Www.OncologyEducation.ca KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI.

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KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without

cetuximab: The CRYSTAL experience

Authors: E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P. Rougier

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CRYSTAL Trial

Van Custem E Proc ASCO 2007

RANDOMI ZE

1:11:1

FOLFIRI + CetuximabN=608

FOLFIRIN=609

10 Endpoint= PFS

N=1217EGFR

expressionvia IHC

* Cetuximab 400 mg/m* Cetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m22 IV weekly IV weekly

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ResultsEfficacy

Grade 3/4 toxicityFOLFIRI

N = 650 (%)

FOLFIRI + Cetuximab

N = 648 (%)

Response Rate 39 47

Median PFS 8.0 8.9

1 yr PFS 23 34

Median OS NR NR

HR = 0.85 (0.73-0.99); p=0.048

p=0.0038

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ResultsPatient Characteristics

n = 1198 n =540Centrally assessed for

KRAS mutation by QT-PCR exon 12/13

Wild-type KRAS(n=348)

Mutant KRAS(n=192)

Male, % 57.8 57.8

Age < 65, % 65.8 59.9

Prior adjuvant Rx, % 21.6 12.5

Treatment, n (%)FOLFIRI

FOLFIRI + Cetuximab176 (51)172 (49)

87 (45)105 (55)

ITT

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ResultsEfficacy

Wild-type KRAS Mutant KRAS

FOLFIRIFOLFIRI + Cetux

FOLFIRIFOLFIRI+ Cetux

Median PFS, mos 8.7 9.9 8.1 7.6

1yr PFS rate, % 25 43 NR NR

ORRCRPR

43.20

43.2

59.3 1.258.1

40.20

40.2

36.20

36.2

SD 43.8 30.8 46.0 46.7

HR = 0.68; p 0.017 HR = 1.07; p 0.75

p 0.025 p 0.46

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KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or

without cetuximab: The OPUS experience

Authors: C Bokemeyer, I Bondarenko, J Hartmann, F De Braud, C Volovat, C Stroh,J Nippgen, I Celik, P Koralewski

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OPUS: Phase II

RANDOMI ZE

1:11:1

FOLFOX + CetuximabN=170

FOLFOXN=168

N=338EGFR+

Metasatic CRC

* Cetuximab 400 mg/m* Cetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m22 IV weekly IV weekly

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ResultsEfficacy

FOLFOX+ Cetuximab

FOLFOX

Response Rate 45.6% 35.7%

Median PFS, months

7.2 7.2

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ResultsPatient Characteristics

n = 337 n =233Centrally assessed for

KRAS mutation by QT-PCR exon 12/13

Wild-type KRAS(n=134)

Mutant KRAS(n=99)

Male, % 55.2 49.5

Age < 65, % 63.4 62.6

Prior adjuvant Rx, % 18.7 17.2

Treatment, n (%)FOLFOX

FOLFOX + Cetuximab73 (54)61 (46)

47 (47)52 (53)

ITT

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ResultsEfficacy

Wild-type KRAS Mutant KRAS

FOLFOXFOLFOX + Cetux

FOLFOXFOLFOX+ Cetux

Median PFS, mos 7.2 7.7 8.6 5.5

1yr PFS rate, % NR NR NR NR

ORRCRPR

37.01.4

35.6

60.73.3

57.4

48.94.3

44.7

32.70

32.7

SD 16.4 4.9 36.2 51.9

HR = 0.57; p 0.016 HR = 1.83; p 0.019

p 0.011 p 0.11

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ResultsToxicity

• No difference in skin rash or other toxicity by KRAS status in CRYSTAL or OPUS

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STUDY COMMENTARY

• Together with Panitumumab monotherapy in 3rd line setting (Van Custem JCO 2007) these two trials demonstrate that monoclonal antibody blockade against EGFR only benefit patients with wild-type KRAS– Similar findings with EGFR TKIs in NSCLC and

pancreatic adenoCA

• No overall survival data reported for either CRYSTAL or OPUS

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• Addition of Cetuximab to first line FOLFOX or FOLFIRI only benefits patients with wild type KRAS– Biologically plausible mAb to receptor will not shut off

signaling if a downstream kinase (KRAS) is constitutively active• Addition of Cetuximab to first line FOLFOX in KRAS

mutant patients appears to be detrimental– ? Biology of this phenomenon

• Optimal sequence of biological therapy in KRAS wild-type patients remains to be determined– Should obtain KRAS mutational status on all patients where

Cetuximab is considered• NCIC CO.17 is the only trial to demonstrate OS benefit

with EGFR mAb– Retrospective survival analysis by KRAS status is eagerly

awaited

Bottom Line for Canadian Medical Oncologists