Investigational drugs targeting fibroblast growth factor receptor in the treatment of non-small cell lung cancer

Introduction: Fibroblast growth factor receptor (FGFR) due to its central role in regulating cell survival, is a promising target for cancer therapeutics. Dysregulation of the FGFR pathway has been observed in several malignancies, including non-small cell lung cancer (NSCLC) particularly in patients with squamous histology.

Areas covered: The aim of this article is to review the most relevant findings of clinical trials investigating drugs targeting FGFR pathway: such as FGFR tyrosine kinase inhibitors (TKIs), FGFR monoclonal antibodies and FGF ligand traps in NSCLC patients.

Expert opinion: At present, clinical activity of drugs targeting FGFR in NSCLC is disappointing. Further studies are needed in order to better identify patients who might benefit from these drugs and to clarify the mechanisms of resistance to these compounds.     

表皮生长因子受体后时代非小细胞肺癌新靶点及治疗进展

作为肺癌驱动基因之一的突变表皮生长因子受体(EGFR)的发现开启了非小细胞肺癌(NSCLC)靶向治疗之门。继EGFR后发现了更多肺癌相关驱动基因,并可成为NSCLC新的治疗靶点(如ALK,ROS1,RET,KRAS,HER2,BRAF,PIK3CA,MEKI/2,MET等)。本文对新发现靶点及针对这些靶点的药物治疗进展进行综述。     

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

Aberrant epidermal growth factor receptor (EGFR) signalling contributes to neoplastic transformation and EGFR inhibition by antibodies and small molecules inhibits cancer cell proliferation and survival. In previously treated patients with non-small cell lung cancer, the administration of gefitinib and erlotinib are associated with objective tumour response rates of 8-19%. However, only erlotinib has been shown definitively to improve patient survival. The likelihood of benefit may be determined by the presence of specific genotypic abnormalities in EGFR or downstream pathway components. Additional evaluation to determine optimal dose/schedule of the agents combined with standard treatments and with other targeted agents in appropriately selected patients are areas of active research.     

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.     

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

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of the newer cytotoxic agents in NSCLC treatment during the last decade the survival rates of patients have reached a plateau. New strategies are clearly needed to improve treatment outcomes. Epidermal growth factor receptor (EGFR) has a key role in cancer development and progression and has been recognised as a target of increasing importance in NSCLC. Gefitinib, erlotinib and cetuximab are EGFR-targeting agents that are being extensively evaluated in NSCLC. EGFR inhibitors demonstrate significant clinical activity in approximately 10-20% of pretreated NSCLC patients. Somatic mutations in the kinase domain of the receptor have been shown to be associated with enhanced sensitivity to EGFR inhibitors. However, four large Phase III randomised, placebo-controlled trials of gefitinib and erlotinib in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the study drugs. Possible reasons include patient selection, drug scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities.     

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

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of the newer cytotoxic agents in NSCLC treatment during the last decade the survival rates of patients have reached a plateau. New strategies are clearly needed to improve treatment outcomes. Epidermal growth factor receptor (EGFR) has a key role in cancer development and progression and has been recognised as a target of increasing importance in NSCLC. Gefitinib, erlotinib and cetuximab are EGFR-targeting agents that are being extensively evaluated in NSCLC. EGFR inhibitors demonstrate significant clinical activity in ~ 10 – 20% of pretreated NSCLC patients. Somatic mutations in the kinase domain of the receptor have been shown to be associated with enhanced sensitivity to EGFR inhibitors. However, four large Phase III randomised, placebo-controlled trials of gefitinib and erlotinib in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the study drugs. Possible reasons include patient selection, drug scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities.     

Chemokines as therapeutic targets in non-small cell lung cancer

Angiogenesis, defined as the generation of new blood vessels from pre-existing vessels, is one of life's essential processes. Inflammation and angiogenesis, while distinct and separable, are closely related processes. One of the hallmarks of chronic inflammation is granulation tissue, a prominent feature of which is neovascularization. Whenever tissue constituents proliferate, repair, or hypertrophy, such change must be accompanied by a proportional increase in capillary blood supply to assure delivery of nutrients, and removal of metabolic waste. This absolute dependence suggests two characteristics of angiogenesis. First, under normal conditions the process must be tightly controlled. Second, in the absence of such strict control, abnormal physiology, or disease is likely to result. The role of angiogenesis in solid tumor growth has attracted a great deal of attention as a potential therapeutic target. Lung cancer is a particularly devastating disease in industrialized countries. The majority of patients with lung cancer are faced with very poor therapeutic options, and gaining insight to the mechanism of angiogenesis in this disease has obvious implications for the design of therapeutic agents. Research in our laboratories has demonstrated that chemokines (chemotactic cytokines) are pivotal determinants of the angiogenic activity of non-small cell lung cancer (NSCLC). This review will focus on the evidence supporting the central role of these molecules in lung cancer angiogenesis, and focus on potential novel means of targeting this family of angiogenic regulators.     

环氧化酶-2及表皮生长因子受体在非小细胞肺癌组织中的表达及临床意义

目的探讨环氧化酶-2（COX-2）与表皮生长因子受体（EGFR）在非小细胞肺癌（NSCLC）组织中的表达及与肺癌发生发展的关系。方法采用免疫组化（SP）法检测56例NSCLC和20例正常肺组织中COX-2与EGFR表达。结果56例NSCLC组织中，COX-2与EGFR表达阳性率分别为64．2％，67．8％，显著高于正常肺组织（P〈0．01），COX-2与EGFR表达与临床分期、病理分级、组织学分型、淋巴结转移密切相关（P〈0．05），肿瘤分期愈晚，细胞分化越羞，淋巴结转移越高，COX-2与EGFR表达阳性率越高，腺癌中COX-2表达明显高于鳞癌，鳞癌中EGFR表达高于腺癌（P〈0．05）。结论COX-2与EGFR在NSCLC中异常表达说明其在肺癌发生发展中有重要作用．可作为判断NSCLC的生物学行为及估计预后的指标。     

表皮生长因子受体及血管内皮生长因子在非小细胞肺癌组织中的表达

目的 观察非小细胞肺癌(NSCLC)组织中表皮生长因子受体(EGFR)和血管内皮生长因子(VEGF)的表达情况以及与临床病理特征的关系.方法 采用免疫组化法检测124例NSCLC组织和15例远离肿块无癌细胞浸润的肺组织(距肿瘤病变＞5 cm)标本EGFR、VEGF的表达.结果 EGFR、VEGF在124例NSCLC标本中的阳性表达率分别为52.4％、66.1％,在15例远离肿块无癌细胞浸润的肺组织(距肿瘤病变＞5 cm)均无表达.Ⅲ期NSCLC组织的VEGF表达率为80.4％ (41/51),高于Ⅰ-Ⅱ期的56.2％ (41/73)(x2=4.24,P＜0.05);淋巴结阳性的NSCLC组织VEGF表达率为78.2％ (50/64),明显高于淋巴结阴性的53.3％(32/60)(x2=4.77,P＜0.05),VEGF和EGFR表达与病理类型、性别、年龄、肿瘤细胞分化等无关.EGFR与VEGF呈正相关关系(r=0.93,P＜0.05).结论 EGFR、VEGF在NSCLC组织中过表达;VEGF可能与TNM分期及淋巴结转移有关,EGFR与VEGF在NSCLC肿瘤血管形成过程中可能起协同作用.     

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.     

治疗非小细胞肺癌新药:表皮生长因子受体酪氨酸激酶抑制剂-dacomitinib

Dacomitinib是一种由辉瑞制药公司研发的第2代口服表皮生长因子受体酪氨酸激酶抑制剂。2018年9月27日,美国食品和药物管理局批准dacomitinib用于EGFR第19外显子缺失突变或第21外显子L858R替换突变的转移性NSCLC患者的一线治疗。本文主要介绍其作用机制、药动学、临床研究及安全性。     

Vascular endothelial growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer

ABSTRACT

Introduction: Angiogenesis is the process by which the tumor develops its potential for growth and distant metastasis. The main proangiogenic switch is vascular endothelial growth factor (VEGF), which, along with its receptor VEGFR, is a target for biological drugs such as multi-targeted tyrosine kinase inhibitors used for many neoplasms, including non-small cell lung cancer (NSCLC).

Areas covered: The fact that angiokinase inhibitors act on several signaling molecules simultaneously means that the use of alternative transmission pathways, which nullifies the effect of drugs directed against a single target, is avoided. Nevertheless, most of these drugs have failed to improve any outcome in NSCLC patients. The authors discuss these points and provide their expert perspectives.

Expert opinion: Multikinase inhibitors are the fruit of research which regards cancer as a complex system of interacting processes. However, the lack of predictive biomarkers of response has limited the development of this class of drugs in NSCLC. Combination trials with chemotherapy, immunotherapy or other targeted drugs are ongoing, and while some have already confirmed the role of antiangiogenic small molecules in integrated regimes, others are still evaluating the efficacy of these drugs and raising questions about their cost and tolerability.     

The potential role of insulin-like growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancer

Importance of the field: Lung cancer is the leading cause of cancer-related mortality worldwide. NSCLC accounts for > 80% of all lung cancers. The treatment of advanced fit NSCLC patients seems to have reached a plateau. Considerable efforts have been initiated to identify new biological agents.

Areas covered in this review: Diagnosis of NSCLC histotype is becoming extremely important to address treatment. While non-squamous histology could start to benefit from the administration of several new drugs only recently, non-adenocarcinoma subtype seems to benefit from the administration of figitumumab (CP-751,871) a fully human anti-IGF 1 receptor (IGF-1R) mAb. In this paper, we reviewed the IGF-1R pathway and its inhibitors.

What the reader will gain: Approaches targeting IGF-1R include small-molecule IGF-1R tyrosine kinase inhibitors (TKIs), which are in preclinical and early clinical phases of development, and the mAbs, among which figitumumab is being investigated in Phase III trials of advanced NSCLC.

Take home message: Figitumumab reported interesting results in the treatment of advanced non-adenocarcinoma NSCLC patients. Overall, in order to administer the optimal treatment to patients, a more definite histological diagnosis is mandatory.     

Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.     

Role of erlotinib in the treatment of non-small cell lung cancer: clinical outcomes in wild-type epidermal growth factor receptor patients

Erlotinib is an orally administered small molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Erlotinib at the standard oral daily dose of 150 mg is approved for the treatment of unselected chemorefractory advanced non-small cell lung cancer patients as well as maintenance therapy after first-line chemotherapy. The European Medicines Agency has recently also approved erlotinib as the first-line therapy in patients with EGFR mutations. Although recent studies have identified higher response rates and improved survival with erlotinib in a subset of patients with EGFR mutations, the survival benefit from single agent erlotinib in chemorefractory patients and in the maintenance setting is well observed in EGFR wild-type patients. The role of single agent erlotinib in the first-line setting in special subsets of EGFR wild-type patients (elderly, poor performance status, non-smokers) needs to be further determined. The combination of erlotinib with other targeted therapies has shown promising results and warrants further studies in EGFR wild-type patients.     

Pyronaridine induces apoptosis in non-small cell lung cancer cells by upregulating death receptor 5 expression and inhibiting epidermal growth factor receptor

Lung cancer is the leading cause of cancer death. Pyronaridine, a synthetic drug of artemisinin, has been used in China for over 30 years for the treatment of malaria, but its effect on non-small cell lung cancer (NSCLC) cells is rarely reported. In this study, we determined the efficacy of pyronaridine in four different NSCLC cell lines and explored its mechanism in H1975. The data showed that pyronaridine could upregulate the expression of TNF-related apoptosis-inducing ligand (TRAIL)-mediated death receptor 5 to promote cellular apoptosis. Meanwhile, the JNK (c-Jun N-terminal kinase) level was detected to be significantly increased after treating with pyronaridine. We used JNK inhibitor and found that it could partially inhibit cell apoptosis. The results showed that epidermal growth factor receptor (EGFR), PI3K, and AKT were downregulated after the treatment of pyronaridine. In summary, pyronaridine can selectively kill NSCLC by regulating TRAIL-mediated apoptosis and downregulating the protein level of EGFR. It is a promising anticancer drug for NSCLC.     

应用于非小细胞肺癌的表皮生长因子受体酪氨酸激酶抑制药个体差异性指标的研究现状

表皮生长因子受体酪氨酸激酶抑制药(EGFR-TKIs)是治疗表皮生长因子受体突变的晚期非小细胞肺癌(NSCLC)的一线用药,在临床应用过程中,可观察到血药浓度及安全性、有效性的个体差异,可能与药物代谢酶和转运体的基因多态性相关.因此,本文对临床常用的6种EGFR-TKIs可能相关的药物遗传学指标和药代动力学指标进行整理...     

Investigational platelet-derived growth factor receptor kinase inhibitors in breast cancer therapy

Introduction: Aberrant regulation of platelet-derived growth factors (PDGFs) and their receptors (PDGFR) has been shown to be involved in many solid tumors, including breast cancer. PDGFR-α and PDGFR-β expressions were documented in breast cancer and are correlated with tumor aggressiveness and metastasis. Preclinical evidence further suggests tumor stimulatory roles of PDGFRs expressed by tumor stroma cells and indicates a deleterious effect of stromal PDGFRs on intratumoral drug uptake.

Areas covered: This review summarizes the present understanding of PDGF signaling in breast cancer based on experimental studies and available clinical trials. It also provides a critical discussion of selected ongoing clinical trials in patients with breast cancer involving PDGFR inhibition with tyrosine kinase inhibitors, specifically in endocrine responsive breast cancer.

Expert opinion: An increased molecular understanding of response and resistance mechanisms to endocrine therapy will be essential for therapeutic advances in PDGFR-directed cancer therapy. Future developments in the field will rely on clinical studies where prospective analyses of target expression in breast cancer cells and in the tumor stroma are included. More selective PDGFR inhibitors with reduced side effects will be crucial for combinatorial therapies. Development of sensitive diagnostics is of critical importance for patient selection and monitoring of therapeutic effects.     

Exploring death receptor pathways as selective targets in cancer therapy

A recent and innovative strategy in cancer therapy is the activation of apoptosis in tumour cells specifically expressing death receptors (DR) belonging to the tumour necrosis factor (TNF) receptor superfamily and including several members known since the early ‘90. Among these, those largely studied for clinical purpose are TNF, CD95, and TRAIL receptors. Promising results are expecting from ongoing phases I/II clinical trials proving the therapeutic efficacy of DR agonistic antibodies and/or recombinant proteins alone or in association to classic and novel chemotherapeutic drugs. However, two key issues need extensive studies, before clinical and safe applications of DRs as effective anticancer drugs can be accepted: i. DR-based cancer therapy must be selective and effective against a broad range of cancers and reduce excessive systemic toxicity toward normal cells and tumour resistance after recurrent treatments; ii. an improved knowledge of mechanisms of alternative signalling triggered by DR ligands and leading to cell survival and apoptotic resistance. Activation of survival pathways regulated by key factors, such as NF-κB, JNK, p38, ERK and PI₃K are the focus of several studies revealing the dark side of DR signalling. The present review focuses on new insights in the signalling and clinical application of TNF, CD95 and TRAIL receptors.