Growth Factor Receptor Targeted Therapies

In human cancer cells, aberrant signaling through the epidermal growth factor receptor (EGFR) has been associated with neoplastic cell proliferation, resistance to apoptosis, migration and stromal invasion, and enhanced angiogenesis. The EGFR (or ErbB-1) is part of a subfamily of four closely related receptors that include HER-2/neu (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4).5 These receptors exist as inactive transmembrane monomers in cells, and dimerize after ligand activation either by homo- or heterodimerization between EGFR and another member of the ErbB receptor family. This dimer-ization results in activation of the intracellular tyrosine kinase domain through autophosphorylation, which in turn initiates a cascade of downstream signaling pathways that include Ras and mitogen-activated protein kinase (MAPK). In cancer cells, various mechanisms for activation of EGFR or related ErbB pathways include receptor overexpression (e.g., as a result of gene amplification in the case of HER-2), receptor mutation (e.g., truncated EGFR that lacks the extracellular domain but has a constitutively activated tyrosine kinase domain that functions independent of ligand), increased autocrine or paracrine expression of the various receptor ligands [e.g., transforming growth factor-alpha (TGF-a), amphiregulin, heparin-binding EGF], or decreased receptor turnover.

Studies have shown that EGFR or HER-2 overexpression in cancer is often associated with a poorer prognosis and resistance to conventional therapies including hormonal therapy, cytotoxic drugs, and radiotherapy.6 Consequently, EGFR and related receptors represent an attractive target for the development of novel cancer therapeutics. The two most promising approaches have been MAbs against the extracellular ligand-binding domain of the receptor and small molecule inhibitors of the receptor intracellular tyrosine kinase enzymatic activity (TKIs).

Inhibition of Extracellular Domain Growth Factor Receptor: Monoclonal Antibodies

Cetuximab (C225 or Erbitux) is a chimeric antibody that binds to EGFR, inhibiting downstream signaling and promoting receptor internalization, and significant growth inhibition has been observed in a variety of human cancer xenograft models.6 Additive effects were seen when cetuxi-mab was combined with various cytotoxic agents and with ionizing radiation. The clinical development has focused on selecting patients with EGFR-overexpressing tumors, and Phase II/III trials have been conducted in head and neck cancer,7 colorectal cancer,8 and advanced non-small cell lung cancer9 (Table 5.2). These latter studies have investigated whether addition of cetuximab can enhance the activity of conventional therapies for these tumor types. Recent data demonstrate that cetuximab, in addition to irinotecan in patients with irinotecan-refractory metastatic colorectal cancer, improves median survival and time to progression.8

HER2 gene amplification occurs in 25% to 30% of breast tumors and contributes to cell growth and malignant transformation, rendering tumors more resistant to both endocrine and conventional chemotherapies.10 Trastuzumab (Herceptin) is a humanized MAb directed against HER2 and, when administered as a weekly intravenous infusion, gave clinical response rates of 35% as first-line therapy for patients with HER2+ve metastatic breast cancer.11 One of the central principles is the appropriate selection of patients with HER2+ve tumors, and validated assays have been developed to identify either HER2 overexpression by immunohistochemistry or HER2 gene amplification by fluorescence in situ hybridization (FISH). The addition of trastuzumab to taxane- or anthracycline-based chemotherapy enhanced both objective response and time to disease progression, which in turn significantly improved overall survival in advanced breast cancer (median, 25 versus 20 months, P < 0.046).12 As such, this represented one of the first examples of modern targeted therapies successfully modifying disease outcome.

TABLE 5.2. Clinical trials with monoclonal antibodies against epidermal growth factor receptor (EGFR).

Metastatic Colon Cancer Phase II Trial 329 EGFR-positive patients after irinotecan failure9

Cetuximab alone

Irinotecan + Cetuximab

Response rate

Median time to progression Survival

10.8% 1.5 months 6.9 months (NS)

22.9% 4.1 months 8.6 months (NS)

Metastatic/Recurrent Head and Neck Cancer Phase III trial8

Cisplatin

Cisplatin + Cetuximab

Response rate Progression-free survival

9.3% 3.4 months

22.6% 3.4 months

Advanced Non-Small Cell Lung Cancer EGFR positive 1st line10

Vinorelbine + Cisplatin

Vinorelbine + Cisplatin + Cetuximab

Response rate 32.2% 53.3%

Response rate 32.2% 53.3%

Inhibition of Intracellular Signaling: Tyrosine Kinase Inhibitors

Imatinib Mesylate (STI-571 or Glivec) When growth factor receptors are bound by their natural ligand, they undergo dimerization with subsequent activation of receptor tyrosine kinase activity, which in turn phospho-rylates downstream signal transduction cascades. Small molecule tyrosine kinase inhibitors (TKIs) specifically target the receptor's internal tyrosine kinase domain. The first to prove effective in the clinic was imatinib mesylate (STI-571 or Gleevec), which targets a small family of tyrosine kinases including ABL, Kit, and platelet-derived growth factor receptor (PDGF), as well as certain oncogenic mutants of these proteins such as the bcr-abl oncogene found in chronic myeloid leukemia.13 The success of this therapy relates to the dominant role that these pivotal kinases play in the pathogenesis of certain tumors; that is, 90% of gastrointestinal stromal tumors (GIST) exhibit aberrant signal transduction through KIT, primarily through activating point mutations in exon 11 that encodes the intracellular region of the protein, with evidence that KIT activation is an early tumorigenic event in most GIST tumors.14 KIT mutations were a strong predictor of response to imatinib in early clinical trials and produced significantly prolonged survival.15 The high level of efficacy appeared independent of tumor bulk and failure of prior chemotherapy, with objective responses in 54% of patients and stable disease in an additional 28% to 37%.16,17 This molecularly targeted therapy has transformed the management of this previously intractable disease.

Gefitinib (Iressa) Several small molecule inhibitors of EGFR tyrosine kinase are in development, including the synthetic anilinoquinazoline gefitinib (Iressa), which is an orally active, potent, and selective inhibitor of EGFR-TK. In experimental models gefitinib induced dose-dependent antiproliferative effects that delayed tumor growth.18 The effects appeared mainly cytostatic, and additional studies suggested that, when given in combination with cytotoxic drugs, gefitinib could enhance their antitumor activity.19 This interaction did not always appear to be dependent on overexpression of EGFR, and the mechanism for any enhanced cytotoxic effect remains unclear.

Evidence of efficacy in Phase II non-small cell lung cancer (NSCLC) studies led to the accelerated approval for gefitinib by the U.S. Food and Drug Administration (FDA) for the treatment of NSCLC in patients previously treated with chemotherapy20,21 (Table 5.3). However, two Phase III randomized trials, INTACT-1 and INTACT-2 (Table 5.4), that compared platinum-based chemotherapy and gefitinib to chemotherapy alone in chemotherapy-naive NSCLC patients, failed to demonstrate a survival advantage for the addition of targeted therapy, despite the preclinical evidence for an additive benefit for gefitinib-chemotherapy combinations.22 Several theories have been proposed to explain the failure of these trials, including the possibility that cytostatic effects of targeted therapy may abrogate the cytotoxic effects of cycle-dependent chemotherapy. Unlike the trastuzumab studies, where patients were selected based on HER2 status, there were insufficient data at the time to predict which biologic markers may correlate with response to gefitinib. This failing may have severely reduced the chance of success in the Phase III setting, which contained patients with a heterogeneous selection of tumor phenotypes.

Clinical trials have been undertaken with gefitinib in other tumor types, including breast cancer. There have been three Phase II monotherapy studies of gefitinib in patients with advanced breast cancer.23-25 Overall, the data are relatively disappointing with low clinical response rates. The only trial to report a significant number of responses included patients with ER+ve tamoxifen-resistant breast cancer,25 the setting in which preclinical models had shown evidence of

TABLE 5.3. Summary of Phase II studies in advanced platinum-refractory non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors (TKIs).
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