Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors

Objectives

Patients with non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) after tumor regression. No approved targeted therapies are currently available after initial EGFR TKI treatment. This study investigated the efficacy of continuing EGFR TKI therapy with local treatments for patients with NSCLC and local progression or minimal/slow progression on TKI therapy.

Materials and Methods

Fifty-five patients with NSCLC treated with EGFR TKIs and developed acquired resistance to the drug were included. Initial response to target therapy, median progression free survival (PFS1), progression pattern, and first progression site were assessed. Median progression free survival to physician assessment progression (PFS2) and difference between PFS1 and PFS2 (PFS difference) were also recorded.

Results and Conclusion

PFS1 was 11.2 months, PFS2 was 20.3 months, and PFS difference was 8.3 months. Nineteen patients (34.5%) who manifested progression received local therapy, and 16 (28.6%) underwent rebiopsy after progression with six positive EGFR T790M mutations detected. Cox proportional hazards regression model showed that only the first line of treatment was significantly correlated with PFS difference. NSCLC patients with acquired resistance to EGFR TKIs could benefit from the same TKI therapy through months to years of disease control.     

非小细胞肺癌脑转移治疗进展

非小细胞肺癌(NSCLC)脑转移的治疗方法包括激素、抗惊厥药物治疗、手术、放疗、化疗.近年来分子靶向治疗如表皮生长因子(EGFR)酪氨酸激酶抑制剂(TKI)成为NSCLC脑转移的新的治疗选择.     

Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer

The majority of patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) respond to first-line EGFR tyrosine kinase inhibitors (TKIs), but nearly all inevitably acquire resistance and develop disease progression. Conventional practice would be to switch treatments to second-line therapy. However, continuing TKIs beyond progression is becoming increasingly commonplace in patients with indolent, small volume asymptomatic growth, who may potentially continue to derive ongoing clinical benefit and to avoid a ‘withdrawal tumour flare’. Nevertheless, there are limitations to our current criteria for assessing disease response, which are based on radiological assessments without considering symptomatic benefit, or the complex molecular and clinical heterogeneity of tumour growth and drug response patterns. In this article, we review the rationale for continuing EGFR inhibitors in patients with EGFR mutant NSCLC beyond disease progression and discuss strategies that have been pursued in the context of molecularly and clinically heterogeneous populations of tumour growth depending on the different clinical scenarios encountered. We discuss the management of systemic disease progression, including continuing EGFR TKIs alone, introducing a drug holiday, or combining TKIs with chemotherapy or other molecularly targeted agents. We also focus on approaches in managing patients with indolent, small volume asymptomatic growth (non-CNS oligometastatic disease progression) and those with oligometastatic EGFR mutant NSCLC with involvement of the central nervous system. We envision future precision medicine strategies through the use of next generation sequencing strategies of serial tumour rebiopsies and circulating plasma DNA to individualise the management for such patients during disease progression.     

Long term responses with cetuximab therapy in glioblastoma multiforme

Glioblastoma multiforme (GBM) is responsible for most of the deaths associated with primary brain tumors. Standard treatment includes maximal surgical resection followed by chemotherapy and concomitant radiotherapy. Most patients, however, recur shortly after treatment. Second line treatment has little efficacy and the majority of patients die soon from the disease. Recent advances in molecular biology have implicated the epidermal growth factor receptor (EGFR) signaling pathways in the progression and resistance to standard therapies for GBM. This has prompted the evaluation of EGFR tyrosine- kinase inhibitors with encouraging results. Cetuximab is a monoclonal antibody targeted against the extra cellular domain of the EGFR with activity against different tumor types, either alone or in combination with chemotherapy and/or radiation therapy. Here we describe three patients with recurrent, heavily pretreated, EGFR expressing GBM who responded to treatment with single agent cetuximab.     

ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinase activity in combination with radiotherapy

Radiation enhances both epithelial growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expression, which are a part of key pathways for tumor progression. Some tumors may not respond well to EGFR inhibitors alone or may develop resistance to EGFR inhibitors. Therefore, drug therapy targeted to VEGF receptors and EGFRs, when combined with radiotherapy (RT), may improve tumor control and provide wider applicability. This article focuses on ZD6474, an inhibitor of EGFR and VEGF receptor signaling in combination with RT. We discuss preclinical and clinical studies with RT and inhibitors of VEGF or EGFR signaling first. We then address issues associated with ZD6474 pharmacokinetic dosing, and scheduling when combined with RT. We also discuss ZD6474 in the context of anti-EGFR therapy resistance. Dual inhibition of EGFR and VEGF receptor signaling pathways shows promise in enhancing RT efficacy.     

EGFR/TP53/RB1三重突变的小细胞肺癌转化研究及治疗进展

表皮生长因子受体（epidermal growth factor receptor,EGFR）突变型非小细胞肺癌（non-small cell lung cancer,NSCLC）患者在接受EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs ）靶向治疗后能获得临床获益,但之后会不可避免地出现获得性耐药,而发生小细胞肺癌（small cell lung cancer,SCLC）组织学转化被认为是一种罕见的耐药机制。随着二代基因检测（next- generation sequencing,NGS）技术的快速发展及广泛应用,研究者发现存在EGFR/TP53/RB1三重突变的NSCLC经靶向治疗后更容易发生SCLC组织学转化,并且转化型SCLC疗效及预后较差。本文对近年来关于EGFR突变的NSCLC发生SCLC组织学转化的研究作一综述,涉及相关的转化机制、可能有效的新型药物及治疗策略,为EGFR/TP53/RB1三重突变的转化型SCLC患者提供更多潜在的临床治疗选择。      

Advances in Targeted Therapy Against Driver Mutations and Epigenetic Alterations in Non-Small Cell Lung Cancer

The incidence and mortality of lung cancer rank top three of all cancers worldwide. Accounting for 85% of the total number of lung cancer, non-small cell lung cancer (NSCLC) is an important factor endangering human health. Recently, targeted therapies against driver mutations and epigenetic alterations have made encouraging advances that benefit NSCLC patients. Druggable driver mutations, which mainly occur in EGFR, KRAS, MET, HER2, ALK, ROS1, RET and BRAF, have been identified in more than a quarter of NSCLC patients. A series of highly selective mutant targeting inhibitors, such as EGFR tyrosine kinase inhibitors and KRAS inhibitors, have been well studied and applied in clinical treatments, which greatly promote the overall survival of NSCLC patients. However, drug resistance has become a major challenge for targeted treatment, and a variety of methods to overcome drug resistance are constantly being developed, including inhibitors against new mutants, combination therapy with other pathway inhibitors, etc. In addition, epigenetics-based therapy is emerging. Epigenetic regulators such as histone deacetylases and non-coding RNA play a crucial role in the development of cancer and drug resistance by affecting multiple signaling pathways. Epigenetics-based therapeutic strategies combined with targeted drugs show great clinical potential. Many agents targeting epigenetic changes are being investigated in preclinical studies, with some already under clinical trials. This article focuses on driver mutations and epigenetic alterations in association with relevant epidemiological data. We introduce the current status of targeted inhibitors and known drug resistance, review advances in major targeted therapies with recent data from preclinical and clinical trials, and discuss the possibility of combination therapy against driver mutations and epigenetic alterations in overcoming drug resistance.     

RAC1 inhibition as a therapeutic target for gefitinib‐resistant non‐small‐cell lung cancer

Although epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (EGFR‐TKI), including gefitinib, provide a significant clinical benefit in non‐small‐cell lung cancer (NSCLC) patients, the acquisition of drug resistance has been known to limit the efficacy of EGFR‐TKI therapy. In this study, we demonstrated the involvement of EGF‐EGFR signaling in NSCLC cell migration and the requirement of RAC1 in EGFR‐mediated progression of NSCLC. We showed the significant role of RAC1 pathway in the cell migration or lamellipodia formation by using gene silencing of RAC1 or induction of constitutive active RAC1 in EGFR‐mutant NSCLC cells. Importantly, the RAC1 inhibition suppressed EGFR‐mutant NSCLC cell migration and growth in vitro, and growth in vivo even in the gefitinib‐resistant cells. In addition, these suppressions by RAC1 inhibition were mediated through MEK or PI3K independent mechanisms. Collectively, these results open up a new opportunity to control the cancer progression by targeting the RAC1 pathway to overcome the resistance to EGFR‐TKI in NSCLC patients.     

Concomitant EGFR Inhibitors Combined with Radiation for Treatment of Non-small Cell Lung Carcinoma

Epidermal growth factor receptor (EGFR) is considered to be one of the key driver genes in non-small celllung cancer (NSCLC). Several clinical trials have shown great promise of EGFR tyrosine kinase inhibitors (TKIs)in the first-line treatment of NSCLC. Many advances have been made in the understanding of EGFR signaltransduction network and the interaction between EGFR and tumor microenvironment in mediating cancersurvival and development. The concomitant targeted therapy and radiation is a new strategy in the treatment ofNSCLC. A number of preclinical studies have demonstrated synergistic anti-tumor activity in the combinationof EGFR inhibitors and radiotherapy in vitro and in vivo. In the present review, we discuss the rationale of thecombination of EGFR inhibitors and radiotherapy in the treatment of NSCLC.     

The Role of EGFR Inhibition in the Treatment of Non‐Small Cell Lung Cancer

The identification of certain molecular mechanisms underlying lung carcinogenesis and progression has led to the development of targeted agents against different families of growth factors and receptors. The epidermal growth factor receptor (EGFR) is one such target for therapeutic exploitation. Inhibition of EGFR downstream signaling can be accomplished through two primary mechanisms: (a) the direct blocking of intracellular kinase activity with small‐molecule tyrosine kinase inhibitors (TKIs) (e.g., gefitinib, erlotinib) and (b) the blocking of EGFR ligand binding using antibodies directed against the extracellular domain of the receptor (e.g., cetuximab). Resistance to available EGFR‐targeted treatments has emerged as a substantial clinical issue in non‐small cell lung cancer (NSCLC). Several novel agents with the potential to overcome such resistance are currently in clinical development, including irreversible EGFR TKIs, monoclonal antibodies, and TKIs directed against multiple signaling pathways. Here we discuss the clinical application of the currently available EGFR‐targeted agents in NSCLC, the underlying mechanisms of resistance, and the novel agents in clinical development that may overcome resistance.     

Targeting epidermal growth factor receptor in lung cancer: Perspective from the Asia–Pacific region

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family that is frequently overexpressed in non‐small cell lung cancer (NSCLC), and has been identified as a novel therapeutic target for lung cancer. The development of small molecule EGFR‐tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib has resulted in paradigm shift in the treatment of advanced NSCLC. The impact of EGFR‐TKI in the treatment of NSCLC is even greater in Asia–Pacific region because one of the greatest clinical benefits of EGFR‐TKI has been seen in patients of East Asian ethnicity. The discovery of somatic mutations in EGFR‐tyrosine kinase domain has so far answered some, but not all, of the questions regarding the clinical response to EGFR‐TKI in NSCLC. In addition, other molecular profiles such as KRAS mutations have also been found to play an important role in EGFR targeted therapy. In this article, we review EGFR targeted therapy in NSCLC with the focus on perspective from the Asia–Pacific region.     

EGFR突变晚期非小细胞肺癌免疫治疗的研究进展

肺癌是全球癌症相关死亡的主要原因。表皮生长因子受体是亚洲肺腺癌患者最常见的突变类型。酪氨酸激酶抑制剂是表皮生长因子受体突变非小细胞肺癌一线首选治疗，但获得性耐药限制了其长期疗效，对于耐药后治疗仍没有有效选择方案。目前，免疫治疗延长了部分患者的生存时间,但在表皮生长因子受体突变非小细胞肺癌中反应较差，介导其疗效不佳的原因仍尚不明确。多种生物标志物的联合评价更能准确预测其免疫治疗疗效并筛选潜在获益人群。联合抗血管生成及新型靶点药物治疗具有免疫增敏作用。本文就表皮生长因子受体突变晚期非小细胞肺癌免疫治疗研究现状、免疫治疗潜在获益人群及免疫联合治疗新策略进行综述。     

Non-small-cell lung cancer

Molecular targeted therapy in combination with chemotherapy or thoracic radiotherapy has been studied in clinical trials. Gefitinib or erlotinib in combination with standard chemotherapy did not improve efficacy on survival over standard chemotherapy alone in chemotherapy-naive patients with advanced NSCLC. On the other hand, bevacizumab in combination with standard chemotherapy improved survival in chemotherapy-naive patients with advanced NSCLC, excluding squamous cell carcinoma. Multi-target tyrosine kinase inhibitors in combination with standard chemotherapy, and anti-EGFR antibodies and EGFR tyrosine kinase inhibitors in combination with thoracic radiotherapy, are under clinical trials.     

肺癌分子分型与靶向治疗研究进展

随着肺癌发生、发展和预后相关分子机制研究的不断深入,肺癌靶向治疗取得了较大的进展,每一种分子分型的发现都会带来相应靶向药物的研究。2004年表皮生长因子受体(epidermal growth factor receptor,EGFR)基因在非小细胞肺癌中的发现,为我们带来了EGFR突变高度敏感有效的酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)。2007年棘皮类微管相关样蛋白-4-间变型淋巴瘤激酶(EML4-ALK)融合基因的出现为肺癌的分子发展带来了新的有效靶点。目前多个肺癌分子靶点及其靶向药物正在研究中。本文旨在回顾并总结肺癌分子分型及其靶向治疗的研究进展。     

Biologically targeted treatment of non-small-cell lung cancer: focus on epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. The postembryonic role of EGFR is normally limited. In cancer, however, abnormal EGFR-tyrosine kinase (TK) activity plays a central role in many of the processes involved in tumor progression, such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Several different approaches have been taken to inhibit EGFR-mediated activity in tumor cells, including monoclonal antibodies directed at the ligand-binding portion of the EGFR and small-molecule agents that directly inhibit the intracellular TK domain of EGFR. Two of these TK inhibitors, gefitinib and erlotinib (OSI-774, Tarceva ), have shown antitumor activity and good tolerability across several tumor types in early dose-finding clinical trials, particularly for non-small-cell lung cancer (NSCLC). In heavily pretreated patients with advanced NSCLC, gefitinib showed clinically significant tumor responses and symptom relief with good tolerability. Based on these results, gefitinib has now been approved for the third-line treatment of advanced NSCLC. The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors     

非小细胞肺癌EGFR靶向治疗和继发耐药机制的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是最常见的肺癌亚型,表皮生长因子受体(epidermal growth factor receptor,EGFR)小分子靶向药物治疗显著地改善了晚期患者的总生存期(overall survival,OS)和生存质量,但几乎所有患者在接受治疗后均出现继发耐药。继发耐药的分子机制虽然取得了一定进展但尚未完全明确。本文结合最新文献阐述了该领域的最新研究进展,包括最新EGFR基因酪氨酸激酶(tyrosine-kinase inhibitor,TKI)域突变的研究、靶向药物的研发和临床试验结果、继发耐药的各种分子机制以及潜在克服耐药的新药物和治疗策略。对于接受EGFR小分子靶向药物治疗出现继发耐药的患者,亟需通过更加全面的分子分型检测明确耐药的分子机制,才能实现个体化治疗。      

Personalizing therapy with targeted agents in non-small cell lung cancer

In the last 6 years, since the first reports of an association between somatic mutations in epidermal growth factor receptor (EGFR) exons 19 and 21 and response to EGFR tyrosine kinase inhibitors (TKIs), treatment of non-small cell lung cancer (NSCLC) has changed dramatically. Based on laboratory and clinical observations, investigators have anticipated that these mutations could be predictive of response to EGFR TKIs and numerous studies have confirmed that the presence of mutation was associated with longer survival in patients receiving targeted therapy. Prospective trials comparing standard platinum-based chemotherapy with EGFR TKIs in patients with and without activating EGFR mutations validated the predictive value of molecular selection of patients for first-line treatment of advanced NSCLC. Recently, preclinical and first-in-human studies have demonstrated impressive activity of ALK TKI in tumors harboring ALK rearrangement. In this article, we review current data on molecular biology of lung cancer and evidence-based patient selection for targeted therapy.     

Current management of advanced non-small cell lung cancer: targeted therapy

Lung cancer is one of the most frequent causes of cancer-related death in the United States. For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy, alone or in combination with radiation therapy, is considered the standard treatment. Although this treatment may result in a modest improvement in patient survival, overall prognosis of these patients remains dismal, and the treatment is nonspecific, nonselective, and toxic. Therefore, new therapeutic strategies are needed. During the past decade, several molecules that contribute to lung cancer progression and metastasis have been identified. Growth factors and proangiogenic factors have been the focus of intense research in cancer since therapeutic approaches for their inhibition do exist. The role of these factors was studied in different organs and tumors and was found to be phenotypically distinct. Several molecular targeted therapies have shown efficacy and had been approved for treatment of specific cancers. Most advanced in clinical research for lung cancer are targeted therapies that inhibit the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathways. Others are signaling pathway inhibitors. The first targeted therapy for lung cancer is gefitinib, an EGFR inhibitor, which was approved in several countries in 2003. Goals of molecular targeted therapy studies include the following: better understanding of the exact role of particular growth factors in specific tumors; establishment of new clinical study designs for biological agents; and tailoring appropriate combinations of conventional chemotherapy and/or radiotherapy with biological therapy for specific patients. Achievement of these goals will hopefully lead to incorporation of biological therapy into the current anticancer arsenal, for the benefit of lung cancer patients.     

Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors and Non-Small Cell Lung Cancer (NSCLC) – Advances in Molecular Diagnostic Techniques to Facilitate Targeted Therapy

A subset of patients with non-small cell lung cancer (NSCLC) respond well to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), due to the presence of sensitising mutations in the gene encoding EGFR. Mutations associated with resistance to first generation EGFR TKIs have also been identified, which lead to therapeutic failure and the requirement for new drugs. Three generations of EGFR TKIs have been developed and either have been, or are being, evaluated as first and/or second line therapeutic agents. In this review, we consider the advances in molecular diagnostic techniques that are used, or are in development, to facilitate the targeted EGFR TKI therapy of patients with NSCLC. A literature search was conducted in May 2017 using PubMed, and spanning the period September 2005 (EU approval date of erlotinib) to May 2017. Search terms used were: EGFR TKI, NSCLC, clinical trial, erlotinib, gefitinib, afatinib, EGFR mutations, Exon 19 deletion, and Leu858Arg. The use of molecular data, in conjunction with other clinical and diagnostic information, will assist physicians to make the best therapeutic choice for each patient with advanced NSCLC. Personalized medicine and a rapidly developing therapy landscape will enable these patients to achieve optimal responses to EGFR TKIs.