Targeted therapies and non-small cell lung cancer: methodological and conceptual challenge for clinical trials

PURPOSE OF REVIEW: Targeted therapies are emerging as important drugs in the treatment of advanced non-small cell lung cancer (NSCLC). Within the past months, there have been considerable contributions to this topic. The results of several important clinical trials have been published. Furthermore, laboratory results have significantly contributed to clear out some molecular mechanisms regulating sensitivity or resistance to these drugs and to provide rational basis for further clinical studies. RECENT FINDINGS: A great part of recently published research on targeted agents in NSCLC regards EGFR inhibitors. Following the demonstration of activity of gefitinib in patients pretreated with chemotherapy, four large randomized trials testing the addition of gefitinib or erlotinib to first-line chemotherapy have been conducted, but failed to show any advantage. Interestingly, erlotinib has shown efficacy compared with placebo in pretreated patients. Mutations in the EGFR gene have shown a strong predictive role for sensitivity to EGFR inhibitors. A number of other targeted agents are currently under investigation: most of the phase II trials maintain a traditional methodology, with response rate as primary measure of activity. SUMMARY: Recent advances will lead to a rapid expansion of further studies aimed to define the best way to use targeted agents in NSCLC. Several methodological issues are still open. The proper selection of patients, the choice of the best study design and the most appropriate end-point for early clinical trials, and the correct modality to integrate these drugs with traditional chemotherapy represent the most challenging points that research is called to answer in the near future.     

Targeted therapies and radiotherapy in lung cancer]

Targeted therapies are now more often used in lung cancer. Inhibitors of EGFR and of angiogenesis have demonstrated a certain activity in this disease. Some experimental in vitro or in vivo studies are in favour of combined targeted therapies and radiation. For example, additive or supra-additive effects have been shown when inhibitors of the EGFR tyrosine kinase were given with radiation. In advanced lung cancer, the combination of bevacizumab with chemotherapy was demonstrated to produce better survival outcomes. But a high rate of fatal hemoptysis was reported with this drug, particularly for central and squamous tumors. This could be a limitation for its use in combination with radiation. Drugs with multiple targets are becoming available; their association with radiation seems to be promising.     

肿瘤的靶向治疗

靶向治疗是针对肿瘤细胞恶性表型的分子靶点,作用于促进肿瘤生长、存活的特异性细胞受体、信号传导等通道,实现抑制肿瘤细胞生长或促进凋亡的抗肿瘤作用。新的靶向治疗药物rituximab、伊马替尼、赫赛汀和全反式维甲酸已开始用于临床治疗,本文综述这些药物的作用机制、适应证、疗效及安全性。与传统细胞毒化疗不同,肿瘤靶向治疗具有特异性抗肿瘤作用,并且毒性明显减少。肿瘤靶向治疗令人鼓舞的初步成果为其进一步发展奠定了基础,提供了典范,开创了肿瘤化疗的新领域。     

Targeted therapies in small cell lung cancer: a review

Small cell lung cancer (SCLC) is an aggressive form of lung cancer that is characterized by a rapid doubling time, early onset of dissemination and high sensitivity to chemotherapy. Despite the potential for cure in patients with limited disease with concurrent chemoradiation and an initial good response to chemotherapy in extensive disease, there is a high chance of disease relapse with an overall poor median survival for both stages. With increasing translational research and a better understanding of the molecular basis of cancer, a number of molecular targets have been identified in various preclinical studies. This review summarizes potentially viable targets and new agents that have been developed and employed in recent, ongoing and future clinical trials to attempt to improve clinical outcomes in this disease.     

Targeted therapies for advanced non-small-cell lung cancer: current status and future implications

Lung cancer remains the leading cause of malignancy-related mortality worldwide, with over one million cases diagnosed yearly. Non-small-cell lung cancer (NSCLC) accounts for >80% of all lung cancers. Because lung cancer is typically diagnosed at an advanced stage, chemotherapy (CT) is the mainstay of management. Conventional treatment of NSCLC has apparently reached a plateau of effectiveness in improving survival of patients, and treatment outcomes must still be considered disappointing. Hence, considerable efforts have been made in order to identify novel targeted agents that interfere with other dysregulated pathways in advanced NSCLC patients. In order to further improve the results of targeted therapy, we should not forget that lung cancer is a heterogeneous disease with multiple mutations, and it is unlikely that any single signaling pathway drives the oncogenic behaviour of all tumours. The relative failure of some targeted therapies may be a result of multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. We summarize the most promising research approaches to the treatment of NSCLC, with particular attention to drugs with multiple targets or combining targeted therapies.     

Targeted therapy using novel agents in the treatment of non-small-cell lung cancer

Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti-epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cb, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC.     

Early clinical trial experience with vaccine therapies in non-small-cell lung cancer

Cancer immunotherapy has made great progress because of advances in immunology and molecular biology. Increased understanding of mechanisms by which lung cancer cells escape the immune system and recognition of key tumor antigens and immune system components involved in tumor ignorance have led to the development of a variety of lung cancer vaccines. Immunotherapy has advanced from using nonspecific immunomodulatory agents to lung cancer-specific tumor antigens and tumor cell-derived vaccines. While understanding of immune processes and malignancy has improved, there is great opportunity for further research of vaccine therapies in non-small-cell lung cancer. Herein, we review the development and evolution of early lung cancer vaccine trials.     

胃肠道肿瘤的靶向治疗

分子靶向治疗在晚期胃肠道肿瘤的治疗中有着重要地位。近年来,已研发了大量的靶向治疗药物并进入了临床试验,以验证其疗效和安全性。各期临床试验均证实,以单克隆抗体和酪氨酸激酶抑制剂为代表的靶向治疗药物有着更好的疗效以及安全性。     

Targeted therapies for esophageal cancer

Esophageal cancer is a highly aggressive neoplasm. In 2005, 14,520 Americans will be diagnosed with esophageal cancer, and more than 90% will die of their disease. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000-more than lung, breast, or colorectal cancer. Although esophageal squamous cell carcinoma cases have steadily declined, the incidence of gastroesophageal junction adenocarcinoma has increased 4%-10% per year among U.S. men since 1976, more rapidly than for any other cancer type, and parallels rises in population trends in obesity and reflux disease.With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past three decades. However, the 5-year overall survival rate (14%) remains poor, even in comparison with the dismal survival rates (4%) from the 1970s. The underlying reasons for this disappointingly low survival rate are multifold: (a) ineffective screening tools and guidelines; (b) cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation; (c) high risk for recurrent disease after esophagectomy or definitive chemoradiotherapy; (d) unreliable noninvasive tools to measure complete response to chemoradiotherapy; and (e) limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease. Clearly, additional strategies are needed to detect esophageal cancer earlier and to improve our systemic treatment options. Over the past decade, the field of drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. This review focuses on novel targeted treatments in development for esophageal squamous cell carcinoma and distal esophageal and gastroesophageal junction adenocarcinoma.     

Targeted cancer therapies

With unprecedented understanding of molecular events underlying human cancer in this genomic era, a large number of drugs specifically targeting hypothesized oncogenic drivers to which tumors are poten...     

胰腺癌的靶向治疗

放化疗联合靶向药物治疗是晚期胰腺癌的主要治疗手段.目前与胰腺癌治疗相关的靶向药物主要有表皮生长因子受体(EGFR)阻断剂、抗血管内皮生长因子(VEGF)单克隆抗体等.其中,厄洛替尼与吉西他滨(GEM)联合已被证实具有延长胰腺癌患者生存期的作用.     

Targeted cancer therapies

The term "targeted cancer therapies" refers to treatment strategies designed to inhibit the product of an oncogene involved in the process of neoplastic transformation. Different categories of targeted therapies can be identified: 1) Therapies directed at oncogenes that are directly involved in the initiation of neoplastic transformation: the use of imatinib for the treatment of CML or GIST is the classical model in this subgroup. Single agent targeted therapies generally produce high response rates in this situation. 2) Therapies directed at oncogenes involved at a later stage of neoplastic transformation. These oncogenes contribute to tumor progression but not necessarily to the onset of malignant transformation. The use of trastuzumab for HER2-amplified breast adenocarcinoma is the classical model in this subgroup. These treatments are associated with low response rates when used as single agent therapy, whereas generally displaying a synergistic or additive effect with classical chemotherapy in models currently available. In contrast, when these targeted therapies are applied to tumor models where the targeted gene is present but not directly involved in the process of malignant transformation, no antitumor efficacy is generally observed. Recently, the identification of HER1 mutations in subsets of lung carcinoma as a predictive factor for response to gefitinib and erlotinib provided an example of how the empiric use of a targeted treatment may enable to identify new nosological entities. The present paper reviews examples of targeted cancer therapies and their results.     

Targeted therapies and radiation therapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related death. Between 80-85% of lung cancers are non-small cell lung carcinomas. One third of the patients are diagnosed with locally advanced stage. In this condition, concomitant radio-chemotherapy is the standard treatment for patients with good performance status. Despite important improvements in the last years, non-small cell lung carcinoma prognosis remains poor, with high rates of both local recurrences and metastases. The heterogeneity of molecular characteristics of non-small cell lung carcinoma cells and a better knowledge of potential targets offer promising developments for new pharmacologic agents. Hereafter we will review the currently most studied pathways and the most promising ones for the treatment of locally advanced unresectable non-small cell lung carcinoma. Two of the most attractive pathways where new agents have been developed and assessed in combination with thoracic radiotherapy or radiochemotherapy are the EGFR pathway (either with the use of monoclonal antibodies or tyrosine kinase inhibitors) and the angiogenesis inhibition. The development of targeted agents could lead to individualized therapeutic combinations taking into account the intrinsic characteristics of tumor cells. Pharmacological modulation of tumour cells radiosensitivity by targeted therapies is only starting, but yet offers promising perspectives.     

Targeting novel and established therapies for non-small cell lung cancer

The prognosis in advanced non-small cell cancer (NSCLC) remains poor despite the introduction of several new cytotoxic drugs in the past decade. New approaches are required, and an improved understanding of lung cancer biology is identifying molecular mechanisms that are potential targets for novel therapies. Antagonists of signalling via the erbB and VEGFR families of transmembrane receptors have promising activity in NSCLC, and survival benefit has already been demonstrated for both erlotinib and bevacizumab. Although some patients enjoy dramatic and sustained responses to some of the new targeted drugs, overall response rates in unselected NSCLC patient groups are modest. This reflects the molecular heterogeneity of the disease; further clinical progress will require improved patient selection for treatment with both novel agents and established chemotherapy drugs. Here, we review recent advances in NSCLC biology likely to provide insight into such selection strategies.