KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience

Carsten Bokemeyer*

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

*Universitätsklinikum EppendorfHamburg, Germany

ASCO disclosure information

• Yes, I have honoraria to disclose

Merck KGaA

• Yes, I have research funding to disclose

Merck KGaA

Epidermal growth factor receptor (EGFR) and KRAS

Cetuximab

• When KRAS geneis mutated, KRAS protein (p21 ras) is active regardless of EGFR activation

• KRAS gene mutations are an early event and are found in 40–45% of CRC patients

• KRAS mutations are generally associated with a poor prognosis

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

EGFR inhibitors in chemorefractory mCRCReference Treatment No. of patients

(% mutant)Objective response

n (%)

Wild-type Mutant

A Lièvre et al, J Clin Oncol 2008

Cetuximab ± CT 114 (32) 34 (44) 0 (0)

S Benvenuti et al, Cancer Res 2007

Panitumumab or cetuximab or Cetuximab + CT

48 (33) 10 (31) 1 (6)

W DeRoock et al,Ann Oncol 2008

Cetuximab or Cetuximab + irinotecan

113 (41) 27 (41) 0 (0)

D Finocchiaro et al, ASCO Proceedings 2007

Cetuximab ± CT 81 (40) 13 (26) 2 (6)

F Di Fiore et al, Br J Cancer 2007

Cetuximab + CT 59 (27) 12 (28) 0 (0)

S Khambata-Ford et al, J Clin Oncol 2007

Cetuximab 80 (38) 5 (10) 0 (0)

RG Amado et al, J Clin Oncol 2008

Panitumumab 208 (40) 21 (17) 0 (0)

OPUS KRAS analysis: Objectives

Objective

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

OPUS: Study design

Primary endpoint

• Overall confirmed response rate (as assessed by independent review)

Secondary endpoints

• PFS time

• OS time

• Rate of curative surgery for metastases

• Safety

Cetuximab + FOLFOX4

400 mg/m2 initial IV infusion (day 1)

then 250 mg/m2 weekly+ oxaliplatin 85 mg/m2 + 5-FU/FA

every 2 weeks

FOLFOX4

Oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks

EGFR-detectablemCRC

Stratification by:

ECOG PS 0/1, 2

R

OPUS: Efficacy results

Outcome FOLFOX(n=169)

Cetuximab + FOLFOX(n=168)

p-value

RR, (%)ITT population

35.7 45.6 0.063a

RR, (%)ECOG PS 0/1

36.8 49.0 0.032a

Median PFS time, (months)

7.2 7.2

Hazard ratio for PFS 0.93 0.62

Bokemeyer C et al, ECCO 2007

aCochran-Mantel-Haenszel (CMH) test

Relating KRAS status to efficacy Methodology

• Efficacy analyses repeated to evaluate the influence of KRAS status on outcomes in OPUS patients

• 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

337 subjects (ITT)

233 subjects: KRAS evaluable population

134 (58%) KRAS wild-type 99 (42%) KRAS mutant

Group A: 61 (46%)

Group B 73 (54%)

Group A52 (53%)

Group B 47 (47%)

FOLFOXCetuximab + FOLFOX

Patient demographics at baseline

KRAS evaluable populationKRAS wild-type

(n=134)%

KRAS mutant(n=99)

%

Age <65 63.4 62.6

Gender, male 55.2 49.5

ECOG PS 0/1 88.8 90.9

Prior adjuvant therapy 18.7 17.2

Involved disease sites 2 77.6 77.8

Liver-limited disease 28.4 25.3

ITT and KRAS evaluable population: Comparability

FOLFOX

Cetuximab + FOLFOX

Months

KRAS population (n=233) HR=0.93; p=0.6609 mPFS Cetuximab + FOLFOX: 7.3 months mPFS FOLFOX: 7.2 months

Months

0.0

0.5

1.0

0.4

0.3

0.2

0.1

0.6

0.7

0.8

0.9

80 2 4 6 10 12

ITT population (n=337) HR=0.93; p=0.6170 mPFS Cetuximab + FOLFOX: 7.2 months mPFS FOLFOX: 7.2 months

80 2 4 6 10 12

0.5

1.0

0.9

0.8

0.7

0.6

0.4

0.3

0.2

0.1

0.0Pro

gre

ssio

n-f

ree

surv

ival

es

tim

ate

Relating KRAS status to efficacy Primary endpoint: Response – KRAS wild-type

FOLFOX (n=73)

%

Cetuximab + FOLFOX

(n=61)%

CR 1.4 3.3

PR 35.6 57.4

SD 41.1 31.1

PD 16.4 4.9

NE 5.5 3.3

RR 37.0 60.7

95% CI 26.0–49.1 47.3–72.9

p=0.011Odds ratio=2.544

(95% CI: 1.238–5.227)

0

10

20

30

40

50

60

70

Res

po

nse

rat

e (%

)

Cetuximab +FOLFOX

FOLFOX

37

61

Relating KRAS status to efficacy Primary endpoint: Response – KRAS mutant

FOLFOX

49

33

Cetuximab +FOLFOX

FOLFOX (n=47)

%

Cetuximab + FOLFOX

(n=52)%

CR 4.3 0

PR 44.7 32.7

SD 36.2 51.9

PD 10.6 13.5

NE 4.3 1.9

RR 48.9 32.7

95% CI 34.1–63.9 20.3–47.1

Res

po

nse

rat

e (%

)

0

10

20

30

40

50

60

70

p=0.106Odds ratio=0.507

(95% CI: 0.223–1.150)

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

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 12

Months

KRAS wild-type: HR=0.57; p=0.016 mPFS Cetuximab + FOLFOX: 7.7 monthsmPFS FOLFOX: 7.2 months

FOLFOX

Cetuximab + FOLFOX

Pro

gre

ssio

n-f

ree

surv

ival

es

tim

ate

Relating KRAS status to efficacySecondary endpoint: PFS – KRAS mutant

KRAS mutant HR=1.83; p=0.0192 mPFS Cetuximab + FOLFOX: 5.5 monthsmPFS FOLFOX: 8.6 months

FOLFOX

Cetuximab + FOLFOX

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 12

Months

Pro

gre

ssio

n-f

ree

surv

ival

es

tim

ate

Relating KRAS status to efficacyProgression-free survival

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 12

Pro

gre

ssio

n-f

ree

surv

ival

es

tim

ate

Months

Cetuximab +FOLFOX wild-type

Cetuximab +FOLFOX mutant

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 12

Months

FOLFOX wild-type

FOLFOX mutant

Cetuximab + FOLFOX HR=0.448; p=0.0009 mPFS Cet + FOLFOX wild-type (n=61): 5.5 monthsmPFS Cet + FOLFOX mutant (n=52): 7.7 months

FOLFOX HR=1.404; p=0.1655 mPFS FOLFOX wild-type (n=73): 7.2 monthsmPFS FOLFOX mutant (n=47): 8.6 months

Relating KRAS status to efficacy Treatment exposure

5-FU Oxaliplatin Cetuximab

FOLFOXalone

Cetuximab + FOLFOX

FOLFOX alone

Cetuximab + FOLFOX

Cetuximab + FOLFOX

KRAS wild-type(n=73/61)

Median duration of treatment, weeks 24.0 24.1 24.0 24.1 25.1

Relative dose intensity ≥80%, % 73 67 82 72 80

KRAS mutant(n=47/52)

Median duration of treatment, weeks 24.0 20.0 24.0 20.5 18.0

Relative dose intensity ≥80%, % 70 64 79 75 92

KRAS wild-type KRAS mutantFOLFOX

n=73 (%)

Cetuximab+ FOLFOXn=61 (%)

FOLFOX

n=47 (%)

Cetuximab+ FOLFOXn=52 (%)

Any 63.0 83.6 78.7 67.3

Neutropenia 32.9 41.0 44.7 25.0

– Febrile neutropenia 1.4 0 4.3 0

Diarrhea 5.5 11.5 12.8 5.8

Peripheral sensory neuropathy

8.2 4.9 2.1 3.8

Acne-like rasha 0 14.8 0 11.5

Infusion-related reactions

0 1.4 0 7.7

Relating KRAS status to efficacyMost common grade 3/4 AEs

aThere was no grade 4 acne-like rash

OPUS trial: Conclusions

• In patients with KRAS wild-type tumors, addition of cetuximab to FOLFOX resulted in a significant and relevant improvement in:

– Response rate (61% vs. 37%; p=0.011)

– Progression-free survival (HR=0.57; p=0.016)

• In patients with KRAS mutant tumors, the addition of cetuximab to FOLFOX had no apparent benefit

• The safety profiles of cetuximab and chemotherapy were generally comparable and consistent with their known safety profiles

Acknowledgements

• The authors would like to thank:

– The patients

– The investigators, co-investigators, and study teams at the 87 centers in 13 countries involved in this study

– The study team at Merck KGaA, Darmstadt, Germany