Eric Van Cutsem*

KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer treated with FOLFIRI with or without cetuximab:The CRYSTAL experience

Eric Van Cutsem*

I Lang, G D’Haens, V Moieseyenko, J Zaluski, G Folprecht, S Tejpar, O Kisker, C Stroh, P Rougier*University Hospital Gasthuisberg, Leuven, Belgium

Disclosure slide

• Research funding / advisory board:– Amgen– Merck KGaA– Novartis– Pfizer– Roche– Sanofi-Aventis

Epidermal growth factor receptor (EGFR) and KRAS

Khambata-Ford S, et al. J Clin Onc 2007;25:3230–7

Anti-EGFR antibodies in mCRC

3rd line • BOND: cetuximab ± irinotecan • NCIC C0.17: cetuximab vs BSC • Panitumumab vs BSC (KRAS wild-type)

2nd line • BOND: cetuximab ± irinotecan• EPIC: irinotecan ± cetuximab

1st line • (Randomized) Phase II studies (chemo + cetuximab)• CRYSTAL: FOLFIRI ± cetuximab• PACCE: chemo/bevacizumab ± panitumumab• CAIRO2: capecitabine/oxaliplatin/bevacizumab ±

cetuximab • Other phase III studies in progress

Retrospective studies supporting the correlation between KRAS mutations and lack of response to

EGFR inhibitors in chemorefractory mCRCReference Treatment No. of patients

(wild-type:mutant)Objective response

n (%)

Wild-type mutant

A Lièvre et al, (J Clin Oncol 2008)

Cetuximab ± CT 114 (78:36) 34 (44) 0 (0)

S Benvenuti et al, (Cancer Res 2007)

Panitumumab or cetuximab or Cetuximab + CT

48 (32:16) 10 (31) 1 (6)

W DeRoock, E Van Cutsem S Tejpar (Ann Oncol 2008)

Cetuximab or Cetuximab + irinotecan

113 (67:46) 27 (41) 0 (0)

D Finocchiaro et al, (ASCO Proceedings 2007)

Cetuximab ± CT 81 (49:32) 13 (26) 2 (6)

F Di Fiore et al, (Br J Cancer 2007)

Cetuximab + CT 59 (43:16) 12 (28) 0 (0)

S Khambata-Ford et al, (J Clin Oncol 2007)

Cetuximab 80 (50:30) 5 (10) 0 (0)

RG Amado et al, (J Clin Oncol 2008)

Panitumumab 208 (124:84) 21 (17) 0 (0)

First-line cetuximab + FOLFIRI: Correlation of KRAS status with efficacy

First-line treatment: cetuximab (6 weeks monotherapy), followed by cetuximab + FOLFIRI (n=52)

Cetuximab Cetuximab + FOLFIRI

Outcome Wild-type Mutant Wild-type Mutant

RR (CR+PR), % 27.6 0 55.2 31.6

p=0.015 p=0.144

Median PFS, months – – 9.4 5.6

HR=2.12p=0.0475

Tabernero J et al, ASCO GI 2008

Stratification factors

• Regions

• ECOG PS

Populations

• Randomized patients n=1217

• Safety population n=1202

• ITT population n=1198

CRYSTAL trial in first-line mCRC

FOLFIRI

Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus+ 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks

Cetuximab + FOLFIRI

Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus+ 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks

EGFR-expressing metastatic CRC

Van Cutsem E et al, ASCO 2007

R

CRYSTAL trial – Primary endpoint PFSITT population independent review


Pro

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0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

Cetuximab + FOLFIRI (n=599) FOLFIRI (n-599)

0 2 4 6 8 10 12 14 16 18 20

CRYSTAL trial - Secondary endpoint: Response rate (independent assessment - ITT)

aCochran-Mantel-Haenszel (CMH) test

p=0.0038a

FOLFIRI Cetuximab + FOLFIRI

FOLFIRI(n=599)

Cetuximab + FOLFIRI(n=599)

% %

CR 0.3 0.5

PR 38.4 46.4

SD 46.7 37.4

PD 9.0 8.8

RR (CR+PR)

95% CI

38.7

[34.8 – 42.8]

46.9

[42.9 – 51.0]

39

47

0

10

20

30

40

50

60

Res

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KRAS analysis: Objective

Objective

A retrospective analysis investigated the impact on progression-free survival and response rate of the KRAS mutation status of tumors in the first-line treatment of metastatic CRC treated with FOLFIRI ± cetuximab

Relating KRAS status to efficacy

• Efficacy analyses repeated on KRAS evaluable population

• Genomic DNA isolated from archived tumor material

• Paraffin-embedded, formalin-fixed tissue

• KRAS mutation status of codons 12/13 determined using quantitative PCR-based assay

KRAS evaluable population

587 subjects analyzed for KRAS mutation status

540 (45%) subjects: KRAS evaluable population

348 (64.4%) KRAS wild-type 192 (35.6%) KRAS mutant

171 subjects with events (49.1%)

Group A: 105 (54.7%) Group B: 87 (45.3%)

101 subjects with events (52.6%)

1198 subjects (ITT)

Group A: 172 (49.4%) Group B: 176 (50.6%)

FOLFIRICetuximab + FOLFIRI

Patient demographics at baseline according to KRAS status

KRAS populationKRAS wild-type

n=348%

KRAS mutantn=192

%

Age <65 65.8 59.9

Gender, male 57.8 57.8

ECOG PS 0/1 96.6 97.9

Prior adjuvant therapy 21.6 12.5

Involved disease sites 2 85.3 83.3

Liver-limited disease 19.3 21.9

ITT and KRAS evaluable population: Comparability

ITT population (n=1198) HR=0.85

mPFS Cetuximab + FOLFIRI: 8.9 monthsmPFS FOLFIRI: 8.0 months

Pro

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Months

0.5

1.0

0.4

0.3

0.2

0.1

0.6

0.7

0.8

0.9

0.080 2 4 6 10 12 14 16 18 20

KRAS population (n=540) HR=0.82 mPFS Cetuximab + FOLFIRI: 9.2 monthsmPFS FOLFIRI: 8.7 months

0.5

1.0

0.4

0.3

0.2

0.1

0.6

0.7

0.9

0.080 2 4 6 10 12 14 16 18 20

0.8

Months

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Cetuximab + FOLFIRI FOLFIRI

Relating KRAS status to efficacyPrimary endpoint: PFS – KRAS wild-type

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

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0 2 4 6 8 10 12 14 16 18

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KRAS wild-type (n=348) HR=0.68; p=0.017

mPFS Cetuximab + FOLFIRI: 9.9 months mPFS FOLFIRI: 8.7 months

1-year PFS rate25% vs 43%

Relating KRAS status to efficacyPrimary endpoint: PFS – KRAS mutant

KRAS mutant (n=192) HR=1.07; p=0.47

mPFS Cetuximab + FOLFIRI: 7.6 months mPFS FOLFIRI: 8.1 months

0 2 4 6 8 10 12 14 16

Months


0.0

0.1

0.2

0.3

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Relating KRAS status to efficacy: PFS

Cetuximab + FOLFIRI HR=0.63; p=0.007 mPFS wild-type (n=172): 9.9 monthsmPFS mutant (n=105): 7.6 months

FOLFIRI HR=0.97; p=0.87 mPFS wild-type (n=176): 8.7 monthsmPFS mutant (n=87): 8.1 months

0.5

1.0

0.4

0.3

0.2

0.1

0.0

0.6

0.7

0.8

0.9

80 2 4 6 10 16

Pro

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Months

Cetuximab +FOLFIRI wild-type

Cetuximab +FOLFIRI mutant

12 14

0.5

1.0

0.4

0.3

0.2

0.1

0.0

0.6

0.7

0.8

0.9

Months

FOLFIRI wild-type

FOLFIRI mutant

80 2 4 6 10 1612 14

43

59

0

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20

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40

50

60

70

Re

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%)

Relating KRAS status to efficacySecondary endpoint: Response – KRAS wild-type

p=0.0025a



FOLFIRICetuximab +

FOLFIRI

n=176%

n=172%

CR 0 1.2

PR 43.2 58.1

SD 43.8 30.8

PD 9.1 5.2

RR (CR+PR) 43.2 59.3

95% CI [35.8%, 50.9%] [51.6%, 66.7%]

4036

0

10

20

30

40

50

60

70

Re

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%)

Relating KRAS status to efficacySecondary endpoint: Response – KRAS mutant

p=0.46a


FOLFIRICetuximab +

FOLFIRI

n=87%

n=105%

CR 0 0

PR 40.2 36.2

SD 46.0 46.7

PD 8.0 9.5

RR (CR+PR) 40.2 36.2

95% CI [29.9%, 51.3%] [27.0%, 46.2%]


Relating KRAS status to outcome: Treatment exposure

5-FU Irinotecan Cetuximab



Cetuximab+ FOLFIRI

KRASwild-type

(n=176/173)

Median duration of treatment, weeks

28.9 32.0 30.0 32.0 32.0

Relative dose intensity ≥ 80% (%)

96 93 82 76 83

KRASmutant

(n=87/105)

Median duration of treatment, weeks

24.7 26.0 24.0 26.0 25.7

Relative dose intensity ≥ 80% (%)

91 90 78 78 84

KRAS wild-type KRAS mutant

FOLFIRI

n=176%

Cetuximab + FOLFIRI

n=173%

FOLFIRI

n=87%

Cetuximab + FOLFIRI

n=105%

Any 50.6 78.0 55.2 72.4

Neutropenia 16.5 25.4 23.0 21.9

– Febrile neutropenia 0.6 0.6 0 3.8

Diarrhea 9.1 17.3 12.6 13.3

Vomiting 2.8 4.6 6.9 2.9

Fatigue 4.5 2.3 2.3 9.5

Acne-like rasha 0 16.2 0 17.1

Infusion-related reactions 0 1.7 0 3.8

aThere was no grade 4 acne-like rash

Relating KRAS status to outcome:Most common grade 3/4 adverse events

Summary of efficacy data

ITT KRAS wild-type KRAS mutant



FOLFIRI Cetuximab+ FOLFIRI

(n=599) (n=599) (n=176) (n=172) (n=87) (n=105)

RR (%) 39 47 43 59 40 36

p=0.0038a p=0.0025a p=0.46a

mPFS (months) 8.0 8.9 8.7 9.9 8.1 7.6

HR 0.85 0.68 1.07

p=0.048 p=0.017 p=0.75


Res

pons

e ra

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%)

59

37

0

10

20

30

40

50

60

70

CRYSTAL(n=540)

OPUS1

(n=233)

43

61

FOLFIRI FOLFOXCetuximab + FOLFIRI

Cetuximab + FOLF0X

CRYSTAL - KRAS wild-type: HR=0.68

p=0.017

32% risk reductionfor progression

OPUS - KRAS wild-type: HR=0.57

p=0.016

43% risk reductionfor progression

1Bokemeyer C et al, ASCO 2008

0.00.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12 14 16 18

Months

PF

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0.00.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12

Months

PF

S e

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Cetuximab + CT in KRAS wild-type: Data consistency

CRYSTAL trial: Conclusions (1)

• Adding cetuximab to FOLFIRI in mCRC leads to a significant increase in PFS (HR=0.85; p=0.048)

• The benefit of cetuximab + FOLFIRI is greater in patients with KRAS wild-type tumors:

– PFS (HR=0.68; p=0.017)

– Response rate 59% vs. 43% (p=0.0025)

• Patients with KRAS mutant tumors do not benefit from the combination of cetuximab and FOLFIRI

• The grade 3/4 adverse event profile was similar in the KRAS wild-type and mutant populations

CRYSTAL trial: Conclusions (2)

• KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy regimen in first-line mCRC

• Patients with KRAS wild-type tumors have a strong benefit from the combination of cetuximab and FOLFIRI

• Cetuximab in combination with a standard first-line treatment for mCRC patients is an important new option in patients with KRAS wild-type tumors

CRYSTAL trial: Acknowledgements

• The authors would like to thank:

– The patients

– The investigators, co-investigators, and study teams at the 201 centers in 32 countries involved inthis study

– The study team at Merck KGaA, Darmstadt, Germany

Documents

Eric Van Cutsem*