ECCO 2009 GI Update: Focus on EGFR Inhibitors in Metastatic Colorectal CA (mCRC)

www.OncologyEducation.ca

ECCO 2009 GI Update:Focus on EGFR Inhibitors in

Metastatic Colorectal CA (mCRC)

Scott Berry

Sunnybrook Odette Cancer Centree

Overview

• EGFR Inhibitors in mCRC– NEW DATA:

– Pmab in combination with chemo data» 1st Line with FOLFOX» 2nd Line with FOLFIRI

– Cetuximab in combination with CAPOX/FOLFOX - MRC COIN Trial

– Updated cetuximab 1st line data• CRYSTAL - updated• OPUS – updated


What did we know before ECCO 2009?


StatisticallySignificant

ResultsIn Red

KRASWT

RR %Median

PFS/TTP(mos)

Median OS(mos)

FIRSTLINE

CRYSTAL(FOLFIRI+/-

Cetux)59 vs 43

9.9 vs 8.7 mos

(HR=0.68)(10 Outcome)

24.9 vs 21.0(HR0.84)P=0.22

OPUS(Rand Phase II

FOLFOX +/- Cetux)61 vs 37

7.7 vs 7.2Mos

(HR=0.57)?

SECONDLINE

EPIC(Iri +/- cetux)

NR

3.98 vs 2.79Mos

(HR=0.77)P=0.095

NR

THIRD LINE

P-mab(Pmab vs BSC)

17 vs 012.3 vs 7.3

Weeks(HR=0.45)

NR(Crossover)

NCIC CO.17(Cetux vs BSC)

NR3.8 vs 1.9

Mos(HR=0.40)

9.5 vs 4.8 Mos

(HR=0.55)


What did we find at ECCO2009? FIRST LINE


R

FOLFOX4 + Pmab 6 mg/kg q 2 wks

FOLFOX4

N= 656 KRAS WT(1183 total - 92% evaluated for KRAS)

1o Outcome: PFS

“PRIME” Study Design

mCRCNo prior oxali> 6 mos after adj 5FUECOG 0-2 www.OncologyEducation.ca

RESULTS

FOLFOXFOLFOX+Pmab

p-value

Response Rate 48% 55% p=0.07

PFS(median) 8 mos 9.6 mos p=0.02

OS (median) 18.8 NE

HR=0.83p=0.16


Gr 3/4 TOXICITY

FOLFOX (%)FOLFOX

+Pmab (%)

Patients with any event 73 80

Skin toxicity 1 30

Neutropenia 47 37

Diarrhea 10 20

Stomatitis 3 6

Hypomagnesemia <1 6

Paronychia 0 2

Pulmonary embolismb4 3 (2 deaths)

Infusion-related reaction (panitumumab) - <1


CRYSTAL Trial Updated

RANDOMI ZE

1:11:1

FOLFIRI + CetuximabN=608

FOLFIRIN=609

10 Endpoint= PFS

N=1217EGFR expressionvia IHC

* Cetuximab 400 mg/m* Cetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m22 IV weekly IV weekly


OPUS: Rand Phase IIUpdated

RANDOMI ZE

1:11:1

FOLFOX + CetuximabN=170

FOLFOXN=168

N=338EGFR+Metasatic CRC

* Cetuximab 400 mg/m* Cetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m22 IV weekly IV weekly


%Evaluated for KRAS

%KRAS WT

CRYSTAL 88% 63%

OPUS 93% 57%


UPDATED CRYSTAL RESULTS

FOLFIRIFOLFIRI

+Cetuximabp-value

Response Rate (%) 40% 57% p<0.0001

PFS (median) 8.4 mos 9.9 mos p=0.0012

OS (median) 20 mos 23.5 mos p=0.01


FOLFOXFOLFOX

+Cetuximabp-value

Response Rate 34% 57% p=0.003

PFS(median) 7.2 mos 8.3 mos p=0.006

OS (median) 18.5 mos 22.8 mos p=0.38

UPDATED OPUS RESULTS


R

CAPOX/ FOLFOX

CAPOX/ FOLFOX + CETUXIMAB

N= 729 KRAS WT(80 % analyzed,56% WT)

1o Outcome: OS

MRC COIN Study Design

First Line mCRC

PS0-2

66% RECEIVED CAPOX


RESULTS

CAPOX/FOLFOX

CAPOX/ FOLFOX+ CETUX

p-value

PFS (median) NS



TOXICITY

CAPOX/FOLFOX(%)

CAPOX/FOLFOX+ Cetux

(%)

Diarrhea 14 25

Rash <1 21

Lethargy 19 26

HFS 4 11

Hypomagnesemia 0 5

Peripheral Neuropathy 19 14


STUDY COMMENTARY

• Capecitabine Arm - Analyses not complete but:– Had much higher rates of non-haem toxicity

leading to dose reductions and trial amendment - reduction of dose form 2000 mg/m2 to 1700 mg/m2 (Adams, Br J Cancer, 2009)

– Hope to have updated analysis at ASCO GI 2010 further examining the issue of efficacy and toxicity of capecitabine cetuximab combination and impact on overall trial results


STUDY COMMENTARY

• Median survivals in both study arms lower than other contemporary first line chemo /biologic trials– ? patient population

• 9% > 75

• 8% ECOG 2

– ? access to subsequent line tx options

What did we find out at ECCO 2009? SECOND LINE



R

FOLFIRI + Pmab 6 mg/kg q 2 wks

FOLFIRI

N= 597 KRAS WT(1186 total - 92% evaluated for KRAS)

1o Outcome: PFS and OS

Study Design

mCRCProgression < 6 mos after 1 prior TherapyNo prior IriECOG 0-2


RESULTS

FOLFIRIFOLFIRI+Pmab

p-value

Response Rate (%) 10% 35% p<0.001

PFS (median) 3.9 mos 5.9 mos p=0.004



Gr 3/4 TOXICITYFOLFIRI FOLFIRI

+Pmab

Patients with any event 52 73

Skin toxicity 2 37

Diarrhea 9 14

Stomatitis 3 8

Pulmonary embolism3 2 5

Dehydration 2 3

Hypomagnesemia <1 3

Paronychia <1 3

Infusion-related reaction (panitumumab) - <1

Fatal adverse events 6 4

Summing Up:What do we know after ECCO 2009?

First Line Trials:KRAS WT

(Significant Results in Red)RR %

Median PFS/TTP

(mos)

Median OS(mos)

CRYSTAL(FOLFIRI+/-Cetux)

Van Cutsem, NEJM

59 vs 439.9 vs 8.7(HR=0.68)

(10 Outcome)

23.5 vs 20(HR=0.80)

PRIME(FOLFOX+/-Pmab)

55 vs 489.6 vs 8.0(HR=0.80)

(10 Outcome)

NS

COIN(CapeOx/FOLFOX+/-Cetux)

NS17.0 vs 17.9(HR=1.04)

P=0.68

OPUS(Rand Phase II

FOLFOX +/- Cetux)57 vs 34

8.3 vs 7.2(HR=0.57)

22.8 vs 18.5(HR=0.86)

p=0.38


Second Line Trials:KRAS WT

(Significant Results in Red)RR %

Median PFS/TTP

(mos)

Median OS(mos)

EPIC(Iri +/- cetux)

NR4.0 vs 2.8(HR=0.77)P=0.095

NR

FOLFIRI +/- Pmab

35 vs 105.9 vs 3.9(HR=0.73)

14.5 vs 12.5(HR=0.85)

P=0.11



Bottom Line for Canadian Medical Oncologists (1)

– EGFR Inhibitors in mCRC - Survival benefit now demonstrated:

• in 3rd line as monotherapy • with FOLFIRI + Cetux 1st line• FOLFIRI + Cetux emerges as credible 1st line

option for KRAS WT patients» ...but not a funded option in Canada at this time

– NCIC CRC.5 will address issue of which chemo + biolologic combination is superior first line

» Chemo + Bevacizumab vs Chemo + Cetuximab» Double biologic arm dropped by intergroup

FOLFOX or FOLFIRI, and bevacizumab

FOLFOX or FOLFIRI, and cetuximab

Previously untreated patients with mCRC

FOLFOX or FOLFIRI, bevacizumab and cetuximab

R

Primary Endpoint: Overall Survival

CALGB 80405 / CRC5NCIC Chair: S Berry

X www.OncologyEducation.ca


Bottom Line for Canadian Medical Oncologists (2)

• EGFR Inhibitors in mCRC - PFS benefit seen with

– FOLFOX + Pmab first line – FOLFIRI + Pmab second line– Further analyses of Pmab combos awaited

• MRC COIN Trial– ? choice of chemo NB : preliminary signal re CAPOX +

cetuximab - further information/analyses of efficacy and safety of COIN trial needed - hopefully available at ASCO GI 2010

Documents

ECCO 2009 GI Update: Focus on EGFR Inhibitors in Metastatic Colorectal CA (mCRC)