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!