The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like erlotinib and gefitinib have been extensively studied. Multiple randomized trials have evaluated the role of EGFR TKIs in advanced stage non-small cell lung cancer (NSCLC) as a monotherapy in the first line, or subsequent lines of therapy, and in the first line in the maintenance setting or in combination with chemotherapy. Most of these trials showed positive results in particular for selected patients with specific clinical characteristic and somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.     

Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors

Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.     

Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase: similarity and differences

Tyrosine kinase inhibitors (TKI) of EGFR are used in advanced non-small cell lung cancer (NSCLC) in 2(nd) and 3(rd) line, and for gefitinib in first line in case of EGFR mutations. These drugs are particularly active in presence of these mutations, with response rate around 60-70%. Pharmacological data suggest an equivalent effect of erlotinib and gefitinib. One phase II study has directly compared the two drugs in 2(nd) line, with a non significant advantage for gefitinib in term of response and progression-free survival. However, skin tolerance profile was statistically better with gefitinib. Indirect comparisons between erlotinib and gefitinib in the phase III trials vs chemotherapy 1(st) line have to be interpreted, with caution and take under consideration the impact of the chemotherapy arm on the Hazard Ratio for Progression-free and overall survival. However, response rates seem to be equivalent. Cohort and phase IV studies have shown no significant difference for response and survival, and a similar tolerance profile.     

Clinical significance and treatment of skin rash from erlotinib in non-small cell lung cancer patients: results of an Experts Panel Meeting

Advances in the knowledge of tumor biology and mechanisms of oncogenesis has granted the singling out of several molecular targets for non-small cell lung cancer (NSCLC) treatment. Among these targets, epidermal growth factor receptor (EGFR), or HER1, has received particular attention in lung cancer treatment. Erlotinib, an orally available inhibitor of EGFR tyrosine kinase in a phase III randomized placebo-controlled trial (BR.21), has been proven to prolong survival in NSCLC patients after first or second line chemotherapy. Skin rash is the most common adverse event associated with erlotinib treatment and it is often cause of negative impact on patients' quality of life. There is no specific treatment for this toxicity due to the lack of evidence-based data and recommendations. A panel of Italian oncologists, who had participated to clinical trials and to the Expanded Access Program for erlotinib in NSCLC treatment, and dermatologists with experience with cutaneous toxicity from EGFR inhibitors, attended a Meeting held in Rome on December 2006 to discuss skin rash from erlotinib and to provide suggestions for managing this frequent side-effect.     

Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence

The discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) in 2004 heralded the era of molecular targeted therapy in NSCLC. First-generation small molecule, reversible tyrosine kinase inhibitors (TKIs) of EGFR, gefitinib and erlotinib, had been approved for second- or third-line treatment of NSCLC prior to the knowledge of these mutations. However, resistance to gefitinib and erlotinib invariably develops after prolonged clinical use. Two second-generation irreversible EGFR TKIs, afatinib (BIBW 2992) and dacomitinib (PF-00299804), that can potentially overcome the majority of these resistances are in late stage clinical development. Here I will review the clinical data of EGFR TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC: whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches.     

Targeted therapy for the treatment of advanced non-small cell lung cancer: a review of the epidermal growth factor receptor antagonists

Lung cancer is the most common cause of cancer death. The vast majority of patients present with non-small cell lung cancer (NSCLC) in advanced inoperable stages. The current first-line treatment for patients with advanced NSCLC includes chemotherapy and palliative radiotherapy, but most patients relapse and eventually succumb to the disease. Advances in our knowledge of cancer cell biology have led to the development of specific molecular-targeted therapeutic agents. Mutations in the epidermal growth factor receptor (EGFR) have been identified in NSCLC cells, and overexpression of the EGFR and its ligands is a common feature of many cancers; therefore, EGFR has become an attractive target for various antitumor strategies. Aberrant signaling from the EGFR is known to be important in the development and progression of NSCLC. Two oral EGFR inhibitors, gefitinib and erlotinib, are small-molecule agents that selectively inhibit the intracellular tyrosine kinase activity of the EGFR. Both have demonstrated antitumor activity in patients with advanced NSCLC who have failed all prior treatment regimens. In addition, the anti-EGFR monoclonal antibody cetuximab has shown promising activity in both first-line and second-line settings in patients with advanced NSCLC. Furthermore, patients with severe comorbidities who would not be eligible for systemic chemotherapy are candidates for these targeted therapies. Finally, these agents have also been shown to be effective for relieving symptoms, maintaining stable disease, and improving quality of life without the adverse events that may be associated with cytotoxic cancer therapies. This report will review the mechanism of action, indications, contraindications, patient selection, and efficacy and side effects of this new class of compounds. It is important for pulmonologists to be aware of this class of compounds, as they can provide benefit to patients with NSCLC who may not have been previously considered for antitumor therapy.     

Epidermal growth factor receptor inhibition strategies in oncology

Molecular targeting strategies for cancer therapy are distinct from conventional chemotherapy and radiotherapy in their potential to provide increased tumor specificity. One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR). The EGFR is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation appears important in tumor growth and progression. Advances in signal transduction biology continue to sharpen our understanding regarding specific contributions of EGFR signaling networks to cancer behavior. Two predominant classes of EGFR inhibitors have been developed including monoclonal antibodies (mAbs) that target the extracellular domain of EGFR, such as cetuximab (Erbitux), and small molecule tyrosine kinase inhibitors (TKIs) that target the receptor catalytic domain of EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva). Mechanisms of action for EGFR inhibitors have been investigated in preclinical model systems. Safety, activity, pharmacokinetics and pharmacodynamics have been assessed in clinical trials. The anti-EGFR mAbs and TKIs have partially overlapping toxicity profiles, but distinct routes of administration, serum half-lives and therefore dosing schedules. Both classes of agents show clear antitumor activity, and cetuximab and gefitinib have been recently FDA approved for colorectal and lung cancer indications respectively. However, the absence of survival benefit for EGFR TKIs in combination with chemotherapy in large-scale phase III lung cancer trials in 2003 underscores a major challenge in anti-EGFR oncology therapeutics; namely to identify those tumors and patients that will respond predictably to EGFR inhibitor approaches. Newly identified mutations in the EGFR catalytic domain that appear to confer sensitivity to EGFR TKIs promise to open new doors of investigation regarding response prediction. Advances will also require enhanced molecular understanding of the overall EGFR signaling network, and improved methods to gauge the dependence of individual tumors on EGFR signaling pathways for growth advantage. Results from newly reported phase III trials in 2004 now confirm a survival advantage for the use of EGFR inhibitors in combination with high-dose radiation in head and neck cancer, and in refractory lung cancer respectively. It appears likely that EGFR inhibitors (and other rationally designed molecular growth inhibitors) will play a meaningful role in cancer therapy in the years to come.     

Targeted therapy in advanced non-small-cell lung cancer

Molecularly targeted therapies have recently expanded the options available for patients with advanced non-small-cell lung cancer (NSCLC). Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathway. The former has emerged as a key regulator of cancer cell proliferation and invasion, and several EGFR inhibitors have been developed. Erlotinib, a small-molecule inhibitor of the EGFR intracellular tyrosine kinase, has been found to improve survival compared with placebo in previously treated patients with advanced NSCLC and is Food and Drug Administration (FDA)-approved in this setting. Clinical and molecular predictors of response to erlotinib, such as a history of never smoking and EGFR gene mutation or amplification, are presently being evaluated to select patients for earlier therapy with erlotinib. Additional EGFR inhibitors are also being examined in randomized trials. The VEGF pathway, a key mediator of angiogenesis, has become an attractive target in multiple malignancies, including lung cancer. Bevacizumab, a monoclonal antibody to VEGF, received FDA approval for use in advanced non-squamous-cell NSCLC in 2006 after a phase III trial reported a significant survival advantage when bevacizumab was added to standard first-line chemotherapy. Small-molecule inhibitors of the VEGF receptor tyrosine kinase, such as sunitinib and sorafenib, have also shown promise in phase II trials and are being further investigated in phase III studies. Because preclinical data suggest a synergistic effect when VEGF and EGFR inhibitors are combined, the concurrent use of erlotinib and bevacizumab has additionally been evaluated in a phase II trial, with encouraging early results suggesting at least equivalent activity to standard salvage chemotherapy, with less toxicity. Several other novel agents are being examined, including inhibitors of histone deacteylases and the 26S proteosome. Research efforts are currently focusing on tailoring such therapies according to predictive clinical and molecular markers.     

Afatinib in first-line setting for NSCLC harbouring common EGFR mutations: new light after the preliminary results of LUX-Lung 7?

The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) changed dramatically the history of non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Several randomized prospective trials confirmed the superiority of these target agents about survival and response rate when comparing with platinum-based chemotherapy. Knowledge about EGFR mutations increased gradually during the development of target agents and different clinical trials. EGFR mutations cannot be considered all equal, but different entities should be considered in our clinical practice: exon 19 deletions, exon 21 mutation (L858R) and uncommon mutation (exon 20, exon 18 and double mutation). Nowadays, we dispose of three different EGFR TKIs (afatinib, erlotinib and gefitinib) approved for the treatment for first-line treatment of patients di NSCLC carrying EGFR, that was compared only by indirect analysis, producing data not always clear and convincing. This research highlight is an overview of data about EGFR TKIs in first-line setting, focusing on differences about exon 19 deletions and L585R mutation in patients treated with different TKIs. In addition, we report the preliminary results of the first head-to-head randomized clinical trial between two different EGFR TKIs, the LUX-Lung 7 (LL7) that compared afatinib and gefitinib showing interesting results.     

The current status of targeted therapy for non‐small cell lung cancer

Lung cancer accounts for more cancer‐related deaths than any other malignancy in Australia and worldwide. Non‐small cell lung cancer (NSCLC) accounts for about 85% of lung cancers and is associated with a 5‐year survival of only 15%. Treatment with platinum‐based doublets in the first‐line setting and single agent chemotherapy in the second‐line setting has improved survival and quality of life in patients with NSCLC. However, the benefits associated with chemotherapy are modest and serve to stress the need for novel therapeutic approaches. In the last decade a range of targeted therapies has been evaluated in NSCLC. Dramatic and often durable responses were seen in patients treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib particularly in females, non‐smokers, patients of East Asian ethnicity and those with adenocarcinomas – a group subsequently found to be enriched for tumours with activating EGFR mutations. Large randomized phase III trials have since established a role for EGFR TKI in the second‐ and third‐line setting as well as a potential role for the monoclonal antibodies bevacizumab and cetuximab, directed at vascular endothelial growth factor and EGFR, respectively, in the combination with chemotherapy in the first‐line setting. Recently it has been shown that patients with EGFR mutations may benefit from gefitinib in the first‐line setting. Other promising agents under evaluation are inhibitors of the insulin‐like growth factor‐1 receptor and inhibitors of recently described ALK gene rearrangements.     

Biomarkers in lung oncology

The survival of advanced non-small-cell lung cancer patients is short in spite of advances in new combination chemotherapy regimens. The benefit of adding antiangiogenic drugs and/or EGFR inhibitors is unclear. For the vast majority of patients without EGFR mutations, treatment approaches based on customization should be pursued. BRCA1 is central to the repair of DNA damage and is an important modulator of the differential effect of chemotherapy. Retrospective and prospective data indicate that low BRCA1 mRNA levels predict better response and survival when patients are treated with cisplatin, non-taxane combinations.For an important subgroup of patients with EGFR mutations, selective treatment with EGFR tyrosine kinase inhibitors is a major advance, with a dramatic impact on clinical outcomes. In a prospective study of customized erlotinib [1], overall response rate was 70% (including 12% complete responses), median progression free survival was 14 months (even longer in women and in patients with del 19), 20% of patients were disease-free at three years, and median survival was 27 months. Nonetheless, these clinical outcomes fall short of curability and continuous treatment with erlotinib or gefitinib is required. It is plausible that several genetically defined subclasses of EGFR mutations could help to improve current clinical outcomes by combining erlotinib or gefitinib with other targeted drugs.     

New antiangiogenetic agents and non-small cell lung cancer

New blood vessel formation, known as angiogenesis is a fundamental event in the process of tumor growth and metastatic dissemination. Due to its central role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology, including the treatment of non-small cell lung cancer (NSCLC). Approaches targeting VEGF include monoclonal antibodies and vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). Bevacizumab (Avastin) is an anti-VEGF recombinant humanized monoclonal antibody. A very recent randomized phase III trial demonstrated a statistically significant advantage in median survival favouring the combination of bevacizumab plus chemotherapy versus chemotherapy alone in the treatment of advanced non-squamous NSCLC. This study represents the first evidence of superior efficacy of targeted therapy combined with chemotherapy over chemotherapy alone in the treatment of NSCLC. ZD6474 is an orally bioavailable inhibitor of VEGFR-2 tyrosine kinase. First evidences of antitumor activity and its excellent toxicity profile make it a promising targeted agent for the treatment of NSCLC. A recent phase I/II study examined the combination of Epidermal Growth Factor Receptor (EGFR)-TKI erlotinib and bevacizumab in patients with non-squamous stage IIIB/IV NSCLC. Data on antitumor activity of this combination have to be considered very promising. Clinical trials of multiple targeted therapy may represent the second generation studies in the treatment of NSCLC.     

Palliativ intendierte First-line-Chemotherapie des metastasierten nichtkleinzelligen Lungenkarzinoms

EGFR-TKI are established as an effective option for second- and third-line-treatment of advanced non-small cell lung cancer. The combination with chemotherapy in nonselected patients did not show an additional benefit compared with chemotherapy alone. With a combination of the EGFR antibody cetuximab or the VEGF antibody bevacizumab with chemotherapy a moderate improvement of overall survival was achieved. Results of comparative trials with molecular targeted therapies and classic chemotherapy as first-line treatment are currently only available for the EGFR-TKI erlotinib and gefitinib which showed impressively the superiority in response rate, progression-free survival, toxicity, and improvement of quality of life for EGFR-TKI in patients harboring an activating mutation of EGFR. For patients with unknown EGFR mutation status or wild-type EGFR the platinum-based chemotherapy combination is still the most effective treatment option.     

非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂耐药机制研究进展

以吉非替尼和厄罗替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂在部分非小细胞肺癌患者中的治疗效果显著,但几乎所有患者最终均表现为耐药.因此,为提高该类药物的效用,对耐药性的研究便显得至关重要.基因突变、细胞表型改变、受体内化、信号通路成分及其调节因子的基因表达改变等都可以导致肿瘤细胞摆脱对表皮生长因子受体信号通路的专一性依赖而产生耐药.     

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.     

Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.     

Treatment of advanced non small cell lung cancer

Lung cancer is the major cause of cancer death in the world. Non Small Cell Lung Cancer (NSCLC) accounts approximately 80-85% of all lung cancer diagnosis; the majority of patients will be diagnosed with non operable, advanced-stage disease. Palliative chemotherapy and/or radiotherapy represent the standard of care of this disease. Platinum based doublets with third generation agents are considered the standard of first line advanced NSCLC treatment. However, data arising from the availability of pemetrexed suggest that histology could play a key role in decision making. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) for therapeutic agents. Bevacizumab is the first recombinant humanized monoclonal antibody (mAb) binding VEGF to demonstrate clinical benefit and a rather survival prolongation in combination with chemotherapy in the treatment of non squamous chemo-naive advanced NSCLC patients. Two types of anti-EGFR targeting agents have reached advanced clinical development: mAbs and small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity (TKIs). Among TKIs gefitinib has been tested in several phase II-III studies showing an improvement in survival and responses in first, second and third line treatment in selected patients with specific clinical and molecular characteristics. Furthermore, erlotinib has showed to significantly improve survival in an unselected population of patients following the failure of one or two chemotherapy regimens. This review will discuss the different therapeutic options for first and second line treatment in the clinical practice.     

Prediction of epidermal growth factor receptor mutations in the plasma/pleural effusion to efficacy of gefitinib treatment in advanced non-small cell lung cancer

Purpose  

Recently, mutations in the epidermal growth factor receptor (EGFR) gene were reported to correlate with EGFR tyrosine kinase inhibitor response in advanced non-small cell lung cancer (NSCLC). In this study, we attempted to detect EGFR mutations in plasma and pleural effusion samples and to make clear its correlations with gefitinib response and survival in NSCLC patients.     

Factors predicting response to EGFR tyrosine kinase inhibitors

Over the past few years, two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) and erlotinib (Tarceva), have been developed for the treatment of patients with cancer. In patients with non-small cell lung cancer (NSCLC), these therapies occasionally demonstrate remarkable and durable activity. However, EGFR TKIs are active in only a small subset of patients. Responders are more often nonsmokers, of East Asian descent, and female, and have tumors with adenocarcinoma histology. In April 2004, two groups reported that a cluster of somatic mutations in the kinase domain of the EGFR are observed in the majority of NSCLCs that demonstrate remarkable responses to EGFR TKIs. These findings have been validated by other investigators and have revolutionized the manner in which clinicians are thinking about their utilization for the treatment of NSCLC. This review focuses on the clinical experience with EGFR TKIs, the present knowledge regarding the biology of EGFR mutations, the limitations of using EGFR mutational status to predict who will respond to EGFR TKIs, and the implications of this information on the use of these agents for the treatment of advanced NSCLC.     

New era of epidermal growth factor receptor-tyrosine kinase inhibitors for lung cancer

Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor (EGFR) activating mutations and the introduction of its tyrosine kinase inhibitors (TKIs) have expanded the treatment options for patients with non-small cell lung cancer. Nowadays, EGFR mutation testing is now a common routine for newly diagnosed lung cancer. First generation TKIs developed, erlotinib and gefitinib, were reversible ones. After a median of 14 mo, eventually all EGFR mutated patients develop resistance to reversible TKIs. Afatinib, dacomitinib and neratinib, second generation inhibitors, are selective and irreversible TKIs. Finally, third generation phase I clinical trials were performed, with lower toxicity profiles, and targeting with more precision the driving clone of this heterogeneous disease.