EGFR-Targeted Anticancer Therapy Leonard B. Saltz, MD Memorial Sloan Kettering Cancer Center, New York, NY

EGF Receptor Signaling Transduction R R RAS RAF PI3-K

pY K

K

pY

SOS GRB2

pY

PTEN

AKT

MEK

STAT MAPK

Gene Transcription Cell Cycle Progression G2

S

Proliferation / Maturation

Survival / Apoptosis

M

G1

Angiogenesis

Metastasis

Current Anti-EGFR agents • Cetuximab • Erlotinib • Panitumumab (approval expected 2006)

Panitumumab • Fully humanized Mab: ? less risk of infusion reactions • IgG2 • 10% single agent activity • Activity with chemo not yet reported • Front line trial in progress

Combination Treatment of HT-29 Colon CA Xenografts with C225 +/- high dose irinotecan 3500

Mean Tumor Volume (mm3)

HT-29 3000

saline

2500 2000 1500

IMCIMC-C225 1000

irinotecan 500

IMCIMC-C225 + irinotecan

0 0

5

10

15

20

25

Days Irinotecan administered at 150mg/kg, q7d X3 Cetuximab admininstered at 1mg/dose, q3d

30

35

40

45

Efficacy Results (C225+CPT-11) Independent Radiology Review (CPT-Refractory Pts, n=120)

PR 27 (22.5%) (95% C.I. 15%-31%) SD

9

( 7%)

(minimum 12 weeks)

• Median Dur. of response (n=27): 186 days • Investigator-reported PR= 23 (19%)

Single Agent C225: InvestigatorReported Response Rate (n=57) • PR = 6 (10.5%, 95% CI 4%-22%) • SD = 21 (36.8%) • All responses confirmed at 4-6 weeks. – Minimum 12 weeks required for stable disease.

• Independent review confirmed 5 PR’s, for response rate of 8.8%.

“BOND” Trial • Randomized Phase II trial in CPT-11refractory CRC • C225+CPT-11 versus C225 • 2:1 randomization, 300 pts • 1o endpoint: response rate

Bond Trial: Results C225 + CPT-11

C225

RR

22.9%

10.8%

PFS

4m

1.6 m

C225 Trials in Refractory CRC C225 + CPT-11

Response Rate 22.5%

C225 + CPT-11

22.9%

C225

10.5%

C225

10.8 %

Cetuximab Skin Toxicity

Cetuximab-related skin rash

Cetuximab-induced paronychial inflamation

Response as a Function of Skin Rash (IMC-C225+CPT-11 in CRC) # patients with major objective response

%

(+) skin rash (n=89)

26/89

29%

(-) skin rash (n=31)

1/31

3% (P