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
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 Metastatic Colorectal

  • 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 Metastatic Colorectal

  • 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 Metastatic Colorectal

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 Metastatic Colorectal

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 Metastatic Colorectal

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 Metastatic Colorectal

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

M Metastatic Colorectal

e

d

ian

M

ean

M

e

d

ian

M

ean

1

.

0

0

1

1

.

.

0

0

(

W

ks)

E

v

e

n

t

s

/N

(

%

)

(

W

ks)

(

W

ks)

E

v

e

n

t

s

/N

(

%

)

(

W

ks)

0

.

9

9

0

0

.

.

9

9

P

P

m

m

ab

ab

+

+

BS

BS

C

C

76/84

76/84

(

(

90)

90)

7.4

7.4

9.9

9.9

P

m

ab

+

BS

C

115/124

(

93)

12.3

19.0

0

.

8

8

10.2

10.2

BS

BS

C

C

A

A

l

l

one

one

95/100

95/100

(

(

95)

95)

7.3

7.3

0

0

.

.

8

8

9.3

BS

C

A

l

one

114/119

(

96)

7.3

0

.

7

7

0

0

.

.

7

7

HR = 0.99 (95% CI: 0.73–1.36)

HR = 0.45 (95% CI: 0.34–0.59)

0

.

6

6

0

0

.

.

6

6

Proportion Event-free

S

t

r

at

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k

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p

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10

12

14

16

18

2

0

2

2

2

4

2

6

2

8

3

0

3

2

3

4

3

6

3

8

4

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4

2

4

4

4

6

4

8

5

0

5

2

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

W

eek

s

W

eek

s

P

P

a

a

t

t

i

i

e

e

n

n

t

t

s

s

a

a

t

t

R

R

i

i

s

s

k

k

P

P

m

m

a

a

b

b

+

+

B

B

SC

SC

8

4

8

4

7

7

8

8

7

7

6

6

7

7

6

2

2

1

2

2

0

6

1

8

0

6

8

5

6

5

5

5

5

5

5

4

5

4

4

4

4

4

4

2

4

2

2

2

2

2

2

2

2

2

2

2

2

1

2

1

1

1

1

1

12

4

11

9

11

2

10

6

8

0

6

9

6

3

5

8

5

0

4

5

4

4

4

4

3

3

2

5

2

1

2

0

1

7

1

3

1

3

1

3

1

0

7

7

6

5

5

10

0

10

9

1

0

7

9

7

1

6

7

1

7

3

6

7

1

2

3

2

7

2

1

2

9

1

1

0

9

1

9

0

8

9

6

8

5

6

5

5

4

5

4

4

4

4

4

4

4

4

4

4

3

4

3

3

3

3

2

3

2

2

2

2

2

2

2

11

9

10

9

9

1

8

1

3

8

2

0

1

5

1

5

1

4

1

1

1

0

9

9

6

6

6

6

5

4

3

3

2

2

2

2

1

B

B

S

S

C

C

A

A

l

l

on

on

e

e

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 Metastatic Colorectal

P

m

m

ab

ab

+

+

BS

BS

C

C

BS

BS

C

C

A

A

l

l

one

one

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 Metastatic Colorectal

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 Metastatic ColorectalKRAS 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 Cancer Symptom Index (FCSI)

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 Cancer Symptom Index (FCSI)

(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 Cancer Symptom Index (FCSI)

  • 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 Cancer Symptom Index (FCSI)

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


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