BOPA 2009

Clinical Update:

Colorectal Cancer

Dr Nick Maisey

Treatment Intent

Adjuvant Palliative

ADJUVANT CHEMOTHERAPY

Moertel et al, 1990 / 1995

CALGB 89803. Saltz et al ASCO 2004

ACCORD-2 Trial, Ychou et al ASCO 2005

PETACC-3, Van Cutsem, ASCO 2005

Irinotecan in Adjuvant Therapy

ACCORD-2: Ychou et al, ASCO 2005 PETACC 3: Van Cutsem et al, ASCO 2005

CALGB 89803: Saltz et al, ASCO 2004

Copyright © American Society of Clinical OncologyAndre, T. et al. J Clin Oncol; 27:3109-3116 2009

Overall survival (A) by treatment arm and (B) by treatment arm and by stage

Oxaliplatin: MOSAIC TrialFU/LV FOLFOX

5Y DFS (III) 58.9% 66.4% 7.5% p=0.005

5Y DFS (II) 79.9% 83.7% 3.8% p=NS

5Y DFS (HRII) 74.6% 82.3% 7.7% p=NS

6Y OS (III) 76% 78.5% 2.5% p=0.045

6Y OS (II) 86.8% 86.9% 0.1% p=NS

Adjuvant Biologics

Bevacizumab

Cetuximab

NSABP C-08

AVANT

QUASAR-2

PETACC-8

Intergroup 0147

NSABP C-08

RStage II / III

CRC

(n=2714)

FOLFOX 6/12

FOLFOX 6/12

AVASTIN 12/12

Wolmark et al, JCO 2009

NSABP-C08

3Y DFS 1.0 1.5 2.0 2.5 3.0

FOLFOX 75.5%

(n=1338)

0.6 0.74 0.81 0.85 0.87

0.0004 0.004 0.02 0.05 0.08

FOLFOX-B 77.4%

(n=1334)

Adjuvant Summary

• Most patients benefit from a FP

• Irinotecan does not work

• Oxaliplatin has small but significant OS effect

• Data supports use of oral FP

• No data to support Biologics

PALLIATIVE CHEMOTHERAPY

Patient outcomes have improved with the evolution of mCRC treatment options

Median OS

Mo

nth

s

BSC5-FU

30

25

20

15

10

5

0

1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 20043. Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM 2004

5. Karapetis, et al. NEJM 2008

Irinotecan1

Capecitabine2

Oxaliplatin3

Cetuximab5

Bevacizumab4

1980s 1990s 2000s 2009

BSC = best supportive care

What order to give the drugs?

Tournigand et al, JCO 2004

Survival and Access to 3 Drugs

Grothey et al, JCO 2004

Avastin: mechanism of action

EARLY BENEFITCONTINUED BENEFIT

Regressionof existing microvasculatureNormalisationof surviving microvasculature

Inhibitionof vessel regrowth and neovascularisation

First-Line Avastin and Irinotecan

Adapted from 1. Hurwitz H et al. N Engl J Med 2004;350(23):2335-42. 2. Hurwitz H et al. J Clin Oncol 2005;23(15):3502-8.

* p<0.001 Avastin + IFL vs IFL alone

4535 39

IFL +placebo1

(n=411)

Overall response rate (%)

Duration of response (months)

Median overall survival (months)*

Median progression-freesurvival (months)*

IFL +Avastin1

(n=402)

5-FU/FA +Avastin2

(n=110)

10.47.1 8.5

20.315.6 18.3

10.66.2 8.8

NO16966: XELOX ± Avastin vsFOLFOX ± Avastin in first-line mCRC

Initial two-arm

open-label study

(n=1 000)

Protocol amended to 2x2 placebo-controlled design after Avastin

Phase III data became available (n=1 400)

RecruitmentJune 2003 – May

2004 XELOX +placebo

n=350FOLFOX4 +

placebo n=351

XELOX + Avastinn=350

FOLFOX4 + Avastinn=349

XELOX n=317

FOLFOX4 n=317

RecruitmentFebruary 2004 – February

2005

Cassidy, et al. J Clin Oncol 2008Cassidy, et al. ASCO GI 2008

Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008

Second Line FOLFOX-B

OS (months)

Est

ima

ted

pro

bab

ilit

y

FOLFOX4 + bevacizumab

FOLFOX4

1.0

0.8

0.6

0.4

0.2

0

Second-line2

Median OS10.8 vs 12.9 months(HR=0.75; p=0.0011)

0 10 20 30 40

12.910.8

Giantonio et al, JCO 2007

829pts pretreated with

5FU + Irinotecan

R

FOLFOX

(RR=8.6%)

FOLFOX-B

(RR=22.7%)

B

(RR=3.3%)

Duration of Treatment?

Bev No Bev

Hurwitz 40.4 wks 27.6 wks

Saltz 27.1 wks* 25.1 wks

*discontinuations for chemo tox

BRiTE:* continuation of bevacizumab post-

first progression significantly increases OS‡

Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008

*Non-randomised, observational trial‡Time from initiation of first-line treatment to death

OS (months)

12.6 19.9 31.8

Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57)

0 5 10 15 20 25 30 35

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed p

rob

abil

ity

p<0.001

Post-progression therapyBevacizumab post-PD (n=642)No bevacizumab post-PD (n=531)No treatment (n=253)

The EGFr Antibodies

Cetuximab In Irinotecan Refractory mCRC

CETUXIMAB + IRINOTECAN CETUXIMAB ALONE

Saltz 2001 Saltz 2004Cunningham 2003

22.5% 22.9% 10.8% 8.8%

(1) Saltz et al, ASCO 2001

(2) Cunningham et al, NEJM 2004

(3) Saltz et al, JCO 2004

The role of KRAS

KRAS wild-type and EGFR inhibitor efficacy in chemorefractory CRC: Response

10 (31)

Reference Treatment

No. of patients (wild-type:

mutant)

Objective responsen (%)

Wild-type Mutant

Lièvre A, et al. J Clin Oncol 2008 CETUXIMAB ± CT 114 (78:36) 34 (44) 0 (0)

Benvenuti S, et al. Cancer Res 2007 Panitumumab or CETUXIMAB or

CETUXIMAB + CT

48 (32:16) 1 (6)

DeRoock W, et al. Ann Oncol 2008 CETUXIMAB or CETUXIMAB +

irinotecan

113 (67:46) 27 (41) 0 (0)

Capuzzo F, et al. Br J Cancer 2008 CETUXIMAB ± CT 81 (49:32) 13 (26) 2 (6)

Di Fiore F, et al. Br J Cancer 2007 CETUXIMAB + CT 59 (43:16) 12 (28) 0 (0)

Khambata-Ford S, et al. J Clin Oncol 2007 CETUXIMAB 80 (50:30) 5 (10) 0 (0)

Amado RG, et al. J Clin Oncol 2008 Panitumumab 208 (124:84) 21 (17) (0)

Karapetis CS, et al. NEJM 2008 CETUXIMAB + BSC or BSC

287 (117:81) 15 (12.8) 1 (1.2)

Wild type rasMutant ras

KRAS mutation on PFS with panitumumab v BSC: a predictive marker

Amado et al, JCO 2008

NCIC CTG C0.17: Overall survival in NCIC CTG C0.17: Overall survival in K-rasK-ras Wild-Type patientsWild-Type patients

HR HR 0.550.55 95% CI (0.41,0.74)95% CI (0.41,0.74)

Log rank p-value:Log rank p-value: <0.0001<0.0001

Study armStudy arm MS MS (months)(months)

95% CI95% CI

Cetuximab + BSCCetuximab + BSC 9.59.5 7.7 – 10.37.7 – 10.3

BSC aloneBSC alone 4.84.8 4.2 – 5.54.2 – 5.5

Karapetis CS, et al. NEJM 2008; 359:17, 1757 -1765

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18

Time from Randomisation (Months)

Pro

port

ion A

live

Cetuximab

BSC

CetuximabBSC

117 108 95 81 52 34 20 9 6 2113 92 69 36 24 17 12 5 3 3

Log rank p<0.001

Cetuximab used First-Line in KRAS w/t mCRC

CRYSTAL1 OPUS2

FOLFIRI

FOLFIRI-C

FOLFOX

FOLFOX-C

N=1217 / 540 N=337 / 233

med PFS 8.7 9.9 7.2 7.7

ORR 43% 59% 37% 61%

med OS 21.0 24.9 - -

(1) Van Cutsem et al, NEJM 2009

(2) Bokemeyer et al, JCO 2009

Palliative Chemotherapy: Summary

• Survival continues to improve• Avastin appears to improve overall survival if used

‘optimally’• Patients with mutated KRAS do not benefit from

cetuximab• Cetuximab confers survival advantage in chemo-

resistant disease• First line cetuximab improves PFS and RR

Neoadjuvant Chemotherapy

Rationale

• ‘In-Vivo’ test of sensitivity

• Kill off microscopic disease

• Down-size to allow operability

Curing Metastatic Disease

Who is considered for curative liver resection?

No Bilobar Disease

No more than 3 mets

No extra-hepatic disease

Marathon runner fitness

Untreatable primary

Insufficient remant liver

Unresectable extra-hepatic disease

Progression through chemo

Resection rate of metastases and tumour response

Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001)

Studies including selected patients(liver metastases only, no extrahepatic disease)(r=0.96; p=0.002)

Phase III studies including nonselected patients with mCRC (dashed line)(r=0.67; p=0.024)

Response rate0.90.80.70.60.50.40.3

Res

ecti

on

rat

e

0.6

0.5

0.4

0.3

0.2

0.1

0

Folprecht G, et al. Ann Oncol 2005;16:1311–1319

Survival after ‘down-sizing’ in initially unresectable disease

Bismuth et al, Ann Surg 1996

Effect of Cetuximab in KRAS w/t tumoursR

esp

on

se r

ate

(%

)

0

10

20

30

40

50

60

70 CRYSTAL OPUS

n=176 n=73n=172 n=61

59

3743

61

Chemotherapy alone

CETUXIMAB + chemotherapy

1. Van Cutsem E, et al.: NEJM 360(14): 1408-17 (2009); 2. Bokemeyer C, et al.: J Clin Oncol 27(5): 663-671 (2009)

RO resection FOLFIRI vs FOLFIRI-C

1.7% vs 4.8%

Odds ratio 3.02 (p=0.002)

EMR 604-CELIM study

Adjuvant therapy for

6 cycles (same schedule as

pre-operatively)R

Patients with technically unresectable/

≥5 liver metastases without extrahepatic disease

ERBITUX +

FOLFOX

(n=56)

8 cycles (~4 months)

Technically

resectable

Primary endpoint: Response rate

4 further treatme

nt cycles

RESECTION

ERBITUX +

FOLFIRI

(n=55)

Technically

unresectable

Folprecht et al. ASCO GI 2009 Abstract no. 296

Response rates

  FOLFOX6 + FOLFIRI + KRAS KRAS All

  ERBITUX ERBITUX wild-type mutant patients

n=53 n=53 n=67 N=28 n=106*

CR/PR 68% 57% 70% 43% 62%

(36 pts) (30 pts) (47 pts) (12 pts) (66 pts)

95% CI 54-80% 42-70% 58-81% 24-63% 52-72%

SD 28% 30% 21% 46% 29%

(15 pts) (16 pts) (14 pts) (13 pts) (31 pts)

PD 4% 13% 9% 11% 8%

(2 pts) (7 pts) (6 pts) (3 pts) (9 pts)

* 106 pts evaluable for efficacy

These are confirmed response rates

Folprecht et al. ASCO GI 2009 Abstract no. 296

Resection rates

  FOLFOX6 + FOLFIRI + KRAS All

  ERBITUX ERBITUX wt patients

n=53 n=53 N=67 n=106*

R0/R1 resect. /RFA 49% 43% NR 46%

 

R0 resections 38% 30% 33% 34%

  (20 pts) (16 pts) (22 pts) (36 pts)

* 106 pts evaluable for efficacy

Folprecht et al. ASCO GI 2009 Abstract no. 296

Bevacizumab: significant pathological response when combined with FOLFOX

1,2

100

80

60

40

20

0

Pat

ho

log

ical

res

po

nse

(%

)

1–8 cycles ≥9 cycles 1–8 cycles ≥9 cycles

FOLFOX FOLFOX + bevacizumab

Major responseComplete response

p=0.007

p=0.011

Pathological response predicts for survival2

Complete response: no residual cellsMajor response: 1–49% residual cellsMinor response: ≥50% residual cells 1. Zorzi, et al. ASCO GI 2009; 2. Blazer, et al. JCO 2008

NO16966: surgery with curative intentP

atie

nts

(%

) 6.1

8.4

12.9

19.2

(n=701) (n=699) (n=178) (n=177)

10

5

0

20

15

10

5

0

Pat

ien

ts (

%)

Placebo Avastin Placebo Avastin

ITT population Patients with liver metastases only

XELOX/FOLFOX4 + AvastinXELOX/FOLFOX4 + placebo

Saltz, et al. WCGC 2007

Neoadjuvant Therapy: Summary

• Metastatic disease can be cured• Higher response rates lead to higher resection rates• Cure depends on successful resection• Cetuximab increases reponse rate and R0 resections• Bevacizumab may augment neoadjuvant chemo