Discussion on Abstracts 362, 363, 364, Discussion on Abstracts 362, 363, 364, 365, and 366365, and 366

or…We still have a lot to learn about or…We still have a lot to learn about colorectal cancercolorectal cancer

Johanna Bendell, MDJohanna Bendell, MD

Director, GI Oncology ResearchDirector, GI Oncology Research

Associate Director, Drug Development Associate Director, Drug Development ProgramProgram

Sarah Cannon Research InstituteSarah 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)

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???

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

1.13

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%– FOLFOX 72.3% vs. 75.8%

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???

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…

1. Huang SM, Canc Res 1999, 2. Buchsbaum DJ, Int J Rad Oncol Biol Phys 2002, 3. Pery D, Cancer Res 19964. 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

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 8.6 17 64

OPUS

FOLFOX 7.2 18.5 37

+ cetux 7.7 22.8 61

PRIME

FOLFOX 8.0 19.7 48

+ pmab 9.6 23.9 55

CRYSTAL

FOLFIRI 8.7 21.0 43.2

+ cetux 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

Kopetz, et al Cancer Res 2009, Liu et al Cancer Res 2007

Oxaliplatin

Srcactivity

Signal Transduction

R R

Y YSrc

Kopetz GI ESMO 2010

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 C-met/Hepatocyte Growth Factor PathwayFactor 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 PopulationPFS, 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