

8

115/124

(

93)

16

95/100

(

95)

8

114/119

(

96)

8

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

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

Weeks

Weeks


Maximum percent decrease in target lesions final analysis kras evaluable group

Mutant

Wild-Type

160

160

140

140

PR (0%)

SD (12%)

PD (70%)

PR (17%)

SD (34%)

PD (36%)

120

120

100

100

80

80

60

60

Pmab

+ BSC

% Change

% Change

40

40

20

20

0

0

-20

-20

-40

-40

-60

-60

-80

-80

Patient

Patient

160

160

140

140

PR (0%)

SD (8%)

PD (60%)

PR (0%)

SD (12%)

PD (75%)

120

120

100

100

80

80

60

60

BSC

Alone

40

40

% Change

% Change

20

20

0

0

-20

-20

-40

-40

-60

-60

-80

-80

Patient

Patient

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

BSC = Best supportive care; Pmab = panitumumab


Overall survival by kras status and treatment

Overall Survival by KRAS Status and Treatment

Median

In Months

Events / N (%)

1.0

Pmab, Wild-type

107 / 124 (86)

8.1

0.9

BSC, Wild-type

110 / 119 (92)

7.6

0.8

Pmab, Mutant

79 / 84 (94)

4.9

0.7

BSC, Mutant

95 / 100 (95)

4.4

0.6

Survival Probability

Wild-type vs. Mutant

(treatment arms combined)

0.5

0.4

HR = 0.67 (95% CI: 0.55–0.82)

adjusted for treatment and randomization factors (ECOG, region)

0.3

0.2

0.1

0.0

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

Months

Pmab WT, N

124

92

58

35

18

9

3

2

1

BSC WT, N

119

82

54

28

18

10

5

1

0

Pmab Mutant, N

84

51

21

10

6

3

3

1

0

BSC Mutant, N

100

55

30

18

11

3

0

0

0


Treatment difference 95 ci for fact nccn colorectal cancer symptom index fcsi

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

Mutant KRAS

WT KRAS

Imputed - LVCF

Panitumumab - BCS

Imputed - LVCF

Panitumumab - BCS

20.00

20.00

16.00

16.00

12.00

12.00

8.00

8.00

4.00

4.00

FCSI Difference

0.00

0.00

-4.00

-4.00

-8.00

-8.00

-12.00

-12.00

-16.00

-16.00

4

8

12

16

4

8

12

16

Week

Week

MCID= -4.0


Treatment difference 95 ci for eortc qlq c30 global health status

14.00

14.00

12.00

12.00

10.00

10.00

8.00

8.00

6.00

6.00

4.00

4.00

2.00

2.00

0.00

0.00

EORTC Global Health

-2.00

-2.00

-4.00

-4.00

-6.00

-6.00

-8.00

-8.00

-10.00

-10.00

-12.00

-12.00

-14.00

-14.00

-16.00

-16.00

4

8

12

16

4

8

12

16

Week

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

Mutant KRAS

WT KRAS

Imputed - LVCF

Panitumumab - BCS

Imputed - LVCF

Panitumumab - BCS

Week

MCID = -7.07


Pfs by minimum post baseline mdlqi score panitumumab landmark safety set a

Median

(Wks)

Events / N (%)

Median

(Wks)

Events / N (%)

52 / 54 (96)

7.6

18 / 18 (100)

7.4

84 / 90 (93)

22.4

≤ 66.667

1.0

≤ 66.667

> 66.667

18 / 18 (100)

7.4

> 66.667

0.9

0.8

0.7

0.6

Proportion Event-Free

0.5

0.4

0.3

0.2

0.1

0

10

20

30

40

50

60

70

80

90

100

0.0

Weeks from Randomization

Weeks from Randomization

0

10

20

30

40

50

60

70

80

90

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

Mutant KRAS

WT KRAS

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.


Conclusions

Conclusions

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

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

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

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


Acknowledgments

Acknowledgments

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


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