Liver Metastases from Colorectal Cancer: Triplet Chemotherapy and Targeted Therapies

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Liver Metastases from Colorectal Cancer Triplet
Chemotherapy and Targeted Therapies
Pr Marc YCHOU Montpellier - France
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CT
30?
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CORRELATION BETWEEN TUMOR RESPONSE AND RESECTION
RATE ?
Patients sélectionnés ? Non-selectionnés
(phase I/II) ? Non-selectionnés (phase III)

• Very high in studies included selected patients
  (Liver metastases only)
• Moderate in studies inluded non selected patients

Folprecht et al. Ann Oncol, 2005
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A Phase I trial to assess the triple combination

• Fixed dose level of simplified LV5FU2
• 8 dose levels planned for CPT-11 and L-OHP at day
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Level CPT-11 (mg/m²) L-OHP (mg/m²)
1 90 60
2 120 60
3 120 85
4 150 85
5 180 85
6 200 85
7 220 85
8 240 85
Ychou M et al. Annals Oncol 200314(3)481-9
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The recommended Phase II Dose
Simplified LV5FU 85 mg/m2 l-OHP 180 mg/m2
CPT-11
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TREATMENT SCHEDULE
FOLFIRINOX
5FU bolus 400 mg/m²
l-OHP 85 mg/m2 2 H
FA 400 mg/m² 2 H
5FU 2400 mg/m² c.i 46 h

CPT11 180 mg/m2 1H30

• Evaluation every 4 cycles
• Total of 12 cycles (pre and post-op)
• Review by independent committee
• ? Inclusion criteria (resectability)
• ? Radiological Tumor Responses

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BEST RESPONSE TO PRE-SURGERY CHEMOTHERAPY
N 34 ()
Complete Response Partial Response Minor Response Overall response rate CI 95 1 (3) 23 (68) 4 (15.4) 24 (71) 56-90
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RESULTS OF SURGERY

ITT (N 34) Eligible (N 26)

R0 9 (26,4 ) 9
(34,6 ) R1() 5
(14,7 ) 5 (19,2 ) Ra()
13 (38,2 ) 9 (34,6 ) R2
1 (2,9 ) 0 Non Operated
6 (17,6 ) 3 (11,5 )


Among the 34 pts (ITT) 79 in CR after
surgery Among the 26 pts (eligibles) 88 in CR
after surgery


() margin lt 2 mm
() resection RF or CS
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SURGICAL COMPLICATIONS

• Biliary Fistula 3
• Moderate Ascitis 1
• Transient Hep.Insuf. 1
• Biliary Infection 1
• Urinary Infection 1

• TOTAL 7/26 30

• No death

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PHASE II RANDOMIZED METHEP TRIALSTUDY DESIGN

• Control Arm
• Standard dose Chemo
• FOLFIRI
• FOLFOX-4

• STRATIFICATION
• Center
• Lung metastases
• Classification of liver metastases
• Classe II
• Unres Vx Contact
• Unres HL lt 30

RANDOM

• Experimental Arms
• Intensified Chemo
• FOLFIRI-High Dose
• FOLFOX-7
• FOLFIRINOX

Primary Endpoint Response after C4 (RECIST)
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CHEMOTHERAPY SCHEDULES
FOLFIRI FOLFOX 4 FOLFIRI High Dose FOLFOX 7 FOLFIRINOX
5FU Bolus 400 mg/m² CI 46h 2400 mg/m² Bolus 400 mg/m² CI 46h 2400 mg/m² Bolus 400 mg/m² CI 46h 2400 mg/m² Bolus 400 mg/m² CI 46h 2400 mg/m² Bolus 400 mg/m² CI 46h 2400 mg/m²
ELVORINE (2h) 200 mg/m² 200 mg/m² 200 mg/m² 200 mg/m² 200 mg/m²
IRINOTECAN 180 mg/m² 260 mg/m² 180 mg/m²
OXALIPLATIN 85 mg/m² 130 mg/m² 85 mg/m²
GCS-F
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Maximal TOXICITY GRADE 3/4 Per Patient
CONTROL (30 pts) FOLFIRI-HD (32 pts) FOLFOX-7 (30 pts) FOLFIRINOX (30 pts)
Neutropenia 33 28 27 33
Thrombopenia 0 3 10 13
Febrile Neutrop. 0 3 0 3
Diarrhea 0 12 7 23
Vomitis 7 9 3 3
Mucites 0 6 0 10
Asthenia 3 19 3 13
Neurotoxicity 7 0 40 17
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REPONSES at Cycle 4 (ITT Analysis)
CONTROL (30 pts) FOLFIRI-HD (32 pts) FOLFOX-7 (30 pts) FOLFIRINOX (30 pts) FOLFIRINOX (30 pts)
Patial Response 33 47 43 43 57
IC 95 1753 2965 2563 2563 3774
Stability 57 50 33 33 40
Progression 3 3 10 10 0
Non evaluable 7 - 13 13 3
PANEL ASSESSMENT
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POST CHEMO RESECTION
CONTROL (30 pts) FOLFIRI-HD (32 pts) FOLFOX-7 (30 pts) FOLFIRINOX (30 pts) TOTAL
Classe II 6/10 9/12 8/10 9/11 74
Unresect. vx contact 0/6 3/4 2/6 4/8 38
Unresect. lt30 Healthy 6/14 6/16 3/14 6/11 38
Total Resections 40 56 43 63 51
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Oct 05
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March 06, after 12 cycles FOLFIRINOX CEA 3,
CA19-9 18
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Epidermal growth factor receptor (EGFR) and
KRAS Role in onset of CRC

• When KRAS geneis mutated, KRAS protein (p21 ras)
  is active regardless of EGFR activation
• KRAS mutations are an early event and occur in
  4045 of CRC patients
• KRAS mutations are associated with poor prognosis

cetuximab
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CELIM Study design
Patients with technically unresectable / 5
liver metastases without extrahepatic metastases
Biopsy EGFR screening
Primary endpoint Response
Randomization
FOLFOX6 cetuximab
FOLFIRI cetuximab
Therapy 8 cycles (4 months)
Evaluation of resectability
Technically resectable
Technically unresectable
4 further treatment cycles
Resection
Therapy continuation for 6 cycles (3 months)
Folprecht G, et al. The Lancet Oncology 2009
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CELIM Response and resection rates in patients
with KRAS wild-type tumors
Cetuximab FOLFOX/FOLFIRI
Patients ()
70
R0-R1-RF rate 46
R0 rate 34
46
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Response rate( n67)
Resections R0 resections (n67)
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ERBIRINOXMulticentre Phase II evaluating
combination of cetuximab to FOLFIRINOX in first
line therapy of unresectable MCRC METHODOLOGY

• Multicentrique Phase II (4 centers in France)
• From April 2006 to April 2008, 42 patients
  recruted
• ENDPOINTS
• Primary Complete Response Rate (CR, RECIST)
• Secondaries
• Objective Response Rate (OR, RECIST)
• Time To Progression (TTP)
• Safety (NCI classification )
• Overall Survival (OS)

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Treatment Schedule
5 FU bolus 400 mg/m²
Cetuximab 400 mg/m² (D1) 250 mg/m²
(subsequent cycles)
oxaliplatin 85 mg/m²
90 min
1h pause
irinotecan 180 mg/m²
5FU infusion 2400 mg/m²
10 min
2h
FA 200 mg/m²
46h
2h (1st cycle) 1h (subsequent cycles)
2h
Weekly
Every 2 Weeks for a total of 12
cycles (Granulocyte colony-stimulating factor
D7-12)
Ychou M, et al. Ann Oncol 2003. Ychou M, et al.
Cancer Chemother Pharmacol 2007.
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PATIENTS CHARACTERISTICS (N 42)
42 patients 04/06 and 04/08 42 patients 04/06 and 04/08
Median Age 60 (32-76)
Gender (M/F) 22/20
PS (0/1) 33/9
Tumor (colon/rectum) 30/12
Resection of Primary Tumor 23
Metastases (synchronous/metachronous) 34/8
Liver 39
Lung 23
Others 14
1 metastatic site gt 1 site 18 24
ACE Nal ACE gt 10N 4 18
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TOXICITIES
Gr 3 (n) Gr 4 (n) Gr 3-4 ()
Neutropeniaª Febrile Neutropenia 18 2 20 3 38 5
Diarrhea 52 0 52
Cutaneous 33 0 33
Vomiting 10 0 10
Neuropathy 19 0 19
ª 4 patients did not receive prophyllactic GCSF 1
Toxic Death (Febrile Neutropenia)
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EFFICACY (ITT)
Tumor Response (RECIST) n 42 ()
CR 5 (12) 4-25
PR 29 (69)
Stable 2 (5)
Progression Non evaluable 1 (2) 5 (12)
Objective Response 34 (81) 66-91
Median duration of CR 12, 3 months 3,9 18,9
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Exemple of Complete Response
2006 Sept
2007 Aug (5 months after end of 12 th cycle)
Sept 2011 Still in Complete Remission
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Included in ERBIRINOX trial
CT 19/02/2007
after 4 cycles Erbirinox
CT 23/04/2007
10 vs 23 mm
19 vs 43 mm
23 vs 48 mm
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CT 23/04/2007
CT 19/02/2007
? Stop CT after C5 due to toxicity ? PET-scan
H fixation only on rectal tumor ? Aug 2007
Surgery No Liver metastases Rectal T ypT2N0
(47 N-) ? Sept 2011 still in Complete Remission
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Triplet Chemotherapy with FOLFIRINOX regimenin
metastatic colorectal cancer (mCRC)
Experience of the Montpellier Cancer
Institute
Patients characteristics Patients characteristics Patients characteristics
n 92
Age (years) Median Range 59 27-76 - -
Gender Male Female 48 44 52 48
Primary tumour Colon Rectum Primary tumour resected 61 31 74 66 34 80
ACE baseline Median Range 31 1-2000 - -
Metastases Synchronous 74 88
Liver Limited Disease Multimetastatic 1 extra-hepatic site 63 21 8 68 23 9
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Patients Characteristic
FOLFIRINOX FOLFIRINOX FOLFIRINOX FOLFIRINOX
Patients LLD (n 63) MM (n21) and others (n8) Total (n92)
FOLFIRINOX only 45 21 66 (71)
FOLFIRINOX bevacizumab 3 0 3 (4)
FOLFIRINOX cetuximab 15 8 23 (25)
Line
1rst line 58 26 84 (91)
2nd line 4 2 6 (7)
gt 2nd line 1 1 2 (2)
Median number of pre-operative courses (Range) 8 (2-12) 8 (2-12) 8 (2-12)

LLD Liver Limited Disease MM Multimetastatic Oth
er Pelvis Recurrence, Lung Limited Disease,
Peritoneal only
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Response rate
Response rate Patients N 92
Complete Response 12 (11)
Partial Response 61 (65)
Stable Disease 13 (14)
Progression 7 (7)
Non Evaluable 1 (1)
Overall Response Rate 73/92, 78 CI9568-86
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Surgical Assessment
Resection of liver metastases after FOLFIRINOX Resection of liver metastases after FOLFIRINOX
LLD n63 ()
Assessment of Secondary Resectability 40 (64)
Resection Rate (R0/R1 and/or Radiofrequency) R0 Resection Rate 34 (57) 18 (53)
Exploratory laparotomy 4 (6)
R2 Resection Rate 2 (3)
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Bevacizumab with FOLFOXIRI (Irinotecan,
Oxaliplatin, fluorouracil, and folinate) as first
line treatment for Metastatic Colorectal Cancer
a Phase II trial
Lancet Oncology, Sept 2010
Masi G1, Loupakis F1,6, Baldi G1, Fornaro L1, Di
Leo A2, Ciarlo A2, Amoroso D3, Granetto C4, Di
Donato S5, Falcone A1,6.
1Division of Medical Oncology, Azienda USL 6 -
Istituto Toscano Tumori Livorno, Italy,
2Division of Medical Oncology, Misericordia e
Dolce Hospital, Prato, Italy, 3Division of
Medical Oncology, Versilia Hospital, Lido di
Camaiore, Italy, 4Division of Medical Oncology,
S. Croce e Carle Hospital, Cuneo, Italy,
5Division of Medical Oncology, S. Chiara
Hospital, Pisa, Italy, 6Department of Oncology,
Transplantation and New Technologies in Medicine,
University of Pisa, Italy
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TREATMENT
Day 1 Day 2 Day 3
BV 5 mg/Kg
Oxaliplatin 85 mg/sqm
CPT-11 165 mg/sqm
5FU flat continuous infusion 3200 mg/sqm
L-LV 200 mg/sqm
2 hours
48 hours
1 hour
30 min
Repeated every 14 days

• So far, 289 cycles of induction treatment with
  FOLFOXIRI plus Bevacizumab were administered and
  the median number of cycles FOLFOXIRI plus
  Bevacizumab was 8 (range 1-16)

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RESPONSE RATE (RECIST CRITERIA)
Total evaluable patients N57
Complete Response (CR) 7 12
Partial Response (PR) 37 65
Overall Response Rate 44 77
Stable Disease (SD) 13 23
Progressive Disease 0 0
Disease Control Rate (CR PR SD) 57 100
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METHEP2 TRIAL DESIGN
Control Arm KRas M FOLFIRI-Béva
FOLFOX-Béva KRas M- FOLFIRI-Cétux
FOLFOX-Cétux

• STRATIFICATION
• Center
• Lung Metastases
• Classification of Liver Metastases

RANDOM
Expérimental Arm KRas M -
FOLFIRINOX-Béva KRas M- - FOLFIRINOX-Cétux
Comparison between Trichemo vs Bichemo Primary EP
resection rate 20 increase needs 256 pts