Dr.

Supreet Singh Nayyar, AFMC

2012

EGFR Inhibitors
Introduction

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o Outcome of patients presenting with stage III-IV HNSCC is still poor, with 5year actuarial survival rates fluctuating between 30% and 40% in most trials o These findings underscore the need to develop novel strategies in the management of patients with advanced HNSCC o Development of EGFR inhibitors is also one of them

Epidermal Growth Factor Receptor

EGFR is a glycoprotein of 170 kDa Encoded by a gene located on chromosome 7p12 Belongs to the ErbB receptor family (Her-1, Her-2, Her-3, and Her-4). EGFR is Her-1 group of receptor These receptors are composed of o An extra-cellular ligand-binding domain o A hydrophobic transmembrane segment o An intracellular tyrosine kinase domain Binding to EGFR of Transforming growth factor alpha (TGF-) results in a conformational change in the receptor promotes homodimerization with other EGFR molecules or heterodimerization with other HER family members (especially Her-2) results in subsequent autoactivation of the tyrosine kinase from the intracellular domain activate an intracellular signalling pathway inhibition of apoptosis, activation of cell proliferation and angiogenesis, as well as an increase in metastatic spread potential

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Dr. Supreet Singh Nayyar, AFMC

2012

The radiobiological rationale

o Cause of radioresistence in H&N cancer Enhanced cellular proliferation after exposure to ionising radiation o Evidence suggests that there is radiation induced release of TGF- activates signalling pathway of EGFR o Most preclinical and clinical studies demonstrated a lower local control after radiation therapy in tumors overexpressing EGFR o Hence use of EGFR inhibitor synergy between RT and EGFR inhibition increase in radiosensitivity o Though at this point, no clear relationship has been demonstrated between EGFR expression (at least as measured by immunohistochemistry) and the level of radiation sensitization achieved with anti-EGFR

EGFR expression in head and neck cancer

o In normal cells, the expression of EGFR ranges from 40,000 to 100,000 receptors per cell o In SCCHN, EGFR and its ligand, TGF-, are overexpressed in 8090% of cases o EGFR overexpression is an early event in SCCHN carcinogenesis o It is already present in "healthy" mucosa (field cancerization) from cancer patients, when compared to healthy controls o This overexpression will increase steadily in parallel to observed histological abnormalities, from hyperplasia to invasive carcinoma, through dysplasia and in situ carcinoma

Inhibition of EGFR activity

o Two complementary therapeutic strategies have been developed o First one targets the extracellular domain of the receptor with monoclonal antibodies (cetuximab, C225, or Erbitux) binding of the antibody to the EGFR prevents activation of the receptor by TGF through competitive inhibition also results in internalization and degradation of the antibodyreceptor complex downregulating EGFR expression o The second strategy targets the intracellular domain of the receptor with low-molecular-weight tyrosine kinase inhibitors (gefitinib, ZD 1839, Iressa; erlotinib, OSI 774, Tarceva) competing with ATP for its binding site on the intracellular domain of EGFR o These two classes of anti-EGFR agents did not meet the expectations in clinical practice when used in monotherapy, resulting more often in a cytostatic than a cytotoxic effect

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Dr. Supreet Singh Nayyar, AFMC

2012

Cetuximab and radiation therapy

o Bonner et al Multinational phase III study RT vs RT + cetuximab 3 yr survival rate 45% for RT & 55% for RT + cetuximab statistically significant survival benefit o Dose 400 mg/m2 1wk prior to radiotherapy 250 mg/m2 wkly till conclusion of radiotherapy o RT dosage 50 63 Gy / 33 38 # / 6-7 wks

Tyrosine kinase inhibitors (TKI) and RT

o No mature studies available at present Cohen et al phase II trial of Geftinib (250 mg OD) + chemoradiotherapy 88% complete response suggestive of strikingly greater than additive effects

Tyrosine Kinase Inibitors (TKIs) gefitinib (Iressa) erlotinib (Tarceva) lapatinib bind selectively to intracellular tyrosine kinase domain of EGFR oral daily Acneiform rashes Worsening of mucositis diarrhea nausea

Monoclonal Antibodies (mAb) cetuximab (Erbitux) panitumumab bind specifically to extracellular ligandbinding domain of EGFR intravenous every 1-3 weeks Acneiform rashes Worsening of mucositis hypersensitivity reactions

Agents

Mechanism

Administration

Adverse Effects

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