Essentials of Oncology

1
Randomized multicenter study of cetuximab plus
FOLFOX or cetuximab plus FOLFIRI in neoadjuvant
treatment of non-resectable colorectal liver
metastases (CELIM study)
G. Folprecht1, T. Gruenberger2, J.T. Hartmann3,
F. Lordick4, J. Stoehlmacher1, W. Bechstein5, D.
Ockert6, T. Herrmann4, T. Liersch7, C.-H. Köhne8
1University Hospital Carl Gustav Carus, Dresden,
Germany, 2University Hospital Vienna, Austria,
3University Hospital Tübingen, Germany, 4National
Center for Tumor Diseases, Heidelberg, Germany,
5University Hospital Frankfurt, Germany,
6Krankenhaus der Barmherzigen Brüder, Trier,
Germany, 7University Hospital Goettingen,
Germany, 8Klinikum Oldenburg, Oldenburg, Germany
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Abstract

• BACKGROUND
• Resectability of colorectal liver metastases
  (mets) can be induced by an effective
  chemotherapy regimen. Combinations of cetuximab
  with FOLFIRI or FOLFOX have been shown to
  increase response and resection rates.
• METHODS
• Patients (pts) with non-resectable liver mets
  were randomized to receive FOLFOX6 or FOLFIRI
  plus cetuximab in this multicenter, randomized
  phase II study. Pts were stratified according to
  the reason for non-resectability (technically
  non-resectable vs. 5 liver mets), the use of
  PET scans at initial staging, and EGFR status.
  Preoperative treatment was planned for 8 cycles.
  In case of persistent non-resectability,
  multidisciplinary evaluation was planned every 4
  cycles.
• RESULTS
• From December 2004 to March 2008, 124 pts were
  screened for the study. 111 pts were randomized
  to receive FOLFOX plus cetuximab (56 pts) or
  FOLFIRI plus cetuximab (55 pts). Median age was
  63 years. Out of the 111 pts, 60 pts (54) were
  judged as technically non-resectable, 20 pts
  (18) were staged with PET, and 81 pts (73) were
  EGFR detectable.
• At the interim analysis in March 2008, response
  and resection data were available from 81 pts.
  Best response was 75.3 (61/81 pts, 95CI
  64.5-84.2, combined analysis for both arms) and
  confirmed response was 59.3 (48/81 pts, 95 CI
  47.7-70.0). KRAS status was available for 86
  pts best response rate in KRAS wild-type pts was
  85.4 (41/48 pts, 95CI 72.2-93.9), and 50
  (7/14 pts) in KRAS mutant pts. Sixteen resections
  were performed in pts with 5 liver mets, 18
  resections in technically non-resectable pts. In
  total, 34/81 pts were resected (42.0, 95CI
  31.1-53.5), 29 with microscopically free margins
  (R0).
• Interim data on toxicity of 98 pts demonstrated
  acne-like rash (32), neutropenia (20), diarrhea
  (15), allergic reaction (6), and neurologic
  toxicity (5) to be the most common preoperative
  grade 3 toxicities in both arms. One patient had
  a fatal pulmonary embolism (2.9).
• CONCLUSION
• In the interim analysis, the combination of
  cetuximab with standard chemotherapy has
  demonstrated high activity and an encouraging
  rate of liver resection.
• Mature resection and response data per treatment
  arm and KRAS status will be reported at the
  meeting.

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Background

• Resection of liver metastases provides favorable
  long-term survival (Adam Ann Surg 2004)
• Resectability of colorectal liver metastases
  depends on - technical resectability-
  prognostic factors
• Number of liver metastases is regarded as an
  important prognostic factor and is an exclusion
  criterion in neoadjuvant trials for resectable
  liver metastases
  (Nordlinger, Lancet 2007)
• Standard systemic chemotherapy regimens for
  colorectal cancer include FOLFOX and FOLFIRI
• For both regimens, high response rates were
  reported in phase II studies and more recently
  in randomized trials such as CRYSTAL (Van
  Cutsem ASCO 2008) and OPUS (Bokemeyer ASCO 2008)
• Multi-institutional randomized trials
  investigating patients with isolated liver
  metastases are lacking

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Patient selection

• Patients with non-resectable, histologically
  confirmed colorectal liver metastases
• Definition of non-resectability
• 5 liver metastases and/or
• liver metastases that are technically
  non-resectable (local surgeon in cooperation with
  local radiologist defined non-resectability based
  on the amount of functional liver tissue
  remaining, infiltration of all liver veins, and
  infiltration of both hepatic arteries, both
  portal branches, or both bile ducts)
• Patients with simultaneous liver metastases were
  eligible if the primary tumor was resected 1
  month prior to chemotherapy.
• (Expected resectability after response to
  chemotherapy was NOT an inclusion criterion)
• No extrahepatic disease
• Karnofsky PS 80 and adequate hepatic, renal,
  and bone marrow function
• No prior chemotherapy (except adjuvant
  chemotherapy 6 months ago) no concurrent
  immunotherapy, chemotherapy or hormone therapy
  no previous malignancy other than colorectal
  cancer, basal cell carcinoma, or pre-invasive
  carcinoma of the cervix no inflammatory bowel
  disease no relevant coronary heart disease
• Informed consent

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Methods

• Patients were randomized to1) FOLFOX6
  (oxaliplatin 100 mg/m², 5-FU 400 mg/m² bol,
  5-FU 2400 mg/m², FA 400 mg/m²) plus
  cetuximab (400 mg/m², then 250 mg/m²)2) FOLFIRI
  (irinotecan 180 mg/m², 5-FU 400 mg/m² bol, 5-FU
  2400 mg/m², FA 400 mg/m²) plus cetuximab
  (400 mg/m², then 250 mg/m²)3) FOLFOX6 (patients
  with negative immunohistochemistry for EGFR)
  This arm was closed after the third patient and
  all subsequent patients were randomized to
  arm (1) or (2)
• Patients were evaluated for response every fourth
  cycle (every 8 weeks)
• Resection was planned in case of resectability
  after 8 cycles If patients were non-resectable,
  resectability was further evaluated with each CT
  scan
• Patients were regarded to have a confirmed
  response if confirmed according to RECIST or if
  the confirmation CT scan was not performed
  because the patient underwent resection
• Central surgical review is being performed (data
  not yet available)

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Patients with non-resectable colorectal liver
metastases(technically non-resectable / 5
liver metastases)without extrahepatic metastases
Biopsy EGFR screening
Randomization
FOLFOX6 cetuximab FOLFIRI cetuximab
Therapy 8 cycles ( 4 months)
Evaluation of resectability
Technically resectable
Technically non-resectable
4 additional CTX cycles
Resection
Therapy continuation for 6 cycles ( 3 months)
Primary endpoint Response
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Enrollment and analysis

• From December 2004 to March 2008, 114 patients
  were randomized into the study
• 17 centers participated actively in the trial
• 43 of patients were randomized at 3 study sites,
  75 at 7 study sites
• 3 patients were randomized to FOLFOX6 (arm closed
  early)
• These patients are not included in the current
  analysis
• 111 patients were randomized to FOLFOX6 plus
  cetuximab or FOLFIRI plus cetuximab
• 2 patients did not receive planned treatment
• 1 patient withdrew consent
• 1 patient retrospectively revealed known
  extrahepatic disease
• 105 patients were evaluable for response
• Presented data are based on an interim analysis
  as of August 15, 2008

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Patient characteristics
    FOLFOX6 FOLFIRI All
    cetuximab cetuximab patients
n56 n55 n111 
       
Median age 65.1 y 62.0 y 63.3 y
Sex      
male 64 64 64
Stratified characteristics      
5 metastases 45 46 45
Technically non-resectable 55 55 55
Staged using PET 16 20 18
EGFR-positive (IHC) 71 75 73
PET is not generally reimbursed in Germany
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Patient characteristics
    FOLFOX6 FOLFIRI All
    cetuximab cetuximab patients
  n56 n55  n111
KRAS (n99)      
wild-type   70 71 71
Primary tumor site      
Rectal cancer 36 52 44
Primary tumor stage      
T3/4 89 83 86
Adjuvant chemotherapy      
yes 9 23 16
Adjuvant radiotherapy      
yes 4 15 8
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Patient characteristics
  FOLFOX6 FOLFIRI All
  cetuximab cetuximab patients
n56 n55  n111
       
Primary UICC stage      
I-II 17 10 13
III 4 16 10
IV 79 74 77
       
Prior liver resection      
yes 17 9 13
       
Synchronous liver metastases      
yes 72 70 71
UICC, International Union Against Cancer
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Patient characteristics
    FOLFOX6 FOLFIRI All
    cetuximab cetuximab patients
  n56 n55  n111
         
Number liver metastases      
lt5   23 31 27
5-10   55 49 52
gt10   20 15 17
NA   2 5 4
         
Fong score (n83)      
0-1 17 10 13
2   17 31 24
3   34 38 36
4-5   32 21 27
Fong score is evaluated for resectable liver
metastasesFong score data not available for all
pts.
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Preoperative toxicity
  FOLFOX6 FOLFIRI All  
  cetuximab cetuximab patients p-value
n54 n55 n109  
All grade 3/4  72 73 73  n.s.
Neutropenia 24 22 23 n.s.
Thrombopenia 9 0 5 0.02
Allergic reaction 11 4 7 n.s.
Skin toxicity 28 38 33 n.s.
Diarrhea 9 18 14 n.s.
Nausea/Vomiting 7 0 4 0.04
Infection 0 9 5 0.02
Neuropathy 20 0 10 0.001
Other neurologic toxicity 6 4 5 n.s.
Alopecia 0 7 4 0.04
grade gt1        
One patient died from pulmonary embolism
Two randomized pts did not receive therapy
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Efficacy Response
  FOLFOX6 FOLFIRI KRAS All
  cetuximab cetuximab wild-type patients
n52 n53 n67 n105
CR/PR 85 66 79 75
(44 pts) (35 pts) (53 pts) (79 pts)
95 CI 71.9-93.1 51.7-78.5 67.4-88.1 65.9-83.1
SD 11 23 13 17
(6 pts) (12 pts) (9 pts) (18 pts)
PD 4 11 8 8
(2 pts) (6 pts) (5 pts) (8 pts)
Responses are not yet confirmed Data regarding response confirmation are still pending for 14 pts Responses are not yet confirmed Data regarding response confirmation are still pending for 14 pts Responses are not yet confirmed Data regarding response confirmation are still pending for 14 pts Responses are not yet confirmed Data regarding response confirmation are still pending for 14 pts Responses are not yet confirmed Data regarding response confirmation are still pending for 14 pts
105 pts evaluable for efficacy
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Resections
  FOLFOX6 FOLFIRI All
  cetuximab cetuximab patients
n52 n53 n105
All resections 40 43 42
  (21 pts) (23 pts) (44 pts)
R0 resections 37 34 35
  (19 pts) (18 pts) (37 pts)
105 pts evaluable for efficacy
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Time to intervention
44 patients were resected, 5 patients had
exploratory laparotomy Median time to
intervention (resection/laparotomy) 5.0
months Median number of cycles prior to
intervention 8
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Resections according to tumor response
Best responses  PR/CR SD PD
n79 n18 n8
R0 resections 35 pts 2 pts 0
Without R0 resection 44 pts 16 pts 8 pts
35/37 of resected pts (95) had a tumor
response The 2 remaining pts had minor responses
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Resections by patient subgroup
  Technically 5 liver KRAS
  non-resectable metastases wild-type
n57 n48 n67
All resections 40 44 43
  (23 pts) (21 pts) (29 pts)
R0 resections 32 40 34
  (18 pts) (19 pts) (23 pts)
Comparison of R0 resections between strata
technically non-resectable and 5 liver mets
p0.4
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Conclusions

• Among patients with initially non-resectable
  liver metastases, 42 had a liver resection and
  35 had an R0 resection
• FOLFOX6 plus cetuximab and FOLFIRI plus cetuximab
  are highly active regimens and induced high
  response rates
• 79 unconfirmed CR/PR in KRAS wild-type patients
• The current data do not allow us to draw
  conclusions regarding differences between FOLFOX6
  and FOLFIRI in the preoperative setting as final
  data are still pending
• There were no major differences in resection
  rates between patients who entered the study with
  technically non-resectable disease and those who
  had 5 liver metastases
• Tumor response is a precondition for resection of
  liver metastases, as nearly all patients
  achieved a tumor response before resection
• Median time to intervention (resection/laparotomy)
  was 5.0 months
• Data for progression-free survival and surgical
  review of resectability are not yet mature and
  will be presented at a later meeting

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We thank...

• All patients
• 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, University Hospital Würzburg,
  Klinikum Passau, University Hospital Frankfurt,
  Klinikum Celle, University Hospital Essen,
  Klinikum Magdeburg, Klinikum Aschersleben,
  University Hospital Mannheim, Klinikum
  Essen-Mitte
• The study was supported byMerck KGaA,
  Sanofi-Aventis, and Pfizer