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Background

Cetuximab and chemotherapy in the treatment of patients with initially “ non-resectable” colorectal (CRC) liver metastases – long term follow up of the CELIM trial.

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Background

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  1. 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,1Thomas Gruenberger,2Wolf Bechstein,3Hans-Rudolf Raab,4Jürgen Weitz,1Florian Lordick,5Joerg Thomas Hartmann,6Hauke Lang,7Tanja Trarbach,8Jan Stoehlmacher-Williams,1TorstenLiersch,9DetlevOckert,10Dirk Jaeger,11 Ulrich Steger,12 Thomas Suedhoff,13Claus-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 BarmherzigenBrüder, Trier, Germany, 11National Center of Tumor Diseases, Heidelberg, Germany, 12University Hospital Würzburg, Germany, 13Klinikum Passau, Germany

  2. 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))

  3. Main inclusioncriteria • 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 extrahepaticdisease

  4. Methods I • Endpoints • The primaryendpoint (responserates), theresectionratesandtheresultsofthesurgicalreviewwerepublished in Folprecht et al, Lancet Oncology 2010 • The currentanalysisdescribesthesecondaryendpointsprogressionfreesurvival, diseasefreesurvivalandoverallsurvival • Treatment Cetuximab:400 mg/m², then 250 mg/m² weekly FOLFOX6:oxaliplatin 100 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m² FOLFIRI: irinotecan 180 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²

  5. Patientswith non-resectable CRC livermets.(technically non-resectable / ≥ 5 livermets.)without extra-hepaticmetastases Randomization Cetuximab+FOLFOX 6 Cetuximab+FOLFIRI Stratification: technically non-resectable / ≥ 5 liver metastases, Staging with PET, EGFR IHC Therapy: 8 cycles (~ 4 months) Evaluation of resectability Technically resectable Technically non-resectable 4 additional chemotherapy cycles Resection Biopsy:EGFR screening Therapy continuation for 6 cycles (~ 3 months) EGFR IHC 0 FOLFOX6 Early closed arm Methods II

  6. Response andresection

  7. Overall andprogressionfreesurvival ··· 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] Probability of survival

  8. Survivalaccordingtotreatment 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 B29.0 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=0.4 Probability of survival

  9. Survivalaccordingto k-ras status ··· Progression free survival ▬ Overall survival k-ras wild type k-ras mutant OS k-raswt36.6 mo.[95% CI: 25.3-47.8] k-rasmut27.4 mo. [95% CI: 15.7-39.1] HR 1.41 [0.84-2.34], n.s. PFS k-raswt11.9 mo.[95% CI: 8.2-15.6] k-rasmut 9.9 mo. [95% CI: 4.5-15.2] HR 1.29 [0.82-2.04], n.s. Probability of survival

  10. Survival in k-ras wtpatients, accordingtotreatment 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 B41.6 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. Probability of survival

  11. Survivalaccordingtometastasectomy ··· 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 resected21.9 mo. [95% CI: 17.1-26.7] HR 0.29 [0.17-0.50], p <‍ ‍0.001 PFSR0 resected 15.4 mo.[95% CI: 11.4-19.5] not resected6.9 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%] Probability of survival

  12. 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 Probability of survival

  13. Survivalaccordingtometastasectomyin patientswith 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 Probability of survival

  14. 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.

  15. Wethank…. … all patientsand all investigatorsatthestudysites: • University Hospital Dresden, • Klinikum Oldenburg, • University HospitalVienna, • University Hospital Tübingen, • University HospitalGöttingen, • University HospitalMünchen rechts der Isar, • Krankenhaus der Barmherzigen Brüder Trier, • University Hospital/ NCT Heidelberg, The study was supportedbyMerck KGaA, Sanofi-Aventis and Pfizer • University HospitalWürzburg, • Klinikum Passau, • University HospitalFrankfurt, • Klinikum Celle, • University HospitalEssen, • Klinikum Magdeburg, • Klinikum Aschersleben, • University HospitalMannheim, • Klinikum Essen-Mitte

  16. Supplemental: CELIM: BlindedReview Baseline Follow-up 32% 60%, p<0.01 Folprecht et al, Lancet Oncology 2010

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