Department of GI Medical Oncology

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 CenterDirector of Network Clinical Research, GI Med Onc

March 28, 2014

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 RectumInternational Statistics

Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014

Incidence

Mortality

1.2 Million

609,000

Worldwide

per annum

USA (2014)

Incidence

Mortality

136,830

50,310

Colorectal cancer is the 3rd most common cancer inmen and the 2nd in women.

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%) Unresectable

+/- Adjuvant Therapy

Surgery

Neoadjuvant/Preoperative

Therapy

First-Line

Second-Line

Palliation

Borderline/PotentiallyResectable

(20%)

NCCN, 2010.

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

Randomize

SurgeryFOLFOX4 FOLFOX4

Surgery

6 cycles (3 months)

N=364 patients

6 cycles(3 months)

Primary endpoint: PFS

Nordlinger et al: Lancet 2008; Lanc Onc 2013

EORTC 40983: PFS in Eligible Patients

HR= 0.77; CI: 0.60-1.00, p=0.041

Periop CT

28.1%

36.2%

+8.1%At 3 years

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :125 171 83 57 37 22 8115 171 115 74 43 21 5

Surgery only

After a median follow-up of 8.5 yrs, no difference in 5-yr OS (51% vs. 48%, p=0.34)

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

Randomize

SurgeryFOLFOX4 + Cetuximab

FOLFOX4 + Cetuximab

FOLFOX

6 cycles (3 months)

N=621 patients

6 cycles(3 months)

Primary endpoint: PFS

Nordlinger et al: Lancet 2008; Lanc Onc 2013

Surgery FOLFOX

New EPOC Phase III Study: Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC

Randomize

SurgeryFOLFOX4 + Cetuximab

FOLFOX4 + Cetuximab

FOLFOX

6 cycles (3 months)

N=272/621 patients

6 cycles(3 months)

Primary endpoint: PFS

Nordlinger et al: Lancet 2008; Lanc Onc 2013

Surgery FOLFOX

New EPOC: Neoadjuvant Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC: PFS

Median PFS 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

Primrose JN, et al. ASCO 2013. Abstract 3504.

Prop

ortio

n pr

ogre

ssio

n fr

ee

1.00

0.75

0.50

0.25

0.00

0 6 12 18 24 30 36 42 48 54 60Time to progression or death (months)

HR: 1.49 (95% CI: 1.04-2.12); P = .030

Number at riskChemo alone

Chemo + Cetuximab 116

117

89

87

65

54

38

24

23

15

12

5

5

3

2

2

1

1

1

0

0

0

Chemo aloneChemo + cetuximab

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

• Tumor tissue from primary tumor or metastasis available for biomarker analysis

• ECOG PS 0-2

• N=1198

Primary Endpoint: PFS

FOLFIRI + Cetuximab

1:1 Randomization

FOLFIRI

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, 34-42).• 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

• N=2445

Primary Endpoint: OS

XELOX

1:1 Randomization

XELOX + Cetuximab

Maughan et al Lancet 2011:

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 8.6 +0.072-year survival

rates 8.83% 9.55% +0.72%

OS (primary analysis) and PFS among KRAS wild-type patients0.

000.

250.

500.

751.

00S

urvi

val

362 306 238 149 80 42 17 3 B

367 316 250 154 83 44 19 1A

N patients at risk:

0 6 12 18 24 30 36 42Time (months)

Arm A (OxFp)

Arm B (OxFp + cetux)

HR point estimate = 1.03895% CI = (0.90, 1.20)Χ2 = 0.18; p = 0.68

Overall Survival Progression-free Survival

361 249 103 42 22 9 6 0

367 245 92 41 18 11 6 1

0 6 12 18 24 30 36 42Time (months)

HR point estimate = 0.95995% CI = (0.84, 1.09)Χ2 = 0.27; p = 0.60

Arm A (OxFp)

Arm B (OxFp + cetux)

CELIM: Phase II

.

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

Primary Endpoint: RR

FOLFOX + cetuximab

1:1 Randomization

FOLFIRI + cetuximab

Folprecht; Lancet Onc, 2010; Annals of Onc, 2014

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, 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]%.

CELIM STUDY – Tumor response and resectability of colorectal liver metastases following neoadjuvant

chemotherapy with cetuximab

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

Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.

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=1183Primary Endpoint: PFS

Panitumumab 6.0 mg/kg q 2 wkFOLFOX4 q 2 wk

1:1 Randomization

FOLFOX4 q 2 wk

Median (mos)(95% CI)

Panitumumab + FOLFOX4

10.1 (9.3-12)

FOLFOX4 7.9 (7.2-9.3)

HR = 0.72 (95% CI: 0.58 – 0.90) Log-rank p-value = 0.004

Median (mos) (95% CI)

Panitumumab + FOLFOX4

7.4 (6.9 – 8.1)

FOLFOX4 9.2 (8.1 – 9.9)

HR = 1.27 (95% CI: 1.04 – 1.55)Log-rank p-value = 0.02

WT KRAS MT KRAS

Pro

porti

on E

vent

-Fre

e

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pro

porti

on E

vent

-Fre

e

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44

Douillard et al: JCO, 2010; NEJM 2013

PRIME (FOLFOX +/- Panitumumab)PFS by KRAS Mutation Status

RR: 55% vs. 48%, P = .068.

PRIME Biomarker Analysis: Analysis of KRAS/NRAS and BRAF Mutations

RAS and BRAF Status FOLFOX4 Alone Panitumumab + FOLFOX4

KRAS exon 2 (codon 12/13) WTMT

331219

325221

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 (%)WTMT

Failure

306 (95)14 (4)1 (0)

308 (96)10 (3)2 (1)

KRAS exon 4 (codons 117/146), n (%)WTMT

Failure

296 (92)15 (5)10 (3)

288 (90)21 (7)11 (3)

NRAS exon 2 (codons 12/13), n (%)WTMT

Failure

307 (96)14 (4)0 (0)

308 (96)8 (3)4 (1)

NRAS exon 3 (codon 61), n (%)WTMT

Failure

305 (95)14 (4)2 (1)

305 (95)12 (4)3 (1)

NRAS exon 4 (codons 117/146), n (%)WTMT

Failure

313 (98)0 (0)8 (2)

316 (99)0 (0)4 (1)

BRAF exon 15 (codon 600), n (%)WTMT

Failure

280 (87)29 (9)12 (4)

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

Douillard et al, 2013.

PRIME: Updated OS Analysis

Prop

ortio

n A

live

(%)

Months

Months

Prop

ortio

n A

live

(%)

Overall Survival in the Primary-Analysis Population

Overall Survival in the Updated-Analysis Population

No.at RiskPanitumumab-FOLFOX4 259 189 88

0FOLFOX4 alone 253 174 65

0

No.at RiskPanitumumab-FOLFOX4 259 189 129 83

49 14FOLFOX4 alone 253 176 104 60

30 8

EventsMedian 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

EventsMedian Mo

no./total no. (%)(95% CI)

Panitumumab- 128/259 (49) 26.0 (21.7–30.4)FOLFOX4

FOLFOX4 alone 148/253 (58) 20.2(17.7–23.1)

FIRE-3 Phase III Study Design

Heinemann V. ASCO 2013. Abstract LBA3506.

Patients• mCRC

• KRAS wild-type

• ECOG PS 0-2

• 1st line therapy; prior adjuvant chemotherapy allowed if completed >6 mo before inclusion

• N=592 Primary endpoint: Response Rate

FOLFIRI + Cetuximab(Cetuximab: 400 mg/m2 loading dose;

250 mg/m2 weekly)

1:1 Randomization

FOLFIRI + Bevacizumab(Bev: 5 mg/kg every 2 weeks)

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% 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%

ORR, Evaluable (N=526) 72.2% 63.1% 1.52(1.05-2.19) 0.017

Heinemann V. ASCO 2013. Abstract LBA3506.

Consort FIRE-3 Diagram

N=592KRAS exon 2 wild-type

ITT population

N=407 (69%)RAS evaluable population

N=65 (16%)‘New’ RAS mutant

N=342RAS wild-type

N= 171 FOLFIRI +Cetuximab

N= 34FOLFIRI

Cetuximab

N= 171 FOLFIRI +

Bevacizumab

N= 31FOLFIRI +

Bevacizumab

N=752mCRC 1st-line

unselected patients

N=58FOLFIRI +Cetuximab

N=55FOLFIRI +

Bevacizumab

N=113KRAS exon 2 mutant

population*

KRAS unknown= 30No treatment= 13

No treatment KRAS mt = 4

Stinzing et al: ESMO, 2013

Eventsn/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

FIRE-3: Overall survival RAS* all wild-type

0.012 24 36 48 60 72

months since start of treatment

171171

No. at risk

128127

7168

3926

209

61

0.75

1.0

0.50

0.25

0.0

Prob

abili

ty o

f sur

viva

l

Δ = 7.5 months

* KRAS and NRAS exon 2, 3 and 4 wild-typeStinzing et al: ESMO, 2013

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 2013. Abstract LBA17.

Pending Trials

CALGB/SWOG 80405: Pending results

RANDOMIZE

FOLFOX or FOLFIRI* + cetuximab

• First-line mCRC

• Amended accrual; N=2300 wild-type patients

FOLFOX or FOLFIRI* + cetuximab + bevacizumab

FOLFOX or FOLFIRI* + bevacizumab

Study amended: Wild-type KRAS tumors only

BOS-2 (EORTC 40091): Phase II KRAS WT Resectable Liver Mets

RANDOMIZE

FOLFOX

• First-line mCRC

• N=360

FOLFOX + bevacizumab

FOLFOX + panitumumab

Study amended: Wild-type KRAS tumors only

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)

http://www.clinicaltrials.gov/ct2/show/NCT01646554?term=BOS-2&rank=2

Patients• mCRC

• KRAS MT

• ECOG PS 0-1

• 1st line therapy; prior adjuvant chemotherapy allowed if completed >12 mo before inclusion

Primary endpoint: PFS

FOLFOX + Aflibercept(Aflibercept: 4 mg/m2)

1:1 Randomization

FOLFOX

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.