Massimo Zeuli Oncologia Medica AIstituto Regina ElenaRoma

zeuli@ifo.it

"The best therapeutic approach to patients with KRAS wild type tumors"

Roma 4 marzo 2011

EGFR-Targeted Monoclonal Antibodies in mCRC

• Cetuximab– IgG1 mAb

– Chimeric protein

• Panitumumab[1]

– IgG2 mAb

– Fully humanized

• Role of Kirsten-ras (K-ras) mutation

1. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23.

HR: 0.54 (95% CI: 0.42-0.71)

P < .0001

Time to Progression

HR: 0.91 (95% CI: 0.68-1.21)

P = .48

OS

• Addition of cetuximab to irinotecan improved the response rate and time to progression but not overall survival

0

20

40

60

80

100

0 2 4 6 8 10 12

Pro

gre

ssio

n F

ree

(%)

00 2 4 6 8 10 12 14 16

MonthsMonths

Aliv

e (%

)

Cunningham D, et al. N Engl J Med. 2004;351:337-345. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

The BOND Study: Survival Data

20

40

60

80

100

Months

Pro

gre

ssio

n F

ree

(%)

0

20

40

60

80

100

0 3 6 9 12 15 18

HR: 0.69 (95% CI: 0.62-0.78)P ≤ .0001

Cetuximab + irinotecan (n = 648)Irinotecan (n = 650)

Median PFS: 4.0 months

Median PFS:

2.6 months

Sobrero AF, et al. EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer.J Clin Oncol. 2008;26:2311-2319. Reprinted with permission from the American Society of Clinical Oncology

EPIC Study of Cetuximab in Second-Line mCRC: PFS

Van Cutsem E, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.J Clin Oncol. 2007;25:1658-1664. Reprinted with permission from the American Society of Clinical Oncology.

Eve

nt

Fre

e (

%)_

0

10

20

30

40

50

60

70

80

90

100

Weeks0 8 16 24 32 40 48 56

HR: 0.54 (95% CI: 0.44-0.66)P < .0001

Panitumumab + BSC (n = 231)BSC (n = 232)

Panitumumab vs BSC in EGFR-Positive CRC: PFS Results

Amado R, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol 2008;26:1626-1634. Reprinted with permission from the American Society of Clinical Oncology.

2 4 6 8 10 12 14 16 18

Median PFS:

7.3 weeks

Median PFS: 12.3 weeks

Pro

gre

ss

ion

Fre

e (

%)

Weeks

0

10

20

30

40

50

60

70

80

90

100

0 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

HR: 0.45 (95% CI: 0.34-0.59)P < .0001

Panitumumab + BSC (n = 124)

BSC (n = 119)

Panitumumab vs BSC in mCRC With Wild-Type K-ras: PFS Results

Weeks2 4 6 8 10 12 14 16 18

Median PFS:

7.3 weeks

Median PFS: 7.4 weeks

Pro

gre

ss

ion

Fre

e (

%)

0

10

20

30

40

50

60

70

80

90

100

0 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

HR: 0.99 (95% CI: 0.73-1.36)

Panitumumab + BSC (n = 84)

BSC Alone (n = 100)

Amado R, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol 2008;26:1626-1634. Reprinted with permission from the American Society of Clinical Oncology.

Panitumumab vs BSC in mCRC With Mutant K-ras: PFS Results

Douillard J et al. JCO 2010;28:4697-4705

Pazienti kras wild type Cetuximab/Panitumumab aumentano l’efficacia

del trattamento chemioterapico

Pazienti kras wild type

Cetuximab/Panitumumab aumentano l’efficacia del trattamento chemioterapico

Bevacizumab aumenta l’efficacia del trattamento chemioterapico

Pozzo C. et al Cancer Treat Rev, 2008

Which regimen should we use as neoadjuvant treatment for liver metastases?

* Of the 37 patients evaluable fortumour KRAS mutation status, 81% had KRAS wild-type tumours.

*

Resection rates following targeted therapies plus chemotherapy in randomized trials

Van Cutsem E, et al. N Engl J Med 2009 Bokemeyer C, et al. J Clin Oncol 2009;27:663–671

Saltz LB et al. J Clin Oncol 2008

FOLFOX + ERBITUX

FOLFOX

FOLFIRI + ERBITUX

FOLFIRI

FOLFOX/XELOX+ bevacizumab

FOLFOX + XELOX

NO

1696

6 L

LD

CR

YS

TA

L

LL

DO

PU

S K

RA

S w

t

0 2 4 6 8 10 12 14

p=NS

Patients (%)

R0 resection rate

9.8

4.1

9.8

4.5

12.3

11.6

Pazienti kras wild type

Cetuximab/Panitumumab aumentano l’efficacia del trattamento chemioterapico

Bevacizumab aumenta l’efficacia del trattamento chemioterapico

Cetuximab aumenta la percentuale di resezioni epatiche R0?

Massimo Zeuli Oncologia Medica AIstituto Regina ElenaRoma

zeuli@ifo.it

"The best therapeutic approach to patients with KRAS wild type tumors"

Roma 4 marzo 2011

?

Pazienti k-ras wild-type, chrono-IFLO+ Cetuximab (Studio POCHER Br J Cancer 2010). I pazienti che non possono essere trattati con questo schema e sono wild-type ricevono in prima linea FOLFIRI + Cetuximab (Studio Crystal N Engl J Med 2009).

FOLFOX4 x 3 mesi Chirurgia FOLFOX4 x 3 mesi(studio EPOC - Lancet 2008):

C: Gruppo “ NON- RESECTABLE”

K-ras Wild Type

K-ras Mutant

1° Linea FOLFIRI + BEVA

FOLFIRI + BEVA

II° Linea FOLFOX FOLFOX

III° Linea Panitumumab MMC + fluoro pirimidina*