Survival with cetuximab / FOLFOX or cetuximab / FOLFIRI of patients with nonresectable colorectal

liver metastases in the CELIM study

Gunnar Folprecht,1 Thomas Gruenberger,2 Wolf Bechstein,3

Florian Lordick,4* Hauke Lang,5 Juergen Weitz,6 Thomas Suedhoff,7 Joerg T Hartmann,8* Torsten Liersch,9 Claus-Henning Koehne10

1University Hospital Carl Gustav Carus, Dresden, Germany, 2University Hospital Vienna, Austria3University Hospital Frankfurt, Germany, 4Klinikum Braunschweig, Germany,

5University Hospital Mainz, Germany, 6University Hospital Heidelberg, Germany, 7Klinikum Passau, Germany,

8University Hospital Kiel, Germany, 9University Hospital Goettingen, Germany, 10 Klinikum Oldenburg, Germany*current institution of the author

149

Background

• CELIM study enrolled patients with non-resectable liver metastases– ≥ 5 liver metastases and/or– liver metastases that are technically non-resectable

defined by local surgeon in cooperation with local radiologist (amount of functional liver tissue remaining, infiltration of non-resectable structures)

• R0 resection in 34% of all patients

• Response rates of 70% in k-ras wild type patients

• An independent surgical review confirmed that resectability based on CT/MRI images (without clinical data) improved

• Current presentation shows survival follow up of June, 2011

Patients with non-resectable colorectal liver metastases(technically non-resectable / ≥ 5 liver metastases)

without extrahepatic disease

Biopsy: EGFR screening

Randomization

FOLFOX6 + cetuximab FOLFIRI + cetuximab

Primary endpoint: Response

Therapy: 8 cycles (~ 4 months)

Evaluation of resectability

Technically non-resectable

4 additional therapy cycles

Technically resectable

Resection

Therapy continuation for 6 cycles (~ 3 months)

Folprecht et al, Lancet Oncology 2010

FOLFOX6

EGFR IHC non-detected

closed early, patients

were randomized to cetuximab arms

Response and resection rates

  All FOLFOX6 + FOLFIRI + K-ras K-ras

  pts cetuximab cetuximab wild-type mutant

n=106 n=53 n=53 n=67 n=27

CR/PR 62% 68% 57% 70% 41%

95% CI 52-72% 54-80% 42-70% 58-81% 22-61%

R0 resections 34% 38% 30% 33% 30%

95% CI 25-44% 25-52% 18-44% 22-45% 14-50%

Folprecht et al, Lancet Oncology 2010

Overall survival by treatment arms

0 12 24 36 48 60

Overall survival in months

all patients (%) 100 90 62 47 28Pts at risk 109 98 67 45 14

Median overall survival in all patients: 33.1 months (95% CI: 25.8-40.4).

N Median

— FOLFOX/Cet 54 35.7(29.9-41.6)

— FOLFIRI/Cet 55 29.0(18.1-39.8)

HR 1.09 (0.69-1.72)

100%

80%

60%

40%

20%

0%

Progression free survival

0 12 24 36 48 60

Progression free survival in months

all patients (%) 100 43 15 6%Pts at risk 106 45 16 5

Median progresison free survival in all patients: 10.8 months (95% CI: 9.3-12.2).

100%

80%

60%

40%

20%

0%

N Median

— FOLFOX/Cet 53 11.2(7.2-15.3)

— FOLFIRI/Cet 53 10.5(8.9-12.2)

HR 1.15 (0.77-1.70)

N Median

— K-ras wild type 69 36.1(24.4-47.8)

— K-ras mutant 28 27.4(15.7-39.1)

HR 1.48 (0.88-2.48)

N Median

— K-ras wild type 67 11.9(8.25-15.6)

— K-ras mutant 27 9.9(4.5-15.2)

HR 1.31 (0.83-2.07)100%

80%

60%

40%

20%

0%

100%

80%

60%

40%

20%

0%

0 12 24 36 48 60

months

0 12 24 36 48 60

months

Overall survivalProgression free survival

Survival by k-ras status

Survivial in the k-ras wild type subset

N Median

— FOLFOX/Cet 34 35.8(30.2-41.4)

— FOLFIRI/Cet 35 41.6(24.8-58.5)

HR 1.01 (0.55-1.86)

N Median

— FOLFOX/Cet 33 12.1(5.2-19.1)

— FOLFIRI/Cet 34 11.5(8.8-14.1)

HR 1.09 (0.66-1.79)

Overall survivalProgression free survival

100%

80%

60%

40%

20%

0%

100%

80%

60%

40%

20%

0%

0 12 24 36 48 60

months

0 12 24 36 48 60

months

Survival and R0 resection

— R0 resected

— Not R0 resected

HR 2.07 (1.35-3.16)

p=0.001

Overall survivalProgression free survival100%

80%

60%

40%

20%

0%

100%

80%

60%

40%

20%

0%

0 12 24 36 48 60 0 12 24 36 48 60

100 89 78 64 49%

100 91 54 37 16%100 91 82 59 46%

100 89 62 47 22%

R0 resected, N=36

not R0 resected, N=70R0 resected (k-ras wt subset, N=22)

not R0 resected (k-ras wt subset, N=45)

HR 2.34 (1.37-4.01)

p=0.002

— R0 resected

— Not R0 resected

Median OS: 46.795%CI: 30.7-62.7

Median OS: 27.395%CI: 21.2-33.3

Median PFS: 15.495%CI: 11.4-19.5

Median PFS: 8.995%CI: 6.7-11.0

Disease free survival after R0 resection

All R0 resected pts.

N Median

DFS 36 9.9 mo.(5.8-14.0)

By number of metastases

at randomization

N Median

< 5 met. 11 16.8

5-10 met. 22 8.2

>10 met. 3 2.5

p<0.001

100%

80%

60%

40%

20%

0%

100%

80%

60%

40%

20%

0%

0 12 24 36 48 60

months

0 12 24 36 48 60

monthsDFS 100 47 19 8%k-ras wt 100 50 18 5%

subset

median DFS in k-ras wt pts: 11.5 mo. DFS was measured from resection to recurrence or death

CELIM: Blinded surgical review

100%

50%

0%

50%

100%| | | | | | | - | - | | | | | - - | - - | | | - | | | | | | - - -

Patient

rese

ctab

le

non

- res

ecta

ble

non-resectable

chemo preferred

resectable

exploration

100%

50%

0%

50%

100%| | | - | | | | - | | - | | | - | | - | | - - | | - | | | - - | | -

Patient

rese

ctab

le

non

- res

ecta

ble

non-resectable

chemo preferred

resectable

exploration

60%, p<0.0132%

Baseline Follow-up

Folprecht et al, Lancet Oncology 2010

As defined in the inclusion criteria, all patients were initially technically non-resectable and/or had ≥ 5 metastases.

CT/MRI images of patients were retrospectively reviewed by a group of surgeons who were blinded to all clinical data and to the imaging time (before / after treatment). Surgeons voted for non-resectable (red), borderline resectable with chemotherapy preferred first (yellow) and resectable/exploratory laparotomy with aim of resection (green/light green).

Survival by surgical review

„non-resectable“ (N=53)

„resectable“ (N=22)

Imaging at baseline After chemotherapy

and cetuximab

100%

80%

60%

40%

20%

0%

100%

80%

60%

40%

20%

0%

0 12 24 36 48 60 0 12 24 36 48 60

monthsAs inclusion criteria, all patients were technically non-resectable and/or had ≥ 5 metastases.

Surgical review based on CT/MRI images only (without any clinical information).

HR 0.81

(0.44-1.50)

p=0.5

„non-resectable“ (N=34)

„resectable“ (N=41)

HR 0.47

(0.27-0.83)

p=0.007

• Multidisciplinary treatment including cetuximab plus FOLFOX6 or FOLFIRI resulted in a median overall survival of 33.1 months and a 4-year OS-rate of 28%

• Patient with R0 resection lived significantly longer than patients with medical treatment alone (HR 2.34 [1.37-4.01] p=0.002).

• In R0 resected patients, 3-year- and 4-year- OS-rates are 64% and 49%.

• Cetuximab/FOLFOX and cetuximab/FOLFIRI showed similar progression-free and overall survival

• With cetuximab plus FOLFOX or FOLFIRI, k-ras wild type had by numbers a longer OS and PFS compared to k-ras mutant patients

• Despite favorable long term survival, median DFS after R0-resection of ~ 10 months demonstrates the need for multidisciplinary cooperation and patient selection, especially in patients with high number of metastases

• Resectability after treatment with cetuximab and FOLFOX or FOLFIRI but not at baseline was associated with longer survival(based on independent surgical review of CT/MRI images without clinical data)

Summary and Conclusions

We thank...

• All patients and their relatives

• All investigators at the study sites University Hospital Dresden Klinikum Oldenburg University Hospital Vienna University Hospital Tübingen University Hospital Göttingen University Hospital Munich Rechts der IsarKlinikum Passau Krankenhaus der Barmherzigen Brüder TrierUniversity Hospital / NCT Heidelberg University Hospital Würzburg University Hospital Frankfurt Klinikum CelleUniversity Hospital Essen Klinikum Magdeburg University Hospital Mannheim Klinikum AscherslebenKlinikum Essen-Mitte

• The companies which supported this studyMerck KGaA, Sanofi-Aventis, and Pfizer