cancer deaths in the u.s. female male increasing evidence egfr overexpressed in nsclc* 80-90%...
TRANSCRIPT
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Department of Thoracic/Head & Neck Medical Oncology
EGFR Targeted Therapy in Recurrent Lung Cancer
Anne S. Tsao, M.D.
Clinical Specialist
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Cancer Deaths in the U.S.Female Male
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• 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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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• 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
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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.
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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
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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%
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Patient #10
Baseline 2 cycles
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Patient #10
Baseline 4 cycles
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Patient #16
Baseline 2 cycles
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Toxicity
Hematologic Grades1/2 Grades3/4
Thrombocytopenia 0 1
Neutropenia 0 7
Neutropenic fever 3 3
Anemia 0 1
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Patient #3
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Patient #12
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Patient #19
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Patient #19
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Pharmacokinetic Results
Pre-Dose and 1-Hr Post Dose Concentration of C225
cycle
C225 c
on
cen
trati
on
(m
g/m
l)
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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
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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