Discussion on Abstracts 362, 363, 364, 365, and 366 or…We still have a lot to learn about colorectal cancer Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Program Sarah Cannon Research Institute

Disclosures I have no relevant disclosures

Adjuvant Studies Abstract #362: AVANT, XELOX-bev vs. FOLFOX-bev vs. FOLFOX alone Abstract #363: N0147, FOLFIRI +/- cetuximab Abstract #364: Time to adjuvant chemotherapy

AVANT Eagerly anticipated given the results of NSABP C-08 3451 patients with high-risk stage II or stage III disease Stage III patient results presented here, 3 year minimum follow up Primary endpoint of DFS Well-designed, well-balanced

AVANT Results DFS (3-year minimum follow-up) DFS HR 1y 1.5y 2y 2.5y 3y HR FOLFOX-bev 1.17 (0.98,1.39) (73% 3y DFS) NSABP 74 vs. 72% 3 y DFS for Stage III HR XELOX-bev 1.07 (0.9,1.28) (75% 3y DFS) No difference HR for DFS at year 1, like NSABP C-08, was in favor of bev arms, but disappears after year 1 Does the DFS at years 2, 2.5, and 3 suggest rebound effect off bev? Sites of recurrence are similar between arms (no worse in bev arms) What about survival after recurrence??? Are they meaningful? Probably not – does not appear suggestive of rebound effect DFS HR 1y 1.5y 2y 2.5y 3y AVANT (X) 0.63 0.61 1.00 1.02 1.12 1.15 1.11 1.13 1.08 C-08 0.6 0.74 0.81 0.85 0.87

AVANT Results INTERIM OS HR FOLFOX-bev 1.31 (1.03,1.67) HR XELOX-bev 1.27 (0.99,1.62) Are these results suggestive of rebound effect? Results are not yet mature Time from recurrence to death No significant difference between the arms, but FOLFOX patients seem to do a bit better? BUT – more patients in FOLFOX arm saw bevacizumab after recurrence (35% vs. 16% and 20%) – did this make a difference?

N0147 – The FOLFIRI Arms Irinotecan-based therapy does not improve survival in the adjuvant setting PETACC-3, ACCORD2, CALGB 89803 3 yr DFS around 60% CALGB 89803 analysis with no difference in K-ras WT vs. mut Cetuximab plus FOLFOX does not improve survival in the adjuvant setting Report on 146 stage III patients treated with FOLFIRI (106) or FOLFIRI-cetuximab (40) Primary endpoint DFS Well-balanced Both arms 65% K-ras WT

N0147 - Results DFS Overall (n=146) 3 yr DFS 86.6% vs. 66.7% FOLFOX 72.3% vs. 75.8% K-ras WT (n=95) 3 yr DFS 92.3% vs. 69.8% K-ras mut (n=46) 3 yr DFS 82.5% vs. 56.3% FOLFOX 64.2% vs. 67.2% OS Overall (n=146) 3 yr OS 91.8% vs. 84.4% K-ras WT (n=95) 3 yr OS 92.0% vs. 85.2% K-ras mut (n=46) 3 yr OS 90.9% vs. 80.6% DFS data in the control arms look in line with previous irinotecan-based data K-ras mut patients benefit too? Small numbers Is micrometastatic disease different? Cetuximab-based treatment arms show very different results from previous studies with irinotecan or cetuximab – why??? CALGB 89803 analysis showed no difference in outcomes in Kras WT vs. Kras mut pts (62 vs. 63% 5 y survival) Ogino S et al, Clin Cancer Res 2009

Irinotecan and Cetuximab – A Story of Synergy Preclinical Synergy of EGFR inhibition and DNA damaging agents Cetuximab suppression of repair after DNA damaging agents1,2,3,4,5 Cetuximab increases pro-apoptotic molecules and decreases anti-apoptotic molecules, rendering cells more sensitive to cytotoxic chemotherapy6 Cellular stress increases EGFR pathway activation5 MDR pathways Certain MDR1 polymorphisms in the setting of EGFR inhibition decrease SN38 efflux7 Clinical Saltz, et al. and BOND 1 Irinotecan-refractory cancers respond to irinotecan plus cetuximab First line irinotecan vs. oxaliplatin cetuximab trials Irinotecan –based therapies seem better We’ll get to this in a moment… Story is not completely clear Huang SM, Canc Res 1999, 2. Buchsbaum DJ, Int J Rad Oncol Biol Phys 2002, 3. Pery D, Cancer Res 1996 4. Huang SM, Clin Cancer Res 2000, 5. Koizumi F, Int J Cancer 2004, 6. Ellis LM, J Clin Oncol 2004, 7. Paule B, Med Oncol 2010

Time to Adjuvant Therapy (TTAC)– an Issue in Trial Design and Overall Patient Treatment Previous adjuvant trials have allowed for patients to start within either 8 weeks (more recent) or 12 weeks postop Is there a difference in outcomes based on when a patient starts adjuvant therapy? Review of 9 adjuvant studies that data on waiting time 8 retrospective, 1 RCT All 5-FU based chemotherapy only Each 4 week delay from start of therapy results in a 12% increase in mortality Implications: Needs to be controlled in clinical trials Needs to be encouraged in health systems – importance of coordinated care

Where are we with adjuvant therapy? Adjuvant bevacizumab: No improvement in DFS or OS Prolonging bevacizumab therapy might hold down disease for some period of time, but at what cost? Adjuvant FOLFIRI plus cetuximab may work Treat patients as quickly as possible after surgery Should be controlled in clinical trials Common paradigms do not hold What works in the metastatic setting does not hold true for the adjuvant setting Is this a difference in tumor biology? Where should we go from here? Adjuvant bevacizumab development should stop for now Metastatic adjuvant setting? Proof of concept as single agent maintenance rx? FOLFIRI-cetuximab vs. FOLFOX? We need new agents We need biomarkers We are not curing more patients with bevacizumab – better in the metastatic adjuvant setting where recurrence rate is higher?

Metastatic Studies Abstract #365: NORDIC VII Study Abstract #366: AMG 102 or AMG 479 with panitumumab

NORDIC VII FLOX vs. FLOX-cetuximab vs. Intermittent FLOX with continuous cetuximab First-line therapy Primary endpoint PFS Arms were well-balanced Previous data of EGFR inhibitors with oxaliplatin-based regimens In K-ras WT patients, only 2 studies have shown an improvement in PFS (OPUS and PRIME) In K-ras mut patients, there are trends towards decreased survivals treating patients with anti-EGFR and oxaliplatin-based regimens Irinotecan-based regimens show stronger data (CRYSTAL)

EGFR Inhibitors in First-Line Therapy - Kras WT patients PFS WT (mo) OS WT (mo) RR WT (%) NORDIC FLOX 8.7 22.0 47 + cetux 7.9 20.1 46 COIN FOLFOX/CAPOX 8.6 17.9 57 +cetux 17 64 OPUS FOLFOX 7.2 18.5 37 7.7 22.8 61 PRIME 8.0 19.7 48 + pmab 9.6 23.9 55 CRYSTAL FOLFIRI 21.0 43.2 9.9 24.9 59.3

NORDIC VII This trial shows no improvement in outcomes for patients with cetuximab plus oxaliplatin-based therapy Is this an issue with the chemotherapy or an interaction with oxaliplatin and cetuximab? Trend towards worse outcomes for cetuximab-treated patients, but numbers are small

One possible reason for oxaliplatin and anti-EGFR negative outcomes Src is acutely and chronically activated by oxaliplatin Combination therapy is synergistic in vitro, in vivo EGFR can be activated by Src in the absence of ligand binding EGFR resistance in vitro is mediated by Src Oxaliplatin R R Src activity Src Y Y Signal Transduction Kopetz, et al Cancer Res 2009, Liu et al Cancer Res 2007 Kopetz GI ESMO 2010 16

New agents for colorectal cancer patients Combination therapies Panitumumab plus AMG 479 (IGF-1R antibody) Panitumumab plus AMG 102 (HGF antibody) K-ras WT patients Refractory to at least one previous chemotherapy and no prior anti-EGFR Primary endpoint RR RR better for AMG 102 plus pmab (31% vs. 21%) IGF-1R plus EGFR inhibitor combinations show no clear signals Median f/u 6.9 months (still early)

C-met/Hepatocyte Growth Factor Pathway Abouander R, 2004

c-met proof of concept in NSCLC - PFS and OS: Met High Population PFS, HR=0.56 OS, HR=0.55 MetMAb+Erlotinib improves both PFS and OS in Met High NSCLC patients Spigel, SCRI, ESMO 2010

c-met proof of concept in NSCLC - PFS and OS: Met Low Population PFS, HR=2.01 OS, HR=3.02 Met Low NSCLC Patients Do Worse with MetMAb+Erlotinib Spigel, SCRI, ESMO 2010

We have movement forward… Targeting of the c-met/HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer as well as NSCLC We await further PFS data Early look shows 5.2 mo vs. 3.7 mo Other c-met inhibitors are currently in trial in colorectal cancer patients Biomarker data will be important in assessing to see if c-met expression in colorectal cancers has same effect on outcomes as NSCLC