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Integration of EGFR targeting into first line therapy: is it time?. Prof Eric Van Cutsem, MD, PhD Leuven, Belgium. The Epidermal Growth Factor Receptor pathway. Scaltriti M & Baselga J. Clin Cancer Research 2006. Anti-EGFR antibodies in mCRC. cetuximab + irinotecan (n=218).

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Integration of EGFR targeting into first line therapy: is it time?

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Integration of egfr targeting into first line therapy is it time

Integration of EGFR targeting into first line therapy: is it time?

Prof Eric Van Cutsem, MD, PhD

Leuven, Belgium


Integration of egfr targeting into first line therapy is it time

The Epidermal Growth Factor Receptor pathway

Scaltriti M & Baselga J. Clin Cancer Research 2006


Anti egfr antibodies in mcrc

Anti-EGFR antibodies in mCRC


Cetuximab irinotecan in irinotecan refractory egfr mcrc response rate primary endpoint

cetuximab + irinotecan

(n=218)

cetuximab

(n=111)

Cetuximab +/- irinotecan in irinotecan refractory EGFR+ mCRC: Response rate (primary endpoint)

56[49-62]

**

60

50

*

32[24-42]

40

Percentage

23[18-29]

30

11[6-18]

20

10

0

Response Rate

Disease Control(CR+PR+SD)

* p=0.0074; ** p<0.001; [] = 95% CI

Cunningham D … Van Cutsem E. N Engl J Med 2004


Cetuximab and panitumumab in chemorefractory egfr expressing crc

Cetuximab and panitumumab in chemorefractory EGFR expressing CRC

¹Van Cutsem E et al, J Clin Onc 2007; ²Jonker D et al, N Engl J Med 2007; ³ Amado R, Van Cutsem E et al; Eur J Cancer (Proc ECCO), 2007


Epic trial cetuximab in second line treament of mcrc

EPIC trial: Cetuximab in second line treament of mCRC

Sobrero A et al. AACR 2007


Anti egfr antibodies in first line treatment of mcrc

Anti-EGFR antibodies in first line treatment of mCRC

  • Phase II studies: high response rates and high disease control rates

    • Fluoropyrimidine/irinotecan + cetuximab

    • Fluoropyrimidine/oxaliplatin + cetuximab

  • Randomized phase II studies

    • CALGB

    • Opus

    • SAKK

    • BOS - EORTC

  • Randomized phase III studies

    • COIN: 3 arm question on duration and on ± cetuximab

    • CAIRO-2: XELOX/bevacizumab ± cetuximab

    • US intergroup: 3 arm: bevacizumab vs cetuximab vs combination

    • Nordic: FOLFOX ± cetuximab

    • FOLFOX ± panitumumab

  • …….


Advanced colorectal cancer calgb 80203

Advanced Colorectal Cancer:CALGB 80203

+ cetuximab

RANDOMI

ZAT

ION

n =

238/2200

FOLFIRI

- cetuximab

Stratify

Prior adj

Prior XRT

+ cetuximab

FOLFOX

- cetuximab

Venook A et al ASCO 2006


Calgb 80203 response cetuximab

CALGB 80203: Response Cetuximab - / +

p = 0.029; chi-sq

p = 0.029; chi-sq

Venook A et al ASCO 2006


Sakk phase ii study preliminary results

SAKK Phase II Study: Preliminary Results

Helbling D, et al. ESMO 2006 A328

AIO CRC Study Group Phase II First-Line study

Heinemann V, et al. ASCO GI, 2007


Opus trial in first line mcrc large randomized phase ii study

OPUS trial in first line mCRC: large randomized phase II study

Bokemeyer C, et al. ECCO 2007 (Abstract No. 3004)


Opus safety

OPUS: safety

aIncludes peripheral sensory neuropathy and neuropathy

bThere were no grade 4 skin reactions or acne-like rash

Magnesium measurements were available only from a subset of patients

Bokemeyer C, et al. ECCO 2007 (Abstract No. 3004)


Coin trial phase iii study

COIN trial: Phase III study

Previously untreated patients with mCRC

  • UK National Cancer Research Institute study, 84 participating centers

  • Current accrual: 1800 (n=2421 planned)

  • Preliminary safety analysis on 804 patients randomized up to June 20061

Cetuximab + oxaliplatin/5-FU or capecitabine

Oxaliplatin + 5-FU or capecitabine

R

Intermittent oxaliplatin + 5-FU or capecitabinea

a12 weeks, monitor and repeat on PD

1Maughan T, et al. ASCO 2007 (Abstract No. 4070)


Coin trial any grade 3 4 toxicity in the first 12 weeks

COIN trial: Any Grade 3 /4 toxicity (%) in the first 12 weeks

† = p<0.001 compared to same regimen minus cetuximab

1Maughan T, et al. ASCO 2007 (Abstract No. 4070)


Coin study chemo type toxicities in the first 12 weeks

COIN study: Chemo-type toxicities (%) in the first 12 weeks

No cetuximab

(Arms A + C)

Cetuximab (C)

(Arm B)

Significance

* p<0.05

† p<0.001

Regimen

Ox + Cap

OxMdG

Ox + Cap

OxMdG

+/- cap

+/- cet

n

333

203

166

102

Neutropenia

2

18

1

26

N & vomiting

7

3

14

7

*

*

Diarrhoea

15

7

25

13

*

All cause 60 day mortality

5.65

5.0

7.2

4.9

Treatment related deaths

0.6

0.5

1.8

1.0

1Maughan T, et al. ASCO 2007 (Abstract No. 4070)


Crystal trial in first line mcrc

CRYSTAL trial in first line mCRC

Cetuximab + FOLFIRI

Cetuximab IV 400 mg/m2 on day 1,

then 250 mg/m2 weekly+ irinotecan (180mg/m2)

+ 5-FU (400 mg/m2 bolus +

2400 mg/m2 as 46-hr

continuous infusion)

+ FA every 2 weeks

Stratification factors:

  • Regions

  • ECOG PS

    Populations

  • Randomized patients n=1217

  • Safety population n=1202

  • ITT population: n=1198

EGFR-expressing

metastatic CRC

R

FOLFIRI

irinotecan (180 mg/m2)

+ 5-FU 400 mg/m2 bolus +

2400 mg/m2 as 46-hr

continuous infusion)

+ FA every 2 weeks

Van Cutsem E, et al. Proc ASCO, 2007


Integration of egfr targeting into first line therapy is it time

0.9

Cetuximab + FOLFIRI, n=599

0.8

FOLFIRI, n=599

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

2

4

6

8

10

12

14

16

18

20

Subjects at risk

FOLFIRI alone

599

492

402

293

178

83

35

16

7

4

1

Cetuximab +

FOLFIRI

599

499

392

298

196

103

58

29

12

5

1

CRYSTAL trial: Primary endpoint PFS ITT population independent review

1.0

HR = 0.851; 95% CI = [0.726-0.998]

Stratified log-rank p-value = 0.0479

8.9 mo

PFS estimate

1-year PFS rate

23% vs 34%

8.0 mo

Progression-free survival time (months)

Van Cutsem E, et al. Proc ASCO, 2007


Crystal trial response rate and surgery with curative intent

FOLFIRI alone Cetuximab + FOLFIRI

10

9.8

9

8

7

6

Percentage (%)

5

4

4.5

3

2

1

0

No residual tumor in patients

with liver metastases

n=134/n=122

CRYSTAL trial: Response Rate and Surgery with curative intent

Liver metastases only population(exploratory)

ITT population(pre-planned)

p=0.0034*

odds ratio 3.0

[95% CI: 1.4 - 6.5]

*CMH test

Van Cutsem E, et al. Proc ASCO, 2007


Crystal trial safety grade 3 4 ae

CRYSTAL trial:Safety: Grade 3/4 AE

aThere were no grade 4 skin reactions

Magnesium levels were measured in only 20% of the patients (0.2% vs. 1.8%)

Van Cutsem E, et al. Proc ASCO, 2007


Integration of egfr targeting into first line therapy is it time

PACCE: Panitumumab Advanced Colorectal Cancer Evaluation

Randomized, Open-Label, Controlled Phase 3b Trial

Panitumumab 6 mg/kg Q2W

Ox-CT

Bevacizumab

Ox-based CT

(eg, FOLFOX)

N = 800

Inv choice

S

C

R

E

E

N

I

N

G

R

A

N

D

O

M

I

Z

E

1:1

Ox-CT

Bevacizumab

Panitumumab 6 mg/kg Q2W

Iri-CT

Bevacizumab

Iri-basedCT

(eg, FOLFIRI)

N = 200

Inv choice

1:1

Iri-CT

Bevacizumab

Stratification Factors: ECOG score, prior adjuvant tx, disease site,Ox doses/Iri regimen, number of metastatic organs

Hecht R et al, Ann Oncol, WCGIC Barcelona 2007


Pacce trial progression free survival ox ct cohort interim analysis may 2007 data cutoff

pmab+bev/Ox-CT

bev/Ox-CT

PACCE trial: Progression-free Survival: Ox-CT Cohort(Interim Analysis, May 2007 Data Cutoff)

Local Reviewb

Central Reviewa

HR = 1.27 (95% CI: 1.07–1.50)*

HR = 1.27 (95% CI: 1.05–1.53)*

*Descriptive only

*Descriptive only

bCensoring based on last day of patient contact or visit Q2W

aCensoring based on last available scan read centrally Q12W

Hecht R, Mitchel E et al, GI Cancers Symposium, Orlando, jan 2008


Calgb 80405 trial phase iii study

CALGB 80405 trial: Phase III study

FOLFOX or FOLFIRI, and bevacizumab

Previously untreated patients with mCRC

FOLFOX or FOLFIRI, and cetuximab

R

FOLFOX or FOLFIRI, bevacizumab and cetuximab

  • Primary endpoint: overall survival

  • Secondary endpoints include response, PFS, toxicity and resection rate

  • Accrual = 1084/2289

  • No safety concerns (regular IDMC review)


Cairo ii trial phase iii study

CAIRO-II trial: Phase III study

Cetuximab + bevacizumab + XELOX

Previously untreated patients with mCRC

  • Accrual complete (n=755)

  • Interim safety analysis (n=381) reported acceptable AEs in both treatment groups

    • Except for cetuximab-associated skin reactions, there was no difference in the incidence of grade 3/4 AEs between treatment groups

R

Bevacizumab + XELOX

Tol J, et al. ECCO 2007 (Abstract No. 3000)


Cairo 2 study overall toxicity

CAIRO-2 studyOverall toxicity

Tol J, et al. ECCO 2007 (Abstract No. 3000)


Eortc phase ii bos study

Resect

ion

EORTC phase II BOS study

Previously untreated patients with resectable mCRC (liver)

Adjuvant therapy for 3 months(same schedule as pre-operatively)

FOLFOX + cetuximab

for 3 months (n=50)

R

FOLFOX + cetuximab

+ bevacizumab

for 3 months (n=50)

Neoadjuvant

therapy


Egfr inhibitors in mcrc questions challenges

EGFR inhibitors in mCRC: questions & challenges

  • Optimal cytotoxic partner?

  • Optimal setting: more advanced disease or first line treatment?

  • Predictive markers for response and activity?

    • Selection of patients?

  • Prediction of and decreasing toxicity?

    • Relevance of correlation skin toxicity and efficacy

  • What is the clinical significance of increased resection rate of metastases with cetuximab in first line ?

  • Can EGFR antibodies be combined with other biologics?

    • bevacizumab?

    • How can we explain negative results of chemo + bevacizumab and panitumumab in first line?

  • Economic burden


Patient selection after egfr inhibitors

Patient Selection After EGFR Inhibitors

  • Skin rash

  • EGFR - IHC

  • Downstream markers?

  • Gene Mutations

  • KRAS

  • EGFR gene copy number, as assessed by FISH ?

  • Ligands: amphiregulin, epiregulin


Cetuximab panitumumab and k ras

Cetuximab / panitumumab and K-RAS

Khambata-Ford S et al, J Clin Onc 2007


Integration of egfr targeting into first line therapy is it time

Mutant

Wild-Type

160

160

140

140

PR (0%)

SD (12%)

PD (70%)

PR (17%)

SD (34%)

PD (36%)

120

120

100

100

80

80

60

60

Pmab

+ BSC

% Change

% Change

40

40

20

20

0

0

-20

-20

-40

-40

-60

-60

-80

-80

Patient

Patient

160

160

140

140

PR (0%)

SD (8%)

PD (60%)

PR (0%)

SD (12%)

PD (75%)

120

120

100

100

80

80

60

60

BSC

Alone

40

40

% Change

% Change

20

20

0

0

-20

-20

-40

-40

-60

-60

-80

-80

Patient

Patient

Chemorefractory patients: Panitumumab + BSC vs BSCMaximum Percent Decrease in Target Lesions Final Analysis, KRAS Evaluable Group

Amado R, Van Cutsem E et al, J Clin Oncol 2008, in press


Integration of egfr targeting into first line therapy is it time

First line treatment with cetuximab

First line treatment: cetuximab (n = 33)

Response rate: 10 %; Stabile disease: 34%

Pessino A, Sobrero A et al, Ann Oncol epub 2007

First line treatment: cetuximab followed by FOLFIRI/cetuximab (n = 52)

Tabernero J et al, GI Cancers symp 2008


Anti egfr antibodies in first line treatment of mcrc1

Anti-EGFR antibodies in first line treatment of mCRC

  • Specific issues/questions?

    • Do anti-EGFR antibodies increase the activity of chemotherapy in first line?

      yes (cetuximab trial), but which subgroup?

      no data in comparison with bevacizumab

    • Do anti-EGFR antibodies increase the toxicity?

      yes

      Is the toxicity in first line acceptable?

      Is there an interaction between panitumumab and bevacizumab?

    • Is KRAS a predictive marker for activity in first line in combination with chemotherapy?

      more data expected

    • Does cetuximab increase the resection rate in first line metastatic CRC?

      probably yes


Integration of egfr targeting into first line therapy is it time

EGFR inhibitors in CRC

  • Are EGFR inhibitors an option in first line treatment of mCRC?

    • Probably yes

    • For who?

      • Biomarker or clinically driven selection?

    • Data:

      • Cetuximab

      • Panitumumab under evalution

  • Are EGFR inhibitors today a standard treatment in first line mCRC?

    • No


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