Integration of EGFR inhibitors and conventional chemotherapy in the treatment of non-small-cell lung cancer

Introduction/Background

Given the limited gains of traditional chemotherapy in improving outcomes in patients with advanced non–small-cell lung cancer (NSCLC), recent research efforts have investigated the integration of targeted agents into the treatment algorithm.

Materials and Methods

Searches of PubMed and of recent results from key oncology congresses were performed to identify relevant articles and abstracts. Initial phase III trials combining the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib with platinum-based doublets as first-line therapy failed to demonstrate an overall survival advantage in unselected patients with NSCLC. However, in recent years, there has been substantial progress in understanding the determinants of response to EGFR TKI therapy, including the presence of activating EGFR mutations, which has been reflected in clinical trials specifically evaluating these patient populations. In addition, evidence suggesting potential mechanistic interference between concurrent EGFR TKIs and chemotherapy has also been observed, fueling interest in sequential or intermittent dosing. EGFR-targeted agents such as the multitargeted TKI vandetanib and the next-generation EGFR TKIs afatinib (BIBW 2992) and PF00299804 are also under clinical investigation for the treatment of NSCLC, both alone and in combination with chemotherapy.

Conclusions

Trials evaluating various regimens of EGFR-targeted agents and chemotherapy are planned and/or underway and will hopefully define the role of integrated therapy in NSCLC.     

Disappearance of an activated EGFR mutation after treatment with EGFR tyrosine kinase inhibitors

A 34-year-old Japanese woman presented with left supraclavicular lymph node swelling. Computed tomography scans revealed a mass on the left lower lobe, pulmonary nodules, and pleural effusion. A lymph node biopsy revealed large-cell carcinoma with an epidermal growth factor receptor (EGFR) deletion mutation, L747-T751 in exon 19. Although malignant pleural effusions carried the same EGFR mutation, progressive pleural effusions after treatment with chemotherapy, gefitinib, and erlotinib did not show any EGFR mutation. A cell line established from the pleural effusion 3 days before the patient expired also did not harbor the EGFR mutation. Histological sections of the lymph node of the patient were similar to those of the xenograft tumor of the cell line. There may be genetic heterogeneity in EGFR mutant tumors.     

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

Purpose

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined.

Methods

We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR.

Results

Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4?%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n?=?6) or erlotinib (n?=?6). The most common mutation was exon 19 deletion (n?=?7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75?%, respectively. The median PFS was 3.67?months (95?% CI: 1.34?C5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53?months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83?months) who were treated with EGFR TKIs.

Conclusions

The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.     

Clinical studies with non-iressa EGFR tyrosine kinase inhibitors

During the last five years there has been interest in developing non-cytotoxic, targeted cancer treatments. This phenomenon has occurred as a result of increased information regarding factors which regulate tumor proliferation, survival, angiogenesis, invasiveness, and metastatic potential. In non-small cell lung cancer many investigators have focused their attention on the epidermal growth factor receptor (EGFR) because this membrane protein, which has an extracellular ligand binding domain, as well as, tyrosine kinase activity on the intracellular portion of the molecule, is expressed in a relatively high proportion of non-small cell lung cancers. Gefitinib which was the first EGFR specific tyrosine kinase inhibitor to be extensively tested in non-small cell lung cancer has shown single agent activity in non-small cell lung cancer. Subsequently, erlotinib, another EGFR specific tyrosine inhibitor, has also demonstrated single agent activity in non-small cell lung cancer. Phase III trials of erlotinib alone or in combination with chemotherapy have been completed, and data are being analyzed. Several dual inhibitors of erb B1 and erb B2 (PKI 166, GW 572016, EKB 569) have been or are being tested in phase I trials. In addition, CI 1033, a pan-erb inhibitor, is also being tested in phase I studies. Diarrhea and rash have been the predominant side effects of these agents. Life threatening toxicity has been rare. Although the erb tyrosine kinase inhibitors are attrative agents to use in treating non-small cell lung cancer because of their relatively benign toxicity profile, more data are needed to define the role of these agents in non-small cell lung cancer.     

EGFR inhibitors in lung cancer

Targeted therapies inhibiting the epidermal growth factor receptor (EGFR) have been introduced in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Many inhibitors of the EGFR have been developed, targeting either the extracellular receptor domain with antibodies or the intracellular tyrosine kinase binding domain with small molecules. The tyrosine kinase inhibitor (TKI) gefitinib (Iressa) was the first targeted drug to be registered for the treatment of NSCLC after failure of chemotherapy. Given concurrently together with platinum combination chemotherapy both TKIs gefitinib and erlotinib (Tarceva) failed to increase activity. Sequential targeted therapy after chemotherapy is currently being investigated further. Studies with the monoclonal antibody cetuximab (Erbitux) combined with chemotherapy are ongoing. Side effects of the small molecules are mainly skin rash and diarrhea, whereas the antibodies do not give diarrhea. Selection of patients, based on molecular markers and patient characteristics, has become an important issue for the further development of these drugs, given there is activity in a relatively small group of patients with NSCLC. Newer drugs inhibiting more than one receptor pathway are being investigated in order to find activity in a broader group of patients.     

EGFR拮抗剂在结直肠癌治疗中的应用

EGFR活化及其信号通路在结直肠癌生物学中起着重要作用。EGFR靶向药物为结直肠癌的治疗开创了新的方向。与酪氨酸激酶抑制剂相比,单克隆抗体已被证明有很高的疗效。西妥昔单抗作为一线、二线用药及用于化疗耐药的病人都是有效的。作为一线药物时,它的加用还可以提高肝转移灶切除率。     

EGFR拮抗剂在结直肠癌治疗中的应用

EGFR活化及其信号通路在结直肠癌生物学中起着重要作用。EGFR靶向药物为结直肠癌的治疗开创了新的方向。与酪氨酸激酶抑制剂相比,单克隆抗体已被证明有很高的疗效。西妥昔单抗作为一线、二线用药及用于化疗耐药的病人都是有效的。作为一线药物时,它的加用还可以提高肝转移灶切除率。     

表皮生长因子受体抑制剂在乳腺癌治疗中的研究

表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌、头颈部肿瘤的治疗方面取得了较好的疗效.在乳腺癌方面,人们最初认为,EGFR的高表达也可能是乳腺癌病人接受EGFR抑制剂的重要条件,而EGFR抑制剂可能对ER阴性、内分泌治疗不敏感的乳腺癌有效.但临床研究结果并不支持上述观点.本文着重讨论EGFR抑制剂在乳腺癌治疗中的现状及前景.     

Prediction of effectiveness of EGFR tyrosine kinase inhibitors for the patients with by EGFR mutations

EGFR-TKI has been synthesized as a potential target for cancer therapy because EGFR is overexpressed and associated with poor prognosis of lung cancer. It was reported that EGFR mutations were more sensitive to EGFRTKI than those without the mutations among lung cancer patients. A subgroup of patients of Asian origin, female sex, adenocarcinoma, and no history of smoking were significantly associated with a high rate of EGFR mutations. These patients with EGFR mutations were not only favorable responders but also had a longer survival than without. In this article, we discuss the EGFR-TKI predictive factors by EGFR mutations.     

Mechanisms of resistance to EGFR inhibitors

The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer, contributing to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis, and metastatic spread. For these reasons, the EGFR is one of the most studied and exploited targets for molecular cancer therapy. Two classes of anti-EGFR agents have entered clinical practice: monoclonal antibodies and small molecules targeting the receptor tyrosine kinase. They have shown activity alone and in combination with conventional antitumor treatments, such as chemotherapy or radiation therapy. However, preclinical and clinical studies have demonstrated the occurrence of spontaneous or acquired resistance to these drugs. Since EGFR is implicated in a wide array of intracellular functions, the phenomenon of resistance to its inhibitors may result from the derangement of different molecular pathways, including autocrine/paracrine production of ligands, receptor mutations, constitutive activation of downstream signaling proteins, and activation of alternative pathways. This review presents the experimental evidence underlying the main mechanisms of resistance to EGFR inhibitors.     

ＥＧＦＲ抑制剂放射增敏机制的研究进展

表皮生长因子受体（ＥＧＦＲ）为肿瘤治疗的重要靶点,ＥＧＦＲ抑制剂可以通过促进细胞凋亡、细胞周期重分布、降低辐射抗性、抑制血管形成、减少放射损伤修复和减少肿瘤细胞再增殖等机制起到放射增敏的效果。靶向治疗联合放疗可能是靶向治疗向前发展的重要途径,也是放射治疗提高自身疗效的良好契机。尽管还有诸多问题尚待解决,但随着基础研究的不断深入,ＥＧＦＲ抑制剂联合放疗会迎来更广阔的临床应用前景。     

表皮生长因子受体靶向抑制剂在食管癌中的应用

食管癌组织中表皮生长因子受体(EGFR)过度表达与肿瘤恶性程度、侵袭转移等呈正相关.EGFR在食管癌组织中的表达可能对放化疗敏感性有预测作用.初步临床研究显示,EGFR靶向抑制剂有一定疗效,正在进行的Ⅱ、Ⅲ临床试验结果值得期待.     

表皮生长因子受体靶向抑制剂在食管癌中的应用

Overexpression of epidermal growth factor receptor (EGFR) in esophageal cancer has been related to tumor grade, vascular invasion and metastasis. The level of EGFR expression may be a predictive marker of esophageal caneer's sensitivity to chemoradiotherapy. EGFR inhibitors have been indicated as an effective targeted therapy, and promising results have been observed in phase Ⅱ and Ⅲ clinical trials.     

EGFR抑制剂与肿瘤细胞放射敏感性

表皮生长因子受体(EGFR)在多种上皮来源的恶性肿瘤中存在过表达,其表达水平与肿瘤的放射敏感性呈负相关.大量研究表明,阻断EGFR表达的靶向抑制剂能够增加肿瘤细胞的放射敏感性,提高放射治疗的疗效,其机制可能与抑制细胞增殖、诱导细胞凋亡、干扰细胞周期分布、延长DNA的损伤修复有关.因此,运用EGFR抑制剂可以增强肿瘤细胞对放射的敏感性.     

Mechanisms of cutaneous toxicities to EGFR inhibitors

The increased target specificity of epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is associated with the reduction or abolition of nonspecific and haematopoietic side effects. However, coincident inhibition of receptor activity in tissues that depend on EGFR signalling for normal function has undesirable consequences. Because of the key role of EGFR signalling in skin, dermatological toxicities have frequently been described with EGFRIs. The resultant significant physical and psycho-social discomfort might lead to interruption or dose modification of anticancer agents. There is an urgent need for an improved understanding of these toxicities to develop adequate staging systems and mechanistically driven therapies, and to ensure quality of life and consistent antineoplastic therapy.     

Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors

Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. SIGNIFICANCE: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.     

MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors

We analyzed MET protein and copy number in NSCLC with or without EGFR mutations untreated with EGFR tyrosine kinase inhibitors (TKIs). MET copy number was examined in 28 NSCLC and 4 human bronchial epithelial cell lines (HBEC) and 100 primary tumors using quantitative real‐time PCR. Positive results were confirmed by array comparative genomic hybridization and fluorescence in‐situ hybridization. Total and phospho‐MET protein expression was determined in 24 NSCLC and 2 HBEC cell lines using Western blot. EGFR mutations were examined for exon 19 deletions, T790M, and L858R. Knockdown of EGFR with siRNA was performed to examine the relation between EGFR and MET activation. High‐level MET amplification was observed in 3 of 28 NSCLC cell lines and in 2 of 100 primary lung tumors that had not been treated with EGFR‐TKIs. MET protein was highly expressed and phosphorylated in all the 3 cell lines with high MET amplification. In contrast, 6 NSCLC cell lines showed phospho‐MET among 21 NSCLC cell lines without MET amplification (p = 0.042). Furthermore, those 6 cell lines harboring phospho‐MET expression without MET amplification were all EGFR mutant (p = 0.0039). siRNA‐mediated knockdown of EGFR abolished phospho‐MET expression in examined 3 EGFR mutant cell lines of which MET gene copy number was not amplified. By contrast, phospho‐MET expression in 2 cell lines with amplified MET gene was not down‐regulated by knockdown of EGFR. Our results indicated that MET amplification was present in untreated NSCLC and EGFR mutation or MET amplification activated MET protein in NSCLC. © 2008 Wiley‐Liss, Inc.     

Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer

Purpose

Although activating mutations in the epidermal growth factor receptor (EGFR) gene are predictive markers for response to EGFR inhibitors, 30–40% of EGFR-mutant non-small cell lung cancer (NSCLC) patients are de novo non-responders. Hence, we sought to explore additional biomarkers of response.

Methods

We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors. A total of 37 patients were enrolled and 34 underwent EGFR inhibitor treatment.

Results

As expected, patients bearing activating EGFR mutations showed increased progression free survival (PFS) compared to patients with wild-type EGFR status (9.3 vs 1.4 months, p = 0.0629). Analysis of baseline tumor RTK profiles revealed that, regardless of EGFR mutation status, higher levels of EGFR relative to MET correlated with longer PFS. At multiple EGFR/MET ratio cut-offs, including 1, 2 and 3, median PFS according to below vs. above cut-offs were 0.4 vs. 6.1 (p = 0.0001), 0.5 vs. 9.3 (p = 0.0006) and 1.0 vs. 11.2 months (p = 0.0008), respectively.

Conclusion

The EGFR/MET ratio measured in tumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors.