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 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

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 Borderline/ Potentially Resectable (20%) First-Line Neoadjuvant/ Preoperative Therapy Second-Line Surgery Palliation +/- Adjuvant Therapy 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 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

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 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

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 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

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

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: 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 1.00 HR: 1.49 (95% CI: 1.04-2.12); 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 116 117 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 2013. Abstract 3504.

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 FOLFIRI + Cetuximab 1:1 Randomization FOLFIRI 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, 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 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:

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

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 .

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, 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 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;28:4697-4705.

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 (7.2-9.3) 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

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 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 (%) Months Overall Survival in the Primary-Analysis Population Overall Survival in the Updated-Analysis Population No.at Risk Panitumumab-FOLFOX4 259 189 88 0 FOLFOX4 alone 253 174 65 0 Panitumumab-FOLFOX4 259 189 129 83 49 14 FOLFOX4 alone 253 176 104 60 30 8 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.

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 2013. Abstract LBA3506.

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 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

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

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 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

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 http://www.clinicaltrials.gov/ct2/show/NCT01508000?term=BOS-2&rank=1

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 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.