Targeting EGFR in Cervical Cancer

1
Targeting EGFR in Cervical Cancer

• Introduction
• EGFR and EGFR Inhibitors
• Cetuximab
• Clinical Studies with Cetuximab
• Cervical Cancer
• Clinical Study with Cetuximab
• Conclusions

2
Introduction EGFR

• EGFR one of 4 members of the ErbB (HER) family
  encoded by the ErbB1 gene
• Transmembrane glycoprotein that homo-
  
  
  or heterdimerizes with family
  members
• Extracellular ligand binding domain
• Transmembrane domain
• Intracellular tyrosine kinase domain
• Activation of EGFR triggers signal transduction
  and cell proliferation
• Ligands EGF, TGF-a, amphiregulin, betacellulin,
  epiregulin, heparin-binding EGF
• Strictly regulated in normal cells with
  controlled cell growth

3
Schematic of the Signaling Pathways of the HER
Family
Yarden,Y and Sliwkowski, M.X. Nature Reviews
Molecular Cell Biology 2127-137, 2001
4
Introduction EGFR

• EGFR is a target for cancer therapy
• Coexpression of high levels of EGFR and its
  ligands lead to transformed phenotype
• Overexpression of EGFR is found epithelial tumors
  and tumor-derived cell lines
• EGFR is expressed in at least 60 of cervical
  cancers
• Overexpression of EGFR correlates with poor
  patient prognosis, decreased survival, and/or
  increased metastasis

5
Introduction EGFR

• In tumor cells, the signal is inappropriately
  turned on
• Receptor mutations
• Adenoca of the lung
• Overexpression of EGFR
• Lung cancer and GBM
• ?Binding of intracellular ligands
• ?Other receptors/crosstalk
• ?Loss of regulatory mechanisms

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Introduction EGFR Inhibitors
(Adapted from Harari and Huang, Semin. Radiat.
Oncol., 11 281-289, 2001)
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Introduction EGFR Inhibitors
(Baselga, J. and Arteaga, C.L. J Clin Onc 23
2445-2459, 2005)
8
Introduction EGFR Inhibitors
Baselga, J. Arteaga, C.L. J Clin Onc 23
2445-2459, 2005
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Introduction Cetuximab

• C225, cetuximab, Erbitux
• Chimerized antibody of the IgG1 subclass
• Highly specific for EGFR (erb1) and its
  heterodimers
• Kd 2.0 x 10-10 M - 1 log higher than the
  natural ligand
• Prevents ligand binding to EGFR
• Stimulates receptor internalizaton
• Blocks receptor dimerization, TK activity,
  phosphorylation, and signal transduction
• C225 alone or with combination chemotherapy has
  activity in colorectal, lung, and head neck
  cancers
• FDA-approval for refractory colorectal cancer in
  2/04 and
  locally advanced/metastatic head neck cancer
  3/06
• On-going clinical trials in many solid tumors

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Introduction Cetuximab

• Initial work led to application for accelerated
  FDA approval
• Initial application filed Fall 2001
• FDA replied with a refusal to file (RTF) letter
  in reply
• Not enough data presented to evaluate drugs
  merit
• Phase 1 studies
• FDA contended that ImClone did not fully
  characterized PK
• Phase 2 study in patients with metastatic
  colorectal cancer (CRC) who progressed on
  irinotecan received irinotecan and cetuximab
• FDA contended ImClone did not document
  progression before starting cetuximab
• This led to two Phase I trials and a randomized
  Phase 2 in CRC
• Phase 1 Washington University, Moffit Cancer
  Center, Sarah Cannon Cancer Center

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Phase 1 Clinical Trial Rationale

• Cetuximab single agent therapy was found safe
  with the most common side effect being acneiform
  skin rash.
• Despite cetuximab activity, PK data justifying
  the dose was limited.
• Preclinical studies suggested the optimal
  biologic dose was defined as the dose that the
  EGFR was completely saturated such that maximal
  inhibition of tumor growth would be achieved.
• This study was designed to perform a detailed
  characterization of the PK of single
  administration cetuximab over a 10-fold dose
  range.

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Phase 1 Clinical Trial Objectives

• To characterize the effects of single doses of
  cetuximab on expression and saturation of EGFR in
  normal skin and tumor tissue
• To characterize PK of single doses of cetuximab
• To evaluate safety and tolerability of single
  dose cetuximab and repeated weekly doses
• To describe any anti-tumor activity
• To monitor for serum anti-cetuximab antibody
  responses

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Phase 1 Clinical Trial PK and PD Studies

• PK of cetuximab performed
• Normal skin biopsies obtained through punch
  biopsy
• Tumor samples obtained by needle biopsy,
  excisional biopsy, or excision resection
• Immunohistochemistry performed on all biopsy
  specimens, evaluating expression and saturation
  of EGFR and a series of related downstream
  proteins (p-MAPK, p27kip1, and Ki67)

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Phase 1 Clinical Trial Inclusion Criteria

• Histologically confirmed advanced epithelial
  malignancy
• ECOG performance status 0-2
• Adequate hematologic, renal, and hepatic function
• No clinically significant cardiac or pulmonary
  disease
• Completion of prior cytotoxic or radiation
  therapy ? 4 weeks prior to enrollment

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Phase 1 Clinical Trial Schema
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Phase 1 Clinical Trial Patient Characteristics
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Phase I Clinical Trial Adverse Events
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Phase 1 Clinical Trial
Serum concentrations reached a peak at 3 h and
were at baseline by 504 h
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Phase 1 Clinical Trial Pharmacokinetics

• Cmax and AUC0-8 increases in a dose proportional
  manner up to 400 mg/m2
• CL was similar following doses of cetuximab 100
  mg/m2

20
Phase 1 Clinical Trial Change of in EGFR
Expression
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Phase 1 Clinical Trial Response Data

• Partial Response 3
• Two patients with colon cancer and one with H N
• Mean 6.3 months, range 4-9 months
• Stable Disease 14
• Mean 4.4 months, range 3-6 months
• Progressive Disease 16

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Cetuximab in Colorectal Cancer

• Colorectal Cancer
• Inclusion criteria for colorectal trials
• Metastatic disease
• Progression after irinotecan-containing therapy
• All tumors stained for EGFR by IHC
• Three trials led to FDA approval
• Randomized, controlled trial (329 patients)
• Irinotecan and cetuximab versus cetuximab
• Open-label, single arm trial (138 patients)
• Irinotecan and cetuximab
• Single agent (57 patients)
• Cetuximab alone

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Cetuximab in Colorectal Cancer
Objective Response Rates per Independent Review
a 95 confidence interval for the difference in
objective response rates. b Cochran-Mantel-Haensze
l test.
24
Cetuximab in Colorectal Cancer
Time to Progression per Independent Review
Hazard ratio of cetuximab irinotecan cetuximab
monotherapy with 95 confidence interval.
25
Cetuximab in Head Neck Cancer
Clinical Efficacy in Locoregionally Advanced SCCHN
a CI confidence interval.
26
Lack of Correlation of EGFR Expression and
Response to Cetuximab
Comparison of Activity with IMC-C225/CPT-11 (in
colorectal cancer) and Transtuzumab (in breast
cancer) by Receptor Expression Level
Baselga, J. J Clin Onc 19 41s-44s, 2001
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Introduction Cervical Cancer

• Incidence and Mortality in 2006
• 2nd in incidence mortality in women in the
  world
• Worldwide
• Incidence 466,000
• Mortality 232,000
• US
• Incidence 9,710
• Mortality 3,700
• Bimodal peak from ages 35-39 and 60-64
• Etiology
• HPV - 1 etiologic agent in 99 tumors
• (HPV 16-most common, 18, 35, 45 and others-less
  common)
• Smoking
• Early frequent sexual activity with multiple
  partners

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Introduction Cervical Cancer

• Pathology
• Histology 80 SCC, 15 Adeno, 5 other
• Progression of Disease in 90 of disease
• CIN1 ? CIN2 ? CIN3 ? CIS in 5-10 years
• CIS ? invasive cancer in 3-10 years
• Spread
• Local extension into other pelvic structures
• Sequentially along LN chains
• Hematogenous spread to lung, bone, liver, and
  brain
• Diagnosis
• Symptoms
• Abnormal vaginal discharge or bleeding
• Pelvic pain
• Leg edema
• Anemia
• Asymptomatic abnormal Pap smear

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Introduction Cervical Cancer

• Staging
• Stage 0
• Carcinoma in situ
• Stage 1
• Disease confined to the cervix
• Stage 2
• Disease beyond cervix but not to the pelvic wall
  and upper two-thirds of vagina may be involved
• Stage 3
• Extension to pelvic side wall and/or lower third
  of vagina
• Stage 4
• Carcinoma beyond true pelvis or involving mucosa
  of the bladder
• or rectum

Stage 1
Stage 2
Stage 3
Stage 4
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Introduction Cervical Cancer

• Staging
• FIGO (Federation of Gynecology Obstetrics
  Staging System)
• Stage IA and IB1 Early stage
• Radical hysterectomy or radiation therapy
• 5 year survival 80-90
• Stage IB2-IVA Locally advanced disease
• Radiation or combined chemoradiation
• 5 year survival 65
• Late stage and recurrent disease
• Palliative chemotherapy novel agents
• 5 year survival lt5

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Cervical Cancer Trial

• To improve the cure rate of women with locally
  advanced cervical cancer by administering the
  cetuximab with concurrent chemoradiation and
  identifying markers of response to this therapy
• Eligibility
• Untreated women with locally advanced cervical
  cancer
• Adequate organ function
• ECOG PS of 0-2
• Approved informed consent

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Cervical Cancer Trial - Objectives

• To evaluate genes or gene mutations predictive of
  response to cetuximab in women with cervical
  cancer
• To correlate evidence of antitumor activity of
  cetuximab monotherapy by PET
• To determine the safety and tolerability of
  cetuximab alone and in combination with
  concurrent chemoradiation

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Schema of Trial
Baseline cervical biopsy and FDG-PET
scan Administer C225 on days 1, 8, and 15 Repeat
cervical biopsy and FDG-PET scan Administer
definitive chemoradiation and C225 Repeat
cervical biopsy and FDG-PET scan Follow for
tumor recurrence and survival
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Success or Failure of Molecular Therapies

• Do we understand the genetics that cause a
  specific persons cancer?
• What else does the drug do to the tumor?
• Does the cell care if that target is inhibited?
• Does the drug get into the tumor?
• Does the drug get into the cell and interact with
  the target?
• Does the drug effectively inhibit the target?
• How long does it take for the cell to compensate?

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Conclusions

• Advances in genetics, genomics, and biology have
  identified a large list of molecules that may be
  important in supporting the malignant phenotype.
• There is a large and rapidly expanding list of
  molecular therapeutics in the pipeline.
• Scientists can not accurately predict which of
  these therapies will be effective in patients
  with cancer. This places an increasing priority
  on the need for carefully conducted clinical
  research.

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Title