Department of Thoracic/Head & Neck Medical Oncology

EGFR Targeted Therapy in Recurrent Lung Cancer

Anne S. Tsao, M.D.

Clinical Specialist

Cancer Deaths in the U.S.Female Male

• Increasing evidence EGFR overexpressed in NSCLC*• 80-90% overexpression• Correlated in many cases with a poor prognosis**

• Decreased survival• Increased metastasis

*Salomon et al. 1995, Rusch et al 1993; B Rusch et al 1997; **Fontanini et al. 1995, Mukaida et al. 1991, Neal et al. 1992, Sainsbury et al. 1987

EGFR Positive Squamous Cell Carcinoma

EGFR Expression and Lung Cancer

EGFR and Lung Cancer

• Resectable stage I-IIIA NSCLC • 130 patients• 78% positive for EGFR • Median follow-up 84 months• Median survival time

• Overexpression worse (18 vs 50 months)• 2-yr (43% vs 70%)• 5-yr (31% vs 46%)

• EGFR overexpression predicts a shortened survival time

Selvaggi et al. PASCO 2002; abs 1345

N U C L E U S

Targeting Cellular Signal Pathways

Apoptotic Pathway

Proliferative Pathway

Ras

Raf MEKK

ERK sek

MAP kinase

jnk/sapkC-myc

C-jun

PI3K

Akt

intermediates

Apoptosis

YEGFR

PP

Rho-B

Ki-67

TKI

mAb

IMC-C225 and ZD1839

Property IMC-C225 ZD1839

Specificity Exclusive to EGFR EGFR but variable

Target

MOA/Activity

External receptor

Interrupts cell cycleInduces apoptosisAnti-angiogenesisDownregulates MMP

Tyrosine kinase

SameSameSameN/A

Administration

Dose Determination

I.V. weekly

Zero-order PK

P.O. daily

MTD-diarrhea

Binding Internalizes receptor Reversible

Adverse Events Acne-like rashGrade 3/4 hypersensitivity (4%)

Acne-like rashDiarrhea

IMC-C225Properties

• IgG1 (chimerized antibody)• Exclusive for EGFR and its

heterodimers

• Prevents repair and survival of tumor cells damaged by the effects of chemotherapy and radiotherapy• Potentiates apoptosis• Inhibits cell cycle progression• Decreases production of angiogenic factors• Inhibits invasion/metastasis

Docetaxel in Lung Cancer

• Activity in front-line lung cancer

• Survival in 2nd-line lung cancer

• Managable toxicities

• Good drug to pair with novel compounds

Second-line NSCLC TAX 317B: Survival

Median 7.5 vs 4.6 moLog-rank p=0.010

1-year 37% vs 12%2 p=0.003

T 75

BSC75

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

90 3 6 12 15 18 21

Survival time (months)

Cu

mu

lati

ve P

rob

ab

ility

Docetaxel 75 mg/m2 vs BSC

Shepherd F, et al. J Clin Oncol 18: 2000

Second-Line NSCLC TAX 320: Overall Survival

Survival time (months)

Cu

mu

lati

ve p

rob

ab

ility

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 3 6 9 12 15 18 21

T100T75V/I

T75 vs V/I1-Year 30% vs 20%p=0.05, 2 Log-rank Test P= 0.13Median 5.7 vs 5.6 mo (NSS)

T100 vs V/I1-Year 23% vs 20%Log-rank test p=0.58Median 5.5 vs 5.6 mo (NSS)

Fossella F, et al. J Clin Oncol 18: 2000

Docetaxel vs. Vinorelbine or Ifosfamide

Phase II Study of Anti-Epidermal Growth Factor Receptor (EGFR)

Antibody Cetuximab in Combination with Docetaxel in Patients with

Recurrent NSCLC

Dept. of Thoracic/Head & Neck Medical Oncology

M. D. Anderson Cancer Center

Poster Discussion ASCO 2002

Abstract #1168

Objectives

• Primary objective • Determine the response rate of Cetuximab +

Docetaxel to patients with refractory/recurrent NSCLC

• Secondary objectives:• Safety/toxicity profile of Cetuximab

• Determining the duration of response & survival

Kim ES, et al. Proc Am Soc Clin Oncol 2002

• Diagnosis of pathologically confirmed NSCLC• Progressive disease while receiving a cytotoxic

chemotherapy regimen.

• Relapsed within 3 months after discontinuing a cytotoxic chemotherapy regimen. (The patient is allowed to take biologic therapy during this time).

• Uni-dimensionally measurable disease (RECIST)

• Must have received prior chemotherapy < 3 months of study entry (neurotoxicity must be ≤ Grade 1 at study entry).

• The patient has immunohistochemical evidence of EGFR expression ( 1+).

• KPS of 60 at study entry

Inclusion Criteria

Exclusion Criteria

• Has received prior anti-EGFR antibody therapy.

• Has received prior docetaxel chemotherapy.

• Has received EGFR small molecule therapy.

• No wide-field radiation within 4 weeks.

• No major surgery within 30 days.

Study Design

Continue Docetaxel/

C225

REGISTRATION

EGFR 1+ (IHC)

DAY 1

DAY 8

DAY 15

Docetaxel 75 mg/m2 q3 wks Cetuximab 400 mg/m2 IV

Cetuximab 250 mg/m2 IV

Cetuximab 250 mg/m2 IV

Off Study Progressive

Disease

Response or Stable Disease

Kim ES, et al. Proc Am Soc Clin Oncol 2002

Patient Characteristicsn = 41

Age (median)

60range

(31-76)

Sex Male 21

Female 20

Performance status

(median)1

range

(0-2)

EGFR Status 1+, 2+ 18%

3+ 82%

Patient #10

Baseline 2 cycles

Patient #10

Baseline 4 cycles

Patient #16

Baseline 2 cycles

Toxicity

Hematologic Grades1/2 Grades3/4

Thrombocytopenia 0 1

Neutropenia 0 7

Neutropenic fever 3 3

Anemia 0 1

Patient #3

Patient #12

Patient #19

Patient #19

Pharmacokinetic Results

Pre-Dose and 1-Hr Post Dose Concentration of C225

cycle

C225 c

on

cen

trati

on

(m

g/m

l)

Conclusions• This combination of docetaxel with Cetuximab has

shown encouraging results thus far in patients with refractory/progressive NSCLC.

• The safety and toxicity of this combination is tolerable.

• Early pharmacokinetic data shows no direct interaction.

• Final data soon

• TTP, survival

• Correlation of response to skin toxicity

Acknowledgements

Edward S. Kim, M.D.

Waun Ki Hong, M.D.

M. D. Anderson Cancer Center

Department of Thoracic/Head and Neck Medical Oncology

Departments of Thoracic/Head and Neck

Medical Oncology

Surgical Oncology

Radiation Oncology

Pathology

Biostatistics