the new epoc study
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No
Does the New EPOC trial eliminate anti-EGFR antibodies
as part of pre-op therapy for curable liver only metastatic
CRC?
The New EPOC Study
Randomize
SurgeryOxaliplatin or Irinotecan with FP + cetuximab
Surgery
6 cycles (3months)
N=268 patients
Oxaliplatin or Irinotecan with FP + cetuximab
Oxaliplatin or Irinotecan with FP
Oxaliplatin or Irinotecan with FP
• 2/3 FOLFOX, 20% CAPOX, 10% FOLFIRI• Primary EP: PFS (HR 0.68)• 268 pts with 212 events required• Trial closed after interim analysis after 123 events showed
detrimental effect
New EPOC StudyChemoN=134
Chemo + CetuxN=137
HR (p-value)
RR (%) 53.7 58.4PFS (mos) 20.5 14.1 1.49 (0.03)OS (mos) NR 39.1 1.48 (0.16)
PFS OS
Primrose et al., ASCO 2013
New EPOC Study• Detriment mainly in patients with
traditionally good prognostic factors!
Primrose et al., ASCO 2013
Why this does not eliminate EGFR antibodies as part of pre-op therapy:• EGFR antibodies improve response rates
• Better response better survival• New EPOC did not include all-RAS
analysis• Possibly oxaliplatin + cetuximab effect• Is the detriment strictly postop?
Response rates with EGFR antibodies in KRAS WT
Trial Regimen N RR P R0
CRYSTAL FOLFIRI + cetuximab 172 59.3% NR 5.1%
FOLFIRI 176 43.2% 2.0%
OPUS FOLFOX + cetuximab 61 61% 0.011 9.8%
FOLFOX 73 37% 4.1%
PRIME FOLFOX + panitumumab 325 55% 0.068 8.3%
FOLFOX 331 48% 7.0%
COIN Oxal/FP + cetuximab 362 64% 0.049 15%
Oxal/FP 367 57% 13%
Patients with non-resectable colorectal liver metastases(technically non-resectable / ≥ 5 liver metastases)
without extrahepatic metastases
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)
CELIM Study
Folprecht et al., Lancet Oncology 2009
CELIM Phase II Study - Results
FOLFOX6 +cetuximab
n=53
FOLFIRI +cetuximab
n=53
Allpatientsn=106
CR/PR 68% 57% 62%
SD 28% 30% 29%
PD 4% 13% 8%
R0 resections 38% 30% 34%
R1-res. or res. with RFA 2% 8% 5%
RFA 9% 6% 8%
Total: R0 / R1 res. / RFA 49% 43% 46%
RFA = radiofrequency ablation.
Folprecht et al., Lancet Oncology 2009
Waterfall plot of resectability at baseline
Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red. Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”
Folprecht et al., Lancet Oncology 2009
Waterfall plot of resectability after chemotherapy
Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red. Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”
Resectability according to imaging increased by 28% (32% → 60%), p<0.01
Folprecht et al., Lancet Oncology 2009
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=36not R0 resected, N=70
R0 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
Importance of all RAS testing
Importance of all RAS testing: Analysis of PRIME study
KRAS exon 2codon 12/13
40%
KRAS exon 3codon 61
4%
KRAS exon 4codon 117/146
6%
NRAS exon 2codon 12/13
3%
NRAS exon 3codon 61
4%
BRAF exon 15codon 600
8%
17%
Oliner et al., ASCO 2013
Oliner et al., ASCO 2013
HR 0.83(KRAS wt cod 12/13)
HR 0.78(all RAS wt)
OS
Detriment!
Is oxaliplatin + EGFR antibodies the wrong
combination?
EGFR antibody mCRC trials - KRAS WT patient subsets
Trial Regimen N RR%
P PFS p OSmos
p
CRYSTAL FOLFIRI + cetuximab 172 59.3% NR 9.9 0.02 24.9 NR
FOLFIRI 176 43.2% 8.7 21.0
OPUS FOLFOX + cetuximab 61 61% 0.011 7.7 0.0163 NR NR
FOLFOX 73 37% 7.2 NR
PRIME FOLFOX + panitumumab 325 55% 0.068 9.6 0.80 23.9 0.072
FOLFOX 331 48% 8.0 19.7
COIN Oxal/FP + cetuximab 362 64% 0.049 8.6 0.60 17.0 0.67
Oxal/FP 367 57% 8.6 17.9NORDIC VII FLOX + cetuximab 303 46% 0.87 7.9 0.66 20.1 0.66 FLOX 47% 8.6 22.0EPIC Irinotecan + cetuximab 648 16.4% <0.0001 4.0 <0.0001 10.7 0.71
Irinotecan 650 4.2% 2.6 10.0
181 FOLFIRI + panitumumab 303 35% <0.001 5.9 0.004 14.5 0.12 FOLFIRI 294 10% 3.9 12.5
Cunningham Irinotecan + cetuximab 218 22.9% 0.007 4.1 <0.001 8.6 0.48 cetuximab 111 10.8% 1.5 6.9
Is there detriment restricted to postoperative EGFR antibody
administration?
slide-18
Analysis of N0147
Stage 3 Colon Cancer(N = 2300)
RANDOMIZE
mFOLFOX6 (12 cycles)• Oxaliplatin 85 mg/m2
• LV 400 mg/m2 & • 5-FU 2,400 mg/m2 over 46 hrs every 2 weeks
mFOLFOX6 + Cetuximab (12 cycles)• mFOLFOX6 • Cetuximab days 1,8 - 400 mg/m2 loading dose - 250 mg/m2 weekly
Alberts. JAMA 2012.
n = 1864; med age 58 (19 – 86)14% ≥ 70 years (n = 258)
slide-19
Disease Free Survival (N=1847)
Arm 3 Year Rates (95% CI)
HR (95% CI)
P-value
FOLFOXN=902
75.8%(72.1%-79.6%)
1.2(0.96-1.5)
0.22
FOLFOX + CmabN=945
72.3%(68.5%-76.4%)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36Time (Months)
% A
live
and
Dis
ease
Fre
e
Fre
e
FOLFOXFOLFOX + Cmab
Alberts. JAMA 2012.
Is there detriment restricted to postoperative EGFR antibody
administration?• Detriments in New EPOC and N0147
remain unexplained• PETACC-8 trial did not show detriment,
even though no benefit to adjuvant
Conclusions:Why New EPOC result do not
eliminate EGFR antibodies as part of pre-op therapy:
• EGFR antibodies improve response rates • Better response improved R0
resections better survival• Reasons for detriment are unexplained
• New EPOC did not include all-RAS analysis
• Possibly oxaliplatin + cetuximab effect• Possibly a postoperative effect
Thank you for your attention!
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