New Oral Multitargeted Antiangiogenics in NSCLC Treatment
Non-small-cell lung cancer is a particularly aggressive cancer. Combination chemotherapy remains the standard therapy for patients with advanced or metastatic disease. However, despite the available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process controlled by a delicate balance between pro- and antiangiogenic factors and their receptors; tumors induce angiogenesis by disrupting this balance and secreting various growth factors. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes monoclonal antibodies against VEGF and VEGF receptor and small molecule inhibitors of VEGF tyrosine kinase activity (tyrosine kinase inhibitors). Tyrosine kinase inhibitors are orally active, small molecules that represent a new class of drugs with a relatively high safety profile. They are targeted therapies that play their anticancer role interfering with specific cell signaling. This review focuses on such oral antiangiogenic agents that have been approved and are in advanced clinical development for the treatment of patients with advanced non-small-cell lung cancer.
Non-small-cell lung cancer (NSCLC) accounts for 85–90% of all lung cancers and had a median survival time of 7–8.3 months and 1-year survival rates of 29–37% for patients who progress beyond first-line therapy.
For patients in the early stage of the disease, surgery and/or radiation offer a chance for curative therapy, but for patients with advanced and metastatic disease, chemotherapy is the mainstay of treatment, represented by platinum-based compounds as first-line treatment. Unfortunately, this treatment strategy is linked to poor outcomes, represented by an overall 5-year survival rate of only 15%, despite a demonstrated clinical benefit.
Tumor angiogenesis is becoming the new target of anticancer therapy because of its biological role in cancer growth and metastatic dissemination. The molecular pathways involved led to the development of two large classes of molecular drugs: monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). As a result of this, new therapeutic options for A-NSCLC have been identified, including those targeting several neoangiogenic pathways such as the VEGF, FGF and PDGF pathways.
The VEGF pathway consists of five glycoproteins: VEGF-A, VEGF-B, VEGF-C, VEGF-D and PIGF. They act by stimulating cellular growth by binding to tyrosine kinase receptors (VEGF receptor [VEGFR]) on the cell surface, dimerizing these receptors and activating them through transphosphorylation. Of the VEGFR family, VEGFR1 and VEGFR2 play a central role in angiogenesis, while VEGFR3 is involved in lympho-angiogenesis; they represent the target of mAbs and TKIs directed against VEGF.
The FGFR family has four members, including FGFR1, FGFR2, FGFR3 and FGFR4, and consists of three extracellular immunoglobulin-type domains (D1–D3), a single-span transmembrane domain and an intracellular split tyrosine kinase domain. There are more than twenty subtypes of ligands that bind to this class of receptors promoting endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures, obtaining the growth of new blood vessels from the pre-existing vasculature. The most important ligands are FGF1 and FGF2, which are more potent angiogenic factors than VEGF or PDGF, with a correlation between serum levels and the risk of cancer progression and metastatic development.
The PDGF family consists of five isoforms of PDGF (A, B, C, D and AB) and two receptors (PDGFR-α and PDGFR-β). It plays a central role in cellular migration and, in a proangiogenic activity, recruiting pericytes and vascular smooth muscle cells.
These multitargeted agents play their anticancer role by inhibiting tumor pathogenesis and neoangiogenesis, and targeting receptors, such as VEGFR, PDGFR, FGFR, Raf and KIT. Some of these compete with the ATP binding site of the catalytic domain of several oncogenic tyrosine kinases. This class of small molecule is often orally available, and this represents an advantage for patients with respect to intravenous administration of standard chemotherapy. They show a different safety profile, and in some trials where small molecules were combined with chemotherapeutic agents the toxicities were represented by the side effects of the chemotherapy plus those of the antiangiogenic agents.
Their most common side effects are hypertension, hand–foot syndrome and cutaneous toxicities; most of them are manageable and reversible with temporary suspension of the drug.
We are going to present the most important oral TKIs and their effective role in clinical practice or development, with all the results obtained from multiple Phase II–III trials.
Abstract and Introduction
Abstract
Non-small-cell lung cancer is a particularly aggressive cancer. Combination chemotherapy remains the standard therapy for patients with advanced or metastatic disease. However, despite the available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process controlled by a delicate balance between pro- and antiangiogenic factors and their receptors; tumors induce angiogenesis by disrupting this balance and secreting various growth factors. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes monoclonal antibodies against VEGF and VEGF receptor and small molecule inhibitors of VEGF tyrosine kinase activity (tyrosine kinase inhibitors). Tyrosine kinase inhibitors are orally active, small molecules that represent a new class of drugs with a relatively high safety profile. They are targeted therapies that play their anticancer role interfering with specific cell signaling. This review focuses on such oral antiangiogenic agents that have been approved and are in advanced clinical development for the treatment of patients with advanced non-small-cell lung cancer.
Introduction
Non-small-cell lung cancer (NSCLC) accounts for 85–90% of all lung cancers and had a median survival time of 7–8.3 months and 1-year survival rates of 29–37% for patients who progress beyond first-line therapy.
For patients in the early stage of the disease, surgery and/or radiation offer a chance for curative therapy, but for patients with advanced and metastatic disease, chemotherapy is the mainstay of treatment, represented by platinum-based compounds as first-line treatment. Unfortunately, this treatment strategy is linked to poor outcomes, represented by an overall 5-year survival rate of only 15%, despite a demonstrated clinical benefit.
Tumor angiogenesis is becoming the new target of anticancer therapy because of its biological role in cancer growth and metastatic dissemination. The molecular pathways involved led to the development of two large classes of molecular drugs: monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). As a result of this, new therapeutic options for A-NSCLC have been identified, including those targeting several neoangiogenic pathways such as the VEGF, FGF and PDGF pathways.
The VEGF pathway consists of five glycoproteins: VEGF-A, VEGF-B, VEGF-C, VEGF-D and PIGF. They act by stimulating cellular growth by binding to tyrosine kinase receptors (VEGF receptor [VEGFR]) on the cell surface, dimerizing these receptors and activating them through transphosphorylation. Of the VEGFR family, VEGFR1 and VEGFR2 play a central role in angiogenesis, while VEGFR3 is involved in lympho-angiogenesis; they represent the target of mAbs and TKIs directed against VEGF.
The FGFR family has four members, including FGFR1, FGFR2, FGFR3 and FGFR4, and consists of three extracellular immunoglobulin-type domains (D1–D3), a single-span transmembrane domain and an intracellular split tyrosine kinase domain. There are more than twenty subtypes of ligands that bind to this class of receptors promoting endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures, obtaining the growth of new blood vessels from the pre-existing vasculature. The most important ligands are FGF1 and FGF2, which are more potent angiogenic factors than VEGF or PDGF, with a correlation between serum levels and the risk of cancer progression and metastatic development.
The PDGF family consists of five isoforms of PDGF (A, B, C, D and AB) and two receptors (PDGFR-α and PDGFR-β). It plays a central role in cellular migration and, in a proangiogenic activity, recruiting pericytes and vascular smooth muscle cells.
These multitargeted agents play their anticancer role by inhibiting tumor pathogenesis and neoangiogenesis, and targeting receptors, such as VEGFR, PDGFR, FGFR, Raf and KIT. Some of these compete with the ATP binding site of the catalytic domain of several oncogenic tyrosine kinases. This class of small molecule is often orally available, and this represents an advantage for patients with respect to intravenous administration of standard chemotherapy. They show a different safety profile, and in some trials where small molecules were combined with chemotherapeutic agents the toxicities were represented by the side effects of the chemotherapy plus those of the antiangiogenic agents.
Their most common side effects are hypertension, hand–foot syndrome and cutaneous toxicities; most of them are manageable and reversible with temporary suspension of the drug.
We are going to present the most important oral TKIs and their effective role in clinical practice or development, with all the results obtained from multiple Phase II–III trials.