Epidermal growth factor receptor tyrosine kinase inhibitors as anticancer agents

The epidermal growth factor receptor (EGFR)-driven autocrine growth pathway has been implicated in the development and progression of the majority of the most common human epithelial cancers, making the blockade of this growth pathway a promising anticancer therapeutic strategy. Different approaches have been developed to block EGFR activation and/or function in cancer cells. In the past 15 years, various anti-EGFR blocking monoclonal antibodies (MAb), recombinant proteins containing transforming growth factor-alpha (TGFalpha) or EGF fused to toxins, and tyrosine kinase inhibitors (TKIs) have been generated and their biological and potentially therapeutic properties characterised. One of these agents, MAb IMC-C225, a chimeric human-mouse IgG1 MAb, is the first anti-EGFR agent to enter phase II to III clinical trials in patients with cancer. Several small compounds that block the ligand-induced activation of the EGFR tyrosine kinase have been developed. Among these EGFR-TKIs, various quinazoline-derived agents have been synthesised and have shown promising activity as anticancer agents in preclinical models. ZD1839 ('Iressa'), an anilinoquinazoline, is an orally active, selective EGFR-TKI which is currently under clinical evaluation in phase II to III clinical trials in patients with cancer. Preclinical data for ZD1839 strongly support the possibility of potentiating the antitumour activity of conventional chemotherapy with agents that selectively block the EGFR.     

Optimal management of patients with non-small cell lung cancer and epidermal growth factor receptor mutations

In recent years, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, which have promising activity and a favourable toxicity profile, have been used in the management of advanced non-small cell lung cancer (NSCLC). The knowledge that EGFR-activating mutations confer sensitivity to EGFR TKIs has led to the design and analysis of phase II and III studies of gefitinib or erlotinib treatment in various clinical scenarios. We review the important NSCLC clinical trials of the efficacy of EGFR TKIs in the context of EGFR-activating mutations. In all phase II single-arm studies or phase III randomized comparative studies, EGFR TKIs as monotherapy were superior to combination chemotherapy in terms of response rate and progression-free survival in patients with activating EGFR mutations. EGFR TKIs have contributed to the superior overall survival time in NSCLC patients with EGFR mutations compared with those patients without EGFR mutations. The results of these studies have led to a paradigm shift in the treatment of patients with advanced NSCLC. NSCLC with EGFR mutations constitutes a new entity requiring different personalized treatment strategies.     

Current status of targeted therapies in advanced gastric cancer

INTRODUCTION: In metastatic gastric cancer, chemotherapy is the standard treatment because it prolongs survival when compared to best supportive care alone. However, even after the use of more effective regimens, the overall survival remains disappointing, justifying the need for new treatment options. AREAS COVERED: Areas covered in this review include the most common molecular pathways, which have provided novel targets in gastric cancer therapy. These therapeutic strategies include EGFR inhibitors, anti-angiogenic agents, cell cycle inhibitors and apoptosis promoters. EXPERT OPINION: Several mAbs and kinase inhibitors, especially those targeting EGFR and VEGF/VEGFR, have already demonstrated promising activity in gastric cancer. The Phase III ToGA trial reported an increase in overall survival for patients with human EGF receptor (HER)2-positive gastric cancer treated with chemotherapy and trastuzumab compared to chemotherapy alone. This means that accurate HER2 testing in gastric cancer is necessary. Final data of ongoing trials with novel agents will be critical to further progress with this cancer.     

Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.     

Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold

Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.     

Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer?

Pancreatic cancer (PCa) is one of the most lethal malignancies in humans. Gemcitabine is the current standard chemotherapy of advanced PCa but it is still far from optimal and novel therapeutic strategies are urgently needed. For the near future, tyrosine kinase inhibitors (TKIs) hold great promise as a therapeutic strategy. Tyrosine kinases (TKs) play a pivotal role in intercellular signal transduction and regulate crucial processes of tumor cells such as proliferation, migration, survival and angiogenesis. Several TKs--such as EGFR, VEGFR, PDGFR and Src--are known to be overexpressed or constitutively activated in PCa. Hence, blocking receptor tyrosine kinases (RTKs) and non-receptor, cytoplasmic tyrosine kinases (CTKs) represents a rational approach to treat PCa. In particular, cetuximab and erlotinib, the monoclonal antibodies against EGFR-1 (ErbB-1) showed promising activity in Phase II and Phase III trials and their combination with gemcitabine resulted in synergistic antitumor activity. In addition, small antiangiogenic molecules such as VEGFR-2 inhibitors, PDGFR inhibitors and multiple receptor targeting agents are under active investigation. Association of chemoresistance with the activity of certain tyrosine kinases (e.g. ErbB-1 and Src) has been described for pancreatic cancer and makes a strong case for combining gemcitabine with TKIs. Combinations of different TKIs might also be used to target the cancer cell micro-environment. Detailed molecular characterization of tumor cells and combinations of appropriate TKIs with cytotoxic agents such as gemcitabine are expected to lead to improved therapy of pancreatic cancer.     

Emerging drugs for non-small cell lung cancer

Lung cancer is the leading cause of cancer death in the world. Therapeutic improvements caused by recent cytotoxic agents seem to have reached a plateau. New therapeutic strategies are, therefore, necessary to improve the cure rate. These include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gene therapy and vaccines. The antiepidermal growth factor receptor (EGFR) group includes compounds acting on the extracellular domain of EGFR, such as IMC-C225 and trastuzumab; small molecules inhibiting EGFR phosphorylation, such as ZD 1839 and OSI-774; or compounds that interfere with one of the downstream steps, such as mitogen-activated protein kinase kinase (MEK) inhibitors. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumour activity. Antiangiogenesis inhibitors include matrix metalloprotease inhibitors (MMPIs), such as marimastat, AG3340, BAY 12-9566, BMS-275291 and Col-3. Antiangiogenic agents offer great potential for the treatment of lung cancer, as shown in preclinical models, whereas emerging data suggest that there are limits to their use as monotherapy in advanced disease. Molecules targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) also seem to control tumour progression and may prolong survival. COX-2 inhibitors are another class of agents currently under evaluation in clinical trials for their chemoprevention role in subjects at high lung cancer risk, and also in patients with non-small cell lung cancer (NSCLC) in combination with standard chemotherapeutics. Genetic and immunologic therapies represent two additional promising modalities. All of these therapies are in different phases of clinical testing and have shown encouraging activity alone or in combination with chemotherapy drugs.     

Emerging drugs for non-small cell lung cancer

Lung cancer is the leading cause of cancer death in the world. Therapeutic improvements caused by recent cytotoxic agents seem to have reached a plateau. New therapeutic strategies are, therefore, necessary to improve the cure rate. These include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gene therapy and vaccines. The antiepidermal growth factor receptor (EGFR) group includes compounds acting on the extracellular domain of EGFR, such as IMC-C225 and trastuzumab; small molecules inhibiting EGFR phosphorylation, such as ZD 1839 and OSI-774; or compounds that interfere with one of the downstream steps, such as mitogen-activated protein kinase kinase (MEK) inhibitors. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumour activity. Antiangiogenesis inhibitors include matrix metalloprotease inhibitors (MMPIs), suchs as marimastat, AG3340, BAY 12-9566, BMS-275291 and Col-3. Antiangiogenic agents offer great potential for the treatment of lung cancer, as shown in preclinical models, whereas emerging data suggest that there are limits to their use as monotherapy in advanced disease. Molecules targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) also seem to control tumour progression and may prolong survival. COX-2 inhibitors are another class of agents currently under evaluation in clinical trials for their chemoprevention role in subjects at high lung cancer risk, and also in patients with non-small cell lung cancer (NSCLC) in combination with standard chemotherapeutics. Genetic and immunologic therapies represent two additional promising modalities. All of these therapies are in different phases of clinical testing and have shown encouraging activity alone or in combination with chemotherapy drugs.     

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.     

The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.     

The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer

The EGFR has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) that have proven effective in a subset of non-small cell lung cancer (NSCLC) patients, many bearing gain-of-function EGFR mutations or egfr gene amplification. However, the majority (～80–90%) of NSCLC patients do not respond to EGFR-specific TKIs and a high rate of acquired resistance to these therapeutics is observed in those that do respond. Thus, EGFR-specific TKIs will not, as single agents, make a high impact on overall lung cancer survival. A number of studies support the activities of other receptor tyrosine kinase pathways including cMet, IGF-1R and FGFRs as mechanisms for both intrinsic and acquired resistance to EGFR TKIs. While the role of cMet and IGF-1R signaling systems as mechanisms of resistance to EGFR TKIs has been widely reviewed in recent years, the potential role of FGFR-dependent signaling as a mechanism for EGFR TKI resistance has more recently emerged and will be highlighted herein. Due to the high degree of homology of FGFRs with VEGFRs and PDGFRs, FGFR-active TKIs already exist via development of VEGFR-targeted TKIs as angiogenesis inhibitors. Thus, these agents could be rapidly advanced into clinical investigations as FGFR inhibitors, either alone or in combination with TKIs selective for EGFR, cMet or IGF-1R as a means to expand the spectrum of NSCLC patients that can be effectively targeted with TKI-directed therapies.     

Monoclonal antibodies targeting the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR, HER1) autocrine pathway contributes to a number of highly relevant processes in cancer development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. The crucial role that EGFR plays in human cancers has led to an extensive search for selective inhibitors of its signaling pathway. The results of a large body of preclinical studies and clinical trials thus far conducted suggest that targeting the EGFR could bring a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR. The most promising strategies in clinical development include monoclonal antibodies, to prevent ligand binding, and small molecules inhibitors of the tyrosine kinase enzymatic activity, that inhibit autophosphorylation and downstream intracellular signaling. Several blocking monoclonal antibodies against the EGFR have been developed. Among these, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibody that has been the first anti-EGFR targeted therapy to enter clinical evaluation in cancer patients in Phase II and III studies, alone or in combination with conventional radiotherapy and chemotherapy. However, other antibodies against EGFR have demonstrated antitumor activity in several preclinical models of human cancer and are currently under investigation in the clinical setting, such as ICR62, ABX-EGF and EMD72000. This review will focus on all the preclinical data available on monoclonal antibodies engineered against the EGF receptor.     

EGFR, HER2 and VEGF pathways: validated targets for cancer treatment

Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody.On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.     

Neratinib: an oral,irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer

Background: The revolutionary success of imatinib, a specific inhibitor of the BCR-ABL tyrosine kinase (TK) in the treatment of chronic myelogenous leukemia ushered in the era of targeted therapies in cancer. The erythroblastic leukemia viral oncogene homolog family of receptor TKs, to which EGFR (HER1) and human epidermal growth factor receptor 2 (HER2)/neu TKs belong, has been implicated in a variety of cancers, and several agents that inhibit these TKs are in clinical use, with many more in various stages of development. Objectives: To summarize current knowledge about neratinib (HKI-272), an oral, irreversible dual inhibitor of EGFR and HER2 and to define its future clinical role, especially in the context of related agents that are either available or in the pipeline. Methods: A Medline search using Pubmed was conducted using the keywords neratinib, HKI-272, EGFR, HER2, lapatinib, trastuzumab, erlotinib, gefitinib, cetuximab and panitumumab. Relevant abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings were also reviewed. Conclusions: Both preclinical and human studies have shown that neratinib has promising activity in both advanced breast cancer and NSCLC with an acceptable safety profile. The data support its continued clinical development.     

Role of EGFR inhibitors in the treatment of central nervous system metastases from non-small cell lung cancer

Brain metastases (BM) are a common occurrence in patients with non-small cell lung cancer (NSCLC). Standard therapy options include whole brain radiotherapy and, in selected patients, surgery or stereotactic radiosurgery. The role of systemic treatment is controversial. There is a strong clinical rationale for the use of targeted therapies, because patients often have a poor performance status, and are not candidates for cytotoxic chemotherapy or radiotherapy, yet treatment is required to improve the extra-cranial disease. The efficacy of epidermal growth factor receptor (EGFR) inhibitors in the treatment of patients with BM from NSCLC has been reported mainly in case reports or small retrospective case series, with only a few prospective trials. Current evidence suggests that the use of EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib should be considered in patients with asymptomatic CNS involvement, when clinical characteristics suggest a high likelihood of response; these characteristics are adenocarcinoma histology, never-smoker status, female gender and East Asian ethnicity. Upfront therapy with EGFR TKIs should be strongly considered in asymptomatic patients harboring activating EGFR mutations. In symptomatic BM, radiotherapy (RT) remains the standard treatment. Based on currently available data, treatment with concurrent RT and EGFR TKIs should be investigated in experimental trials only.     

Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.     

Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance

Tyrosine kinases (TKs) are involved in key signaling events/pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Deregulated activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to inhibit specific kinases whose constitutive activity results in specific cancer types. These TKIs have been found to demonstrate effective anticancer activity and some of them have been approved by the Food and Drug Administration for clinical use or are in clinical trials. However, these targeted therapeutic agents are also transported by ATP-binding cassette (ABC) transporters, resulting in altered pharmacokinetics or development of resistance to these drugs in cancer patients. This review covers the recent findings on the interactions of clinically important TKIs with ABC drug transporters. Future research efforts in the development of novel TKIs with specific targets, seeking improved activity, should consider these underlying causes of resistance to TKIs in cancer cells.     

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.     

Epidermal growth factor receptor inhibitors in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.     

Erlotinib in non-small cell lung cancer: a review

Erlotinib (Tarceva, OSI-774; Pfizer, Inc.) is an orally-active, targeted inhibitor of the epidermal growth factor receptor (EGFR/HER1), which is part of a key regulatory pathway in cancer. Patients with advanced, incurable non-small cell lung cancer (NSCLC) may derive a clinical benefit from first- and second-line chemotherapy, but third-line treatment with available cytotoxic agents is not effective. Remarkably, EGFR/HER1 antagonists have demonstrated activity as second- and even third-line treatment for this disease. Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival, progression free survival and time to disease related symptoms (cough, pain, shortness of breath) compared with treatment with best supportive care in patients who have failed standard first- or second-line chemotherapy. This paper reviews the pharmacology, preclinical and clinical data to support the use of erlotinib in NSCLC.