Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) in the first-line treatment of mCRC: OPUS, a phase II study

*Carsten Bokemeyer , Elzbieta Staroslawska, Marek Nowacki, Irina Mitashok, Elena Kuznetsova, Paolo Cortes, Carlos Garcia Girón, Oksana Tarasova, Angela Zubel, Yaroslav Shparyk

*University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

OPUS OPUS study design

Cetuximab + FOLFOX-4

400 mg/m2 initial IV infusion (day 1)then 250 mg/m2 weekly+ oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks

FOLFOX-4

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

EGFR-expressing metastatic CRC

Stratification factors: ECOG PS 0-1, 2

R

Treatment until progression, symptomatic deterioration or unacceptable toxicity

OPUS Best overall confirmed responses

(IRC)

FOLFOX-4

(n=168)

Cetuximab +

FOLFOX-4 (n=169)

CR 0.6% 1.2%

PR 35.1% 44.4%

* Cochran-Mantel-Haenszel (CMH) test

Odds ratio = 1.516, p=0.064*

35.7

81.0

45.6

85.2

0

10

20

30

40

50

60

70

80

90

ORR DCR

perc

enta

ge p

atie

nts,

%

FOLFOX-4 Cetuximab + FOLFOX-4

OPUS Efficacy: response rate all

patients and ECOG 0-1 stratum

Response rate, % Cetuximab + FOLFOX-4

FOLFOX-4

All 45.6

(n=169)

35.7

(n=168)

ECOG 0-1* 49.0

(n=153)

36.8

(n=152)

* p=0.032**, Odds ratio: 1.648 [95% CI:1.043, 2.604]

**Cochran-Mantel-Haenszel (CMH) test

OPUS

OR [95% CI]

Favors FOLFOXFavors Cetuximab + FOLFOX

Subgroup (number of patients)

Efficacy by subgroups

2.00 [1.02, 3.93]1 (74 vs 69)One metastatic site

2.11 [0.88, 5.07]Liver metastasis only

Yes (50 vs 39)

≤10 000 / mm3 (124 vs 131)Leucocytes 2.00 [1.19, 3.35]

2.07 [1.03, 4.14]>upper normal limit (82 vs 63)LDH

Alkaline phosphatase

<300 U/L (128 vs 128) 2.04 [1.22, 3.42]

1.82 [1.03, 3.21]

1.14 [0.57, 2.31]

<65 years (96 vs 109)

≥65 years (73 vs 59)

Age

2.29 [1.18, 4.46]

1.12 [0.61, 2.04]

Western Europe (72 vs 75)

Eastern Europe (97 vs 93)

Region

All ITT subjects (n= 169 vs 168)

0.1110 25

ECOG 0/1 1.648 [1.043, 2.604]

1.516 [0.97, 2.35]

OPUS Association between skin reactions

and response rate

13

66.7

53.2

42.2

0

10

20

30

40

50

60

70

80

Grade 0 Grade 1 Grade 2 Grade 3-4*

Ove

rall

resp

on

se r

ate

(%)

Cetuximab + FOLFOX-4, n=168 (IRC data)

n=23 n=59 n=62 n=24

Maximum skin reactions during first 21 days of treatment

*There were no grade 4 skin reactions

OPUS Safety in treated patientsSafety population

n=338

Cetuximab + FOLFOX-4

n= 170, %

FOLFOX-4

n= 168, %

Any grade 3/4 AE in 3 subjects

Neutropenia 27.6 31.5

Diarrhea 7.1 6.0

Leucopenia 7.1 5.4

Fatigue

Neurotoxicity †

3.5

3.5

3.0

6.0

Cetuximab related grade 3/4 toxicity

Skin reactions* 14.1** 0

Infusion-related reactions*

Hypomagnesemia

4.1

2.0

1.8

0

Treatment-related deaths

Cetuximab

Chemotherapy

0

0.6

-

0.6†Includes peripheral sensory neuropathy and neuropathy.*Special AE category **There were no grade 4 skin reactions or acne-like rash

OPUS Conclusions

The addition of cetuximab to FOLFOX-4 increased the RR of FOLFOX-4 by approximately 10% (45.6% vs 35.7%). There was an approximately 50% higher chance of achieving a CR or PR for those patients receiving cetuximab plus FOLFOX-4 (OR = 1.52)

Patients with baseline ECOG PS 0-1 had a statistically significant higher (65%; OR = 1.65) chance for response (49.0% vs 36.8%)

Analysis of prognostic factors for response uniformly showed an increased chance of a response by 50 to >100% in most subgroups under cetuximab plus FOLFOX-4 compared to FOLFOX-4 alone

Cetuximab in combination with FOLFOX - 4 was generally well-tolerated