Cetuximab and chemotherapy in the

treatment of patients with

initially “non-resectable”

colorectal (CRC) liver metastases –

long term follow up of the CELIM trial

Gunnar Folprecht,1 Thomas Gruenberger,2 Wolf Bechstein,3 Hans-Rudolf Raab,4

Jürgen Weitz,1 Florian Lordick,5 Joerg Thomas Hartmann,6 Hauke Lang,7 Tanja Trarbach,8 Jan

Stoehlmacher-Williams,1 Torsten Liersch,9 Detlev Ockert,10 Dirk Jaeger,11 Ulrich Steger,12

Thomas Suedhoff,13 Claus-Henning Köhne4

1University Hospital Carl Gustav Carus, Dresden, Germany, 2University Vienna, Vienna, Austria, 3University Hospital Frankfurt, Germany, 4Klinikum Oldenburg, Germany, 5University Cancer Center Leipzig, Germany, 6University Kiel, Germany, 7University Hospital Mainz,

Germany, 8 West German Cancer Center, Essen, Germany, 9University Hospital Göttingen, Germany, 10Krankenhaus der Barmherzigen Brüder, Trier, Germany, 11National Center of Tumor Diseases,

Heidelberg, Germany, 12University Hospital Würzburg, Germany, 13Klinikum Passau, Germany

Background

• Resection of liver metastases provides favorable long-term survival (Adam Ann Surg 2004)

• Resectability of colorectal liver metastases depends on technical resectability and prognostic factors

• Number of liver metastases is an important prognostic factor and pts with > 4 metastases were excluded from a neoadjuvant trial for resectable liver metastases (Nordlinger, Lancet 2007)

• In primarily non-resectable liver metastases, resection rate correlates with response to chemotherapy

• Cetuximab increases response rates and deepness of response when added to FOLFIRI or FOLFOX (Van Cutsem JCO 2011, Bokemeyer Ann Oncol 2011, Mansmann 2013 (ASCO abstr 3630))

Main inclusion criteria

Patients with non-resectable colorectal liver metastases

Definition of non-resectability:– ≥ 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)

Expected resectability after response to chemotherapy was not an inclusion criterion

No extrahepatic disease

Methods I

Endpoints

The primary endpoint (response rates), the resection rates and the results of the surgical review were published in Folprecht et al, Lancet Oncology 2010

The current analysis describes the secondary endpoints progression free survival, disease free survival and overall survival

TreatmentCetuximab: 400 mg/m², then 250 mg/m² weeklyFOLFOX6: oxaliplatin 100 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²FOLFIRI: irinotecan 180 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²

Technically non-resectable

Cetuximab+FOLFOX 6 Cetuximab+FOLFIRIStratification: technically non-resectable / ≥ 5 liver metastases,

Staging with PET, EGFR IHC

Patients with non-resectable CRC liver mets.(technically non-resectable / ≥ 5 liver mets.)without extra-hepatic metastases

Randomization

Biopsy: EGFR screening

Therapy: 8 cycles (~ 4 months)

Technically resectable

Resection

Therapy continuation for 6 cycles (~ 3 months)

Evaluation of resectability

4 additional chemotherapy cycles

FOLFOX6

Early closed arm

EGFR IHC 0

Methods II

  FOLFOX FOLFIRI All

  cetuximab cetuximab patients

n=53 n=53 n=106

CR/PR 68% 57% 62%

95% CI 54-80% 42-70% 52-72%

R0 resections 38% 30% 34%

R0 / R1 resect. / RFA 49% 43% 46%

  KRAS wild-type KRAS mutant

n=67 n=27

CR/PR 70% 41%

95% CI 58-81% 22-61%

Response and resection

Overall and progression free survival

··· Progression free survival

▬ Overall survival

All randomized patients

95% CI interval

OS median 35.7 mo. [95% CI: 27.2-44.2]3 year 48.3 % [95% CI: 38.9-57.7] 5 year 27.5 % [95% CI: 18.7-36.3]

PFS median 10.8 mo. [95% CI: 9.3-12.2] 3 year 5.7% [95% CI: 1.4-10.0]

Pro

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Survival according to treatment arm

··· Progression free survival

▬ Overall survival

Arm A (FOLFOX/Cetuximab)

Arm B (FOLFIRI/Cetuximab)

OS Arm A 35.8 mo. [95% CI: 28.1-43.6]Arm B 29.0 mo. [95% CI: 16.0-41.9]

HR 1.03 [0.66-1.61], p=0.9

PFS Arm A 11.2 mo. [95% CI: 7.2-15.3] Arm B 10.5 mo. [95% CI: 8.9-12.2]

HR 1.18 [0.79-1.74], p=0.4Pro

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of

surv

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Survival according to k-ras status

··· Progression free survival

▬ Overall survival

k-ras wild type

k-ras mutant

OS k-ras wt 36.6 mo. [95% CI: 25.3-47.8]k-ras mut 27.4 mo. [95% CI: 15.7-39.1]

HR 1.41 [0.84-2.34], n.s.

PFS k-ras wt 11.9 mo. [95% CI: 8.2-15.6] k-ras mut 9.9 mo. [95% CI: 4.5-15.2]

HR 1.29 [0.82-2.04], n.s. Pro

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Survival in k-ras wt patients, according to treatment arm

··· Progression free survival

▬ Overall survival

Arm A, k-ras wild type

Arm B, k-ras wild type

OS Arm A 36.1 mo. [95% CI: 21.1-51.1] Arm B 41.6 mo. [95% CI: 22.6-60.6]

HR 0.86 [0.48-1.53], n.s.

PFS Arm A 12.1 mo. [95% CI: 5.2-19.1] Arm B 11.5 mo. [95% CI: 8.8-14.1]

HR 1.13 [0.69-1.85], n.s. Pro

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Survival according to metastasectomy

··· Progression free survival

▬ Overall survival

R0 resected patients

R1 resection / ablation

Not resected patients

 OS R0 resected 53.9 mo. [95% CI: 35.9-71.9]

not resected 21.9 mo. [95% CI: 17.1-26.7] HR 0.29 [0.17-0.50], p <‍ 0.001

PFS R0 resected 15.4 mo. [95% CI: 11.4-19.5] not resected 6.9 mo. [95% CI: 5.9-8.0]

HR 0.31 [0.19-0.50]p <‍ 0.001

5 year survival in R0 resected patients: 46.2% [95% CI: 29.5-62.9%]

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DFS after R0 resection

··· Disease free survival after resection

All patients

< 5 metastases

5-10 metastases

> 10 metastases

 DFS 9.9 [95% CI: 5.8-14.0] months

Comparison between groups:p <‍ 0.001

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Survival according to metastasectomyin patients with PR/CR

▬ Overall survival in patients with PR/CR and

R0 resection

R1 resection / ablation

Without resection

R0 resection vs. no resection:HR 0.42 [95% CI: 0.21-0.86], p=0.021

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Summary / conclusions

• Patients in this multidisciplinary study were treated

• with an effective systemic therapy and

• in a consequent multidisciplinary approach.

• In the ITT population, the median OS was 35.7 months,

the 5 year survival rate 27.5%.

• The 5 year survival rate of R0 resected patients after cetuximab based

“conversional” therapy was 46.2%.

• Resection had a significant influence on overall survival

in all patients and in patients responding to treatment.

• The influence of number of metastatic lesions on the prognosis was confirmed.

• A difference between the treatment arms was not detected in a direct

comparison.

Due to small sample size, differences cannot be excluded

• The known predictive value of k-ras mutations on OS/PFS could not be

confirmed with the current patient number in contrast to other trials, which have

shown a higher efficacy of cetuximab in k-ras wild type patients.

We thank….

… all patients and all investigators at the study sites:

• University Hospital Dresden, • Klinikum Oldenburg, • University Hospital Vienna, • University Hospital Tübingen, • University Hospital Göttingen, • University Hospital

München rechts der Isar, • Krankenhaus der Barmherzigen

Brüder Trier, • University Hospital / NCT Heidelberg,

The study was supported by Merck KGaA, Sanofi-Aventis and Pfizer

• University Hospital Würzburg, • Klinikum Passau, • University Hospital Frankfurt, • Klinikum Celle, • University Hospital Essen, • Klinikum Magdeburg, • Klinikum Aschersleben, • University Hospital Mannheim, • Klinikum Essen-Mitte

Supplemental: CELIM: Blinded Review

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non-resectable

chemo preferred

resectable

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non-resectable

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60%, p<0.0132%

Baseline Follow-up

Folprecht et al, Lancet Oncology 2010