1. 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

2. 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.

3. Cancers of the Colon and Rectum International Statistics
Worldwide
Colorectal cancer is the 3rd most common cancer in
men and the 2nd in women.
Incidence
Mortality
1.2 Million
609,000
per annum
USA (2014)
Incidence
Mortality
136,830
50,310
Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014

5. 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%.

6. Management of MCRC: An Evolving Treatment Algorithm
Diagnosis of MCRC
Resectable (20%)
Unresectable
Borderline/
Potentially
Resectable (20%)
First-Line
Neoadjuvant/
Preoperative Therapy
Second-Line
Surgery
Palliation
+/- Adjuvant Therapy
NCCN, 2010.

7. MDACC Algorithms: The complexity of treating mCRC

8. 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.

9. Original EPOC Trial: Phase III EORTC 40983
Randomi ze
FOLFOX4
Surgery
FOLFOX4
6 cycles
(3 months)
6 cycles
(3 months)
Surgery
Primary endpoint: PFS
N=364 patients
Nordlinger et al: Lancet 2008; Lanc Onc 2013

10. EORTC 40983: PFS in Eligible Patients
HR= 0.77; CI: , p=0.041
100 90
+8.1% At 3 years 80
Periop CT 70 60 50
36.2% 40 30
Surgery only 20
28.1%
After a median follow-up of 8.5 yrs, no difference
in 5-yr OS (51% vs. 48%, p=0.34) 10
(years) 1 2 3 4 5 6 O N
Number of patients at risk :
125
171 83 57 37 22 8
115
171
115 74 43 21 5

11. 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

12. New EPOC Phase III Study: Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC
Randomi ze
FOLFOX4
+ Cetuximab
Surgery
FOLFOX4
+ Cetuximab
6 cycles
(3 months)
6 cycles
(3 months)
FOLFOX
Surgery
FOLFOX
Primary endpoint: PFS
N=621 patients
Nordlinger et al: Lancet 2008; Lanc Onc 2013

13. New EPOC Phase III Study: Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC
Randomi ze
FOLFOX4
+ Cetuximab
Surgery
FOLFOX4
+ Cetuximab
6 cycles
(3 months)
6 cycles
(3 months)
FOLFOX
Surgery
FOLFOX
Primary endpoint: PFS
N=272/621 patients
Nordlinger et al: Lancet 2008; Lanc Onc 2013

14. Proportion progression free Time to progression or death (months)
New EPOC: Neoadjuvant Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC: PFS
Median PFS significantly worse with cetuximab: months vs months with chemotherapy alone
Study stopped at predefined futility analysis
Immature data, but more events unlikely to change result
1.00
HR: 1.49 (95% CI: ); P = .030
0.75
Proportion progression free
0.50
0.25
Chemo alone Chemo + cetuximab
0.00 6 12 18 24 30 36 42 48 54 60
Time to progression or death (months)
Number at risk Chemo alone Chemo + Cetuximab
89 87
65 54
38 24
23 15
12 5
5 3
2 2
1 1
1 0
0 0
Primrose JN, et al. ASCO Abstract 3504.

15. 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.

16. Pivotal trials in mCRC of EGFR inhibition

17. CRYSTAL Study Phase III
Patients
Previously untreated mCRC, EGFR + pts
Tumor tissue from primary tumor or metastasis available for biomarker analysis
ECOG PS 0-2
N=1198
FOLFIRI + Cetuximab
1:1 Randomization
FOLFIRI
Primary Endpoint: PFS
Van Cutsem et al: NEJM, 2009; Van Cutsem et al: JCO 2011

18. 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, to 1.07; P = 0.31).
UPDATE: Improved median OS for the investigational arm of (23.5 v months; HR: 0.796; P = .0093)
The ORR in each arm was 46% (95% CI, 42-50) and 38% (95% CI, ).
Rate of surgery and R0 resection (7.9% v 4.6%; odds ratio, 1.823; 95% CI, to 3.472; P = and 5.1% v 2.0%; odds ratio, 2.650; 95% CI, to 6.490; P = .0265, respectively). .
Van Cutsem et al: NEJM, 2009; Van Cutsem et al: JCO 2011

19. COIN Study Phase III Primary Endpoint: OS Patients
Previously untreated mCRC
Tumor tissue from primary tumor or metastasis available for biomarker analysis
ECOG PS 0-2
N=2445
XELOX
1:1 Randomization
XELOX + Cetuximab
Primary Endpoint: OS
Maughan et al Lancet 2011:

20. OS (primary analysis) and PFS among KRAS wild-type patients
Overall Survival
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%
Arm A
Arm B
Diff.
Median PFS: mo
8.6
+0.07
2-year survival rates
8.83%
9.55%
+0.72%
1.00
HR point estimate = 1.038
95% CI = (0.90, 1.20)
Χ2 = 0.18; p = 0.68
0.75
HR point estimate = 0.959
95% CI = (0.84, 1.09)
Χ2 = 0.27; p = 0.60
Survival
0.50
0.25
Arm A (OxFp)
Arm A (OxFp)
Arm B (OxFp + cetux)
Arm B (OxFp + cetux)
0.00 6 12 18 24 30 36 42 6 12 18 24 30 36 42
Time (months)
Time (months)
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

21. CELIM: Phase II Primary Endpoint: RR Patients
Previously untreated, surgically unresectable mCRC
≥5 liver metastases
Tumor tissue from primary tumor or metastasis available for biomarker analysis
ECOG PS 0-2
N=114
FOLFOX + cetuximab
1:1 Randomization
FOLFIRI + cetuximab
Primary Endpoint: RR
Folprecht; Lancet Onc, 2010; Annals of Onc, 2014 .

22. 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 KRAS- mutated tumors (OR 3.42, ; p=0.0080).
Update: The median OS was 35.7M vs 29M HR 1.03 [95% CI: ], p=0.9).
The median PFS was 10.8M vs. 10.5M, HR 1.18 [95% CI: ], 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: ] months, and the 5-year OS rate was 46.2 [95% CI: ]%.

23. New Data to Support EGFR Inhibition as Neoadjuvant Therapy
Does it change my current opinion about the role of EGFR in neoadjuvant chemotherapy? No

24. 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
N=1183
Panitumumab 6.0 mg/kg q 2 wk FOLFOX4 q 2 wk
1:1 Randomization
FOLFOX4 q 2 wk
Primary Endpoint: PFS
Douillard JY, et al. J Clin Oncol. 2010;28:

25. PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status
WT KRAS
MT KRAS
RR: 55% vs. 48%, P = .068.
Median (mos) (95% CI)
Panitumumab + FOLFOX4
10.1 (9.3-12)
FOLFOX4
7.9 ( )
Median (mos) (95% CI)
Panitumumab + FOLFOX4
7.4 (6.9 – 8.1)
FOLFOX4
9.2 (8.1 – 9.9)
HR = 0.72 (95% CI: 0.58 – 0.90)
Log-rank p-value = 0.004
HR = 1.27 (95% CI: 1.04 – 1.55)
Log-rank p-value = 0.02
Douillard et al: JCO, 2010; NEJM 2013

26. PRIME Biomarker Analysis: Analysis of KRAS/NRAS and BRAF Mutations
RAS and BRAF Status
FOLFOX4 Alone
Panitumumab + FOLFOX4
KRAS exon 2 (codon 12/13) WT MT
331
219
325
221
WT KRAS exon 2 tumors tested for RAS and BRAF
(n = 321)
(n = 320)
WT KRAS exon 2/MT other RAS, n (%)
57 (18)
51 (16)
KRAS exon 3 (codon 61), n (%)
Failure
306 (95)
14 (4)
1 (0)
308 (96)
10 (3)
2 (1)
KRAS exon 4 (codons 117/146), n (%)
296 (92)
15 (5)
288 (90)
21 (7)
11 (3)
NRAS exon 2 (codons 12/13), n (%)
307 (96)
0 (0)
8 (3)
4 (1)
NRAS exon 3 (codon 61), n (%)
305 (95)
12 (4)
3 (1)
NRAS exon 4 (codons 117/146), n (%)
313 (98)
8 (2)
316 (99)
BRAF exon 15 (codon 600), n (%)
280 (87)
29 (9)
286 (89)
24 (8)
Oliner J, et al. J Clin Oncol. 2013;31(Suppl): Abstract Oliner J, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 2275.

27. Revised PRIME Consort Diagram
Douillard et al: NEJM, 2013

28. PRIME: Updated OS Analysis
Proportion Alive (%)
Months
Overall Survival in the Primary-Analysis Population
Overall Survival in the Updated-Analysis Population
No.at Risk
Panitumumab-FOLFOX
FOLFOX4 alone
Panitumumab-FOLFOX
FOLFOX4 alone
Events Median Mo
no./total no. (%) (95% CI)
Panitumumab- 204/259 (79) 25.8 (21.7–29.7) FOLFOX4
FOLFOX4 alone 218/253 (86) 20.2(17.6–23.6)
Hazard ratio, 0.78 (95% CI, 0.62–0.99) P=0.043
Hazard ratio, 0.77 (95% CI, 0.64–0.94) P=0.009
Panitumumab- 128/259 (49) 26.0 (21.7–30.4) FOLFOX4
FOLFOX4 alone 148/253 (58) 20.2(17.7–23.1)
Douillard et al, 2013.

29. FIRE-3 Phase III Study Design
Patients
mCRC
KRAS wild-type
ECOG PS 0-2
1st line therapy; prior adjuvant chemotherapy allowed if completed >6 mo before inclusion
N=592
FOLFIRI + Cetuximab (Cetuximab: 400 mg/m2 loading dose; 250 mg/m2 weekly)
1:1 Randomization
FOLFIRI + Bevacizumab (Bev: 5 mg/kg every 2 weeks)
Primary endpoint: Response Rate
Heinemann V. ASCO Abstract LBA3506.

30. FIRE-3: Overall Response Rate
Endpoint
FOLFIRI + Cetuximab
FOLFIRI + Bevacizumab OR
P Value
ORR, intent-to-treat (ITT) population (N=592)
62.0%
58.0%
( )
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%
ORR, Evaluable (N=526)
72.2%
63.1%
1.52 ( )
0.017
Heinemann V. ASCO Abstract LBA3506.

31. Consort FIRE-3 Diagram KRAS unknown= 30 No treatment= 13
mCRC 1st-line unselected patients
KRAS unknown= 30
No treatment= 13
No treatment KRAS mt = 4
N=592
KRAS exon 2 wild-type ITT population
N=113
KRAS exon 2 mutant population*
N=407 (69%)
RAS evaluable population
N=58
FOLFIRI +
Cetuximab
N=55
FOLFIRI +
Bevacizumab
N=342
RAS wild-type
N=65 (16%)
‘New’ RAS mutant
N= 171
FOLFIRI +
Cetuximab
N= 171
FOLFIRI +
Bevacizumab
N= 34
FOLFIRI
Cetuximab
N= 31
FOLFIRI +
Bevacizumab
Stinzing et al: ESMO, 2013 31 31

32. 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
HR 0.70 (95% CI: 0.53 – 0.92)
p (log-rank)= 0.011
1.0
0.75
Probability of survival
0.50
Δ = 7.5 months
0.25
0.0
0.0 12 24 36 48 60 72
months since start of treatment
No. at risk
171
128
127 71 68 39 26 20 9 6 1
Stinzing et al: ESMO, 2013
* KRAS and NRAS exon 2, 3 and 4 wild-type 32 32

33. FIRE-3 Update: Overall Survival by All-RAS Mutation Status
Study Population
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
Stintzing S. European Cancer Conference Abstract LBA17.

34. Pending Trials

35. CALGB/SWOG 80405: Pending results
PleXus Communications
4/19/2017
CALGB/SWOG 80405: Pending results
Study amended: Wild-type KRAS tumors only
RANDOMIZE
FOLFOX or FOLFIRI* + cetuximab
First-line mCRC
Amended accrual; N=2300 wild-type patients
FOLFOX or FOLFIRI* + cetuximab + bevacizumab
FOLFOX or FOLFIRI* + bevacizumab

36. BOS-2 (EORTC 40091): Phase II KRAS WT Resectable Liver Mets
PleXus Communications
4/19/2017
BOS-2 (EORTC 40091): Phase II KRAS WT Resectable Liver Mets
Study amended: Wild-type KRAS tumors only
RANDOMIZE
FOLFOX
First-line mCRC
N=360
FOLFOX + bevacizumab
FOLFOX + panitumumab
Primary Endpoint: PFS

37. BOS -3 (EORTC-1207) Phase II/III Study Design (Pending)
Patients
mCRC
KRAS MT
ECOG PS 0-1
1st line therapy; prior adjuvant chemotherapy allowed if completed >12 mo before inclusion
FOLFOX + Aflibercept (Aflibercept: 4 mg/m2)
1:1 Randomization
FOLFOX
Primary endpoint: PFS

38. 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.