DOES THE NEW EPOC TRIAL
ELIMINATE ANTI-EGFR ANTIBODIES
AS PART OF PRE-OP THERAPY FOR
CURABLE LIVER-ONLY MCRC?
YES!
Cathy Eng, M.D., F.A.C.P.
Associate Professor
Associate Medical Director, Colorectal Center
Director of Network Clinical Research, GI Med Onc
March 28, 2014
Department of GI Medical Oncology
Disclosures:
 The presenter is the first of the sessions
so please be kind .
 In this setting, it is presumed we will be
providing neoadjuvant chemotherapy
regardless
 In the perspective of the actual clinical
setting, it is recommended that each
patient is evaluated on a individual basis.
Cancers of the Colon and Rectum
International Statistics
Colorectal cancer is the 3rd most
Worldwide
common cancer in
men and the 2nd in women.
Incidence
Mortality
1.2 Million
609,000
per annum
USA (2014)
Incidence
136,830
Mortality
50,310
Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014
Facts about mCRC:
 There is NO standard approach to surgically resect




patients with liver metastases.
The liver is the most common site of metastatic
disease.
Approximately, 20% of patients will have surgically
resectable disease at presentation
Approximately, 20% of patients after neoaduvuant
chemotherapy will be downsized to be potentially
resectable.
The expected 5-yr OS of a surgically unresectable
patient is 13%.
 The 5-yr OS of a patient with surgically resectable disease
is 33-58%.
http://seer.cancer.gov/statfacts/html/colorect.html
Management of MCRC:
An Evolving Treatment Algorithm
Diagnosis of MCRC
Resectable (20%)
Neoadjuvant/
Preoperative
Therapy
Unresectable
Borderline/
Potentially
Resectable
(20%)
First-Line
Second-Line
Surgery
+/- Adjuvant Therapy
NCCN, 2010.
Palliation
MDACC Algorithms: The
complexity of treating mCRC
Pivotal Trials of mCRC with
Surgically Resectable Liver
Metastasis
• Keep in mind, there are limited studies overall
• Most studies have been small single institution phase II
studies or retrospective analyses.
Original EPOC Trial:
Phase III EORTC 40983
FOLFOX4
Surgery
FOLFOX4
6 cycles
6 cycles
(3 months)
(3 months)
Surgery
N=364 patients
Nordlinger et al: Lancet 2008; Lanc Onc 2013
Primary endpoint: PFS
EORTC 40983: PFS in Eligible Patients
HR= 0.77; CI: 0.60-1.00, p=0.041
100
90
+8.1%
At 3 years
80
Periop CT
70
60
50
36.2%
40
30
Surgery only
28.1%
After a median follow-up of 8.5 yrs, no difference
in 5-yr OS (51% vs. 48%, p=0.34)
20
10
0
(years)
0
O N
125 171
115 171
1
2
3
Number of patients at risk :
83
57
37
115
74
43
4
5
22
8
21
5
6
Why consider anti-EGFR therapy
in the neoadjuvant setting?
 Incorporate biologic therapy
 Hope for additional benefit when using enriched pt pop
 KRAS WT patients may have increased benefit from an
EGFR inhibitor to optimize outcome
 Avoid class effect toxicities of anti-VEGF therapy:
 Long t1/2 requiring dose to be held prior to surgery
 GI perforation
 Wound healing
 Original EPOC study showed ~8% improvement in 3-yr
PFS with neoadjuvant FOLFOX in mCRC patients with
operable liver metastases
Nordlinger et al, Lancet 2008
New EPOC Phase III Study: Chemotherapy
± Cetuximab in Operable KRAS-WT mCRC
FOLFOX4
+ Cetuximab
Surgery
FOLFOX4
+ Cetuximab
6 cycles
6 cycles
(3 months)
(3 months)
FOLFOX
N=621 patients
Nordlinger et al: Lancet 2008; Lanc Onc 2013
Surgery
FOLFOX
Primary endpoint: PFS
New EPOC Phase III Study: Chemotherapy
± Cetuximab in Operable KRAS-WT mCRC
FOLFOX4
+ Cetuximab
Surgery
FOLFOX4
+ Cetuximab
6 cycles
6 cycles
(3 months)
(3 months)
FOLFOX
Surgery
FOLFOX
Primary endpoint: PFS
N=272/621 patients
Nordlinger et al: Lancet 2008; Lanc Onc 2013
Proportion progression free
New EPOC: Neoadjuvant Chemotherapy ±
Cetuximab in Operable KRAS-WT mCRC: PFS
 Median PFS
1.00
HR: 1.49 (95% CI: 1.04-2.12); P = .030
0.75
0.50
0.25
Chemo alone
Chemo + cetuximab
0.00
0
6 12 18 24 30 36 42 48 54
Time to progression or death (months)
Number at risk
Chemo alone
116 89
Chemo + Cetuximab
117 87
60
65
38
23
12
5
2
1
1
0
54
24
15
5
3
2
1
0
0
Primrose JN, et al. ASCO 2013. Abstract 3504.
significantly
worse with
cetuximab: 14.1
months vs 20.5
months with
chemotherapy
alone
 Study stopped at
predefined futility
analysis
 Immature data, but
more events
unlikely to change
result
Why did the new EPOC study fail?
 KRAS is a predictive marker of potential benefit
for EGFR inhibition.
 Cetuximab does not have a role in the adjuvant
setting
 Phase III N0147: FOLFOX +/- cetuximab failed to
demonstrate improvement in DFS in stage III colon
cancer
 3-yr DFS: 74.6% vs 71.5% with the addition of
cetuximab (HR, 1.21; 95% CI, 0.98–1.49; P=.08)
 Or is it the chemotherapy backbone of FOLFOX
and cetuximab?
Alberts et al: JAMA. Apr 4, 2012; 307(13): 1383–1393.
Pivotal trials in mCRC of EGFR
inhibition
CRYSTAL Study Phase III
Patients
• Previously untreated mCRC,
EGFR + pts
FOLFIRI + Cetuximab
• Tumor tissue from primary
tumor or metastasis available
for biomarker analysis
1:1 Randomization
• ECOG PS 0-2
FOLFIRI
• N=1198
Primary Endpoint: PFS
Van Cutsem et al: NEJM, 2009; Van Cutsem et al: JCO 2011
CRYSTAL STUDY - Cetuximab and Chemotherapy
as Initial Treatment for Metastatic Colorectal Cancer
•
The PFS was 8.9M vs. 8.0M.
• HR = 0.85 (95% CI: 0.72 to 0.99; P = 0.048).
•
The PFS for KRAS WT tumors was 9.9M vs. 8.7M
•
HR = 0.68 (95% CI, 0.50 to 0.94)
•
There was no initial significant difference in OS (HR, 0.93; 95% CI, 0.81
to 1.07; P = 0.31).
•
UPDATE: Improved median OS for the investigational arm of (23.5 v
20.0 months; HR: 0.796; P = .0093)
•
The ORR in each arm was 46% (95% CI, 42-50) and 38% (95% CI, 3442).
•
Rate of surgery and R0 resection (7.9% v 4.6%; odds ratio, 1.823; 95% CI,
0.957 to 3.472; P = .0633 and 5.1% v 2.0%; odds ratio, 2.650; 95% CI, 1.083
to 6.490; P = .0265, respectively).
Van Cutsem et al: NEJM, 2009; Van Cutsem et al: JCO 2011
COIN Study Phase III
Patients
• Previously untreated mCRC
• Tumor tissue from primary
tumor or metastasis available
for biomarker analysis
• ECOG PS 0-2
XELOX
1:1 Randomization
• N=2445
XELOX + Cetuximab
Primary Endpoint: OS
Maughan et al Lancet 2011:
OS (primary analysis) and PFS
among KRAS wild-type patients
Progression-free Survival
Arm A
Arm B
Diff.
Median OS : mo
17.9
17.0
-0.92
2-year survival rates
36.1%
34.4%
-1.66%
0.75
1.00
Overall Survival
Arm A
Arm B
Diff.
Median PFS: mo
8.6
8.6
+0.07
2-year survival rates
8.83%
9.55%
+0.72%
HR point estimate = 1.038
95% CI = (0.90, 1.20)
Χ2 = 0.18; p = 0.68
0.00
0.25
Survival
0.50
HR point estimate = 0.959
95% CI = (0.84, 1.09)
Χ2 = 0.27; p = 0.60
0
Arm A (OxFp)
Arm A (OxFp)
Arm B (OxFp + cetux)
Arm B (OxFp + cetux)
6
12
18
24
Time (months)
30
36
42
0
6
12
18
24
30
Time (months)
36
42
N patients at risk:
A
367
316
250
154
83
44
19
1
367
245
92
41
18
11
6
1
B
362
306
238
149
80
42
17
3
361
249
103
42
22
9
6
0
CELIM: Phase II
Patients
• Previously untreated, surgically
unresectable mCRC
FOLFOX + cetuximab
• ≥5 liver metastases
• Tumor tissue from primary
tumor or metastasis available
for biomarker analysis
• ECOG PS 0-2
1:1 Randomization
FOLFIRI + cetuximab
• N=114
Primary Endpoint: RR
.
Folprecht; Lancet Onc, 2010; Annals of Onc, 2014
CELIM STUDY – Tumor response and resectability of
colorectal liver metastases following neoadjuvant
chemotherapy with cetuximab
Results:
 RR in 36 (68%) of 53 patients in group A, and 30 (57%) of 53 patients in
group B (p=0.23).
 In a retrospective analysis of response by KRAS status, RR was noted
47 (70%) of 67 patients versus 11 (41%) of 27 patients with KRASmutated tumors (OR 3.42, 1.35-8.66; p=0.0080).
 Update: The median OS was 35.7M vs 29M HR 1.03 [95% CI: 0.66-1.61],
p=0.9).
•
The median PFS was 10.8M vs. 10.5M, HR 1.18 [95% CI: 0.79-1.74],
p=0.4).
•
Patients who underwent R0 resection (n=36) had a better median OS
53.9M vs. 21.9M, p<0.001).
•
The median disease-free survival for R0 resected patients was 9.9 [95% CI:
5.8-14.0] months, and the 5-year OS rate was 46.2 [95% CI: 29.5-62.9]%.
New Data to Support EGFR
Inhibition as Neoadjuvant
Therapy
Does it change my current opinion about the
role of EGFR in neoadjuvant chemotherapy?
No
Update on PRIME Study Phase III
Patients
• Previously untreated mCRC
• Fluorouracil-based adjuvant
chemotherapy allowed if PD
occurred
≥6 mo after completion; no
oxaliplatin
• Tumor tissue from primary
tumor or metastasis available
for biomarker analysis
• ECOG PS 0-2
Panitumumab 6.0 mg/kg q 2 wk
FOLFOX4 q 2 wk
1:1 Randomization
FOLFOX4 q 2 wk
Primary Endpoint: PFS
• N=1183
Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.
PRIME (FOLFOX +/- Panitumumab)
PFS by KRAS Mutation Status
WT KRAS
MT KRAS
100%
90%
80%
RR: 55% vs. 48%, P = .068.
70%
60%
50%
40%
30%
20%
10%
0%
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Proportion Event-Free
Proportion Event-Free
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Months
Months
Median (mos)
(95% CI)
Median (mos)
(95% CI)
Panitumumab +
FOLFOX4
10.1 (9.3-12)
Panitumumab
+ FOLFOX4
7.4 (6.9 – 8.1)
FOLFOX4
7.9 (7.2-9.3)
FOLFOX4
9.2 (8.1 – 9.9)
HR = 0.72 (95% CI: 0.58 – 0.90)
HR = 1.27 (95% CI: 1.04 – 1.55)
Log-rank p-value = 0.004
Log-rank p-value = 0.02
Douillard et al: JCO, 2010; NEJM 2013
PRIME Biomarker Analysis: Analysis of
KRAS/NRAS and BRAF Mutations
RAS and BRAF Status
WT
MT
WT KRAS exon 2 tumors tested for RAS and BRAF
WT KRAS exon 2/MT other RAS, n (%)
WT
KRAS exon 3 (codon 61), n (%)
MT
Failure
WT
KRAS exon 4 (codons 117/146), n (%)
MT
Failure
WT
NRAS exon 2 (codons 12/13), n (%)
MT
Failure
WT
NRAS exon 3 (codon 61), n (%)
MT
Failure
WT
NRAS exon 4 (codons 117/146), n (%)
MT
Failure
WT
BRAF exon 15 (codon 600), n (%)
MT
Failure
KRAS exon 2 (codon 12/13)
FOLFOX4 Alone
331
219
(n = 321)
57 (18)
306 (95)
14 (4)
1 (0)
296 (92)
15 (5)
10 (3)
307 (96)
14 (4)
0 (0)
305 (95)
14 (4)
2 (1)
313 (98)
0 (0)
8 (2)
280 (87)
29 (9)
12 (4)
Panitumumab + FOLFOX4
325
221
(n = 320)
51 (16)
308 (96)
10 (3)
2 (1)
288 (90)
21 (7)
11 (3)
308 (96)
8 (3)
4 (1)
305 (95)
12 (4)
3 (1)
316 (99)
0 (0)
4 (1)
286 (89)
24 (8)
10 (3)
Oliner J, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3511. Oliner J, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 2275.
Revised PRIME Consort Diagram
Douillard et al: NEJM, 2013
PRIME: Updated OS Analysis
Proportion Alive (%)
Overall Survival in the Primary-Analysis Population
No.at Risk
Panitumumab-FOLFOX4
FOLFOX4 alone
Events
Median Mo
no./total no. (%)
(95% CI)
Panitumumab- 128/259 (49)
FOLFOX4
26.0 (21.7–30.4)
FOLFOX4 alone 148/253 (58)
20.2(17.7–23.1)
Hazard ratio, 0.78 (95% CI, 0.62–0.99)
P=0.043
Months
259
253
189
174
88
65
0
0
Overall Survival in the Updated-Analysis Population
Proportion Alive (%)
Events
Median Mo
no./total no. (%)
(95% CI)
Panitumumab- 204/259 (79)
FOLFOX4
FOLFOX4 alone 218/253 (86) 20.2(17.6–23.6)
Hazard ratio, 0.77 (95% CI, 0.64–0.94)
P=0.009
Months
No.at Risk
Panitumumab-FOLFOX4
FOLFOX4 alone
Douillard et al, 2013.
25.8 (21.7–29.7)
259
253
189
176
129
104
83
60
49
30
14
8
FIRE-3 Phase III Study Design
Patients
• mCRC
FOLFIRI + Cetuximab
(Cetuximab: 400 mg/m2 loading dose;
250 mg/m2 weekly)
• KRAS wild-type
• ECOG PS 0-2
• 1st line therapy; prior
adjuvant chemotherapy
allowed if completed
>6 mo before inclusion
• N=592
1:1 Randomization
FOLFIRI + Bevacizumab
(Bev: 5 mg/kg every 2 weeks)
Primary endpoint: Response Rate
Heinemann V. ASCO 2013. Abstract LBA3506.
FIRE-3: Overall Response Rate
FOLFIRI +
Cetuximab
FOLFIRI +
Bevacizumab
OR
P Value
62.0%
58.0%
1.18
(0.85-1.64)
0.183
Complete response
4.4%
1.4%
Partial response
57.6%
56.6%
Stable disease
17.5%
28.8%
Progressive disease
7.1%
5.4%
Not evaluable
13.1%
7.8%
72.2%
63.1%
1.52
(1.05-2.19)
0.017
Endpoint
ORR, intent-to-treat
(ITT) population
(N=592)
ORR, Evaluable (N=526)
Heinemann V. ASCO 2013. Abstract LBA3506.
Consort FIRE-3 Diagram
N=752
mCRC 1st-line
unselected patients
N=592
KRAS exon 2 wild-type
ITT population
KRAS unknown= 30
No treatment= 13
No treatment KRAS
mt = 4
N=113
KRAS exon 2 mutant
population*
N=407 (69%)
RAS evaluable population
N=342
RAS wild-type
N= 171
FOLFIRI +
Cetuximab
N= 171
FOLFIRI +
Bevacizumab
N=65 (16%)
‘New’ RAS mutant
N= 34
FOLFIRI
Cetuximab
N=58
FOLFIRI +
Cetuximab
N=55
FOLFIRI +
Bevacizumab
N= 31
FOLFIRI +
Bevacizumab
Stinzing et al: ESMO, 2013
FIRE-3: Overall survival RAS* all wild-type
Events
n/N (%)
Median
(months)
95% CI
― FOLFIRI + Cetuximab
91/171
(53.2%)
33.1
24.5 – 39.4
― FOLFIRI + Bevacizumab
110/171
(64.3%)
25.6
22.7 – 28.6
1.0
Probability of survival
0.75
HR 0.70 (95% CI: 0.53 – 0.92)
p (log-rank)= 0.011
0.50
Δ = 7.5 months
0.25
0.0
12
No. at
risk
171
171
128
127
Stinzing et al: ESMO, 2013
48
36
24
months since start of treatment
71
68
39
26
20
9
60
72
6
1
* KRAS and NRAS exon 2, 3 and 4 wild-type
FIRE-3 Update: Overall Survival by
All-RAS Mutation Status
FOLFIRI +
Cetuximab
FOLFIRI +
Bevacizumab
HR
P
Value
ITT (N=592)
28.7 months
25.0 months
0.77
0.017
RAS WT (n=342)
33.1 months
25.6 months
0.70
0.011
RAS MT (n=65)
16.4 months
20.6 months
1.20
0.57
BRAF MT (n=48)
12.3 months
13.7 months
0.87
0.65
Study Population
Stintzing S. European Cancer Conference 2013. Abstract LBA17.
Pending Trials
CALGB/SWOG 80405:
Pending results
Study amended: Wild-type KRAS tumors only
• First-line
mCRC
• Amended
accrual;
N=2300
wild-type
patients
R
A
N
D
O
M
I
Z
E
FOLFOX or FOLFIRI* + cetuximab
FOLFOX or FOLFIRI* +
cetuximab + bevacizumab
FOLFOX or FOLFIRI* +
bevacizumab
BOS-2 (EORTC 40091): Phase II
KRAS WT Resectable Liver Mets
Study amended: Wild-type KRAS tumors only
• First-line
mCRC
• N=360
R
A
N
D
O
M
I
Z
E
FOLFOX
FOLFOX + bevacizumab
FOLFOX + panitumumab
Primary Endpoint: PFS
http://www.clinicaltrials.gov/ct2/show/NCT01508000?term=BOS-2&rank=1
BOS -3 (EORTC-1207) Phase II/III Study
Design (Pending)
Patients
• mCRC
FOLFOX + Aflibercept
(Aflibercept: 4 mg/m2)
• KRAS MT
• ECOG PS 0-1
1:1 Randomization
• 1st line therapy; prior
adjuvant chemotherapy
allowed if completed
>12 mo before inclusion
FOLFOX
Primary endpoint: PFS
http://www.clinicaltrials.gov/ct2/show/NCT01646554?term=BOS-2&rank=2
Conclusions:
 The data from the new EPOC trial indicates
FOLFOX/cetuximab can be deleterious in surgically
resectable KRAS WT patients
 Due to the rare RAS MT?
 Does EGFR inhibition require macroscopic disease for
efficacy ~ irinotecan?
 Is it the backbone?
 CELIM was underpowered
 The use of FOLFOX/FOLFIRI + anti-EGFR therapy in a
KRAS WT patient does not result necessarily in superior
RR vs. anti-VEGF therapy.
 Pending final results of FIRE-3, CALGB 80405, BOS-2 and BOS-
3
 If you are considering EGFR inhibition, must consider all RAS
MT testing.