Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.     

Erlotinib in advanced non-small-cell lung cancer after gefitinib failure

Purpose  To evaluate the efficacy and safety of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib treatment. Patients and methods  Patients with advanced or metastatic NSCLC, who had progressed after gefitinib treatment, were included in this study; patients received erlotinib 150 mg/day until disease progression or intolerable toxicity. Results  Twenty-one patients were included in this study. Among them, 14 (66.7%) were male and 7 (33.3%) were female; median age was 63 years; 10 (47.6%) patients were smokers; 9 (42.9%)patients had squamous cell carcinoma subtype; 8 (38.1%) patients had adenocarcinoma subtype and 4 (19%) patients had the other NSCLC subtype. Out of 21 patients, 2 (9.5%) had PR and 4 (19.0%) had SD, giving an overall response rate of 9.5% and a disease control rate of 28.5%. The median TTP were 55 days, the median OS were 135 days. Two patients with PR to erlotinib treatment were female never smokers with adenocarcinoma histology and both had partial response to prior gefitinib treatment. Three of four patients with a SD to erlotinib treatment also had SD from prior gefitinib therapy. Smoking history, histology and response to erlotinib were significantly correlated with survival. The most common toxic effects were skin rash. Conclusions  Erlotinib may be an option for a more highly selected subset of patients, especially those who had already benefited from prior gefitinib treatment.     

厄洛替尼治疗晚期非小细胞肺癌的临床观察

目的 观察厄洛替尼单药治疗晚期非小细胞肺癌(NSCLC)的疗效和不良反应.方法 104例晚期NSCLC患者给予厄洛替尼150 mg口服治疗,每日1次,服用至疾病进展或出现不可耐受的不良反应.采用实体瘤的疗效评价标准评价疗效.采用美国国家癌症研究所毒性评价标准评价不良反应.结果 104例患者均可评价疗效,客观有效率为27.9%(29/104),疾病控制率为76.0%(79/104),中位无进展生存时间为5.1个月,中位生存时间为13.1个月,1年总生存率为61.5%.多因素生存分析显示,PS评分为0～1分、腺癌和治疗后出现皮疹的患者具有显著的生存优势(均P<0.05);而吸烟和肝转移则显著增加了死亡风险(均P<0.05).厄洛替尼治疗晚期NSCLC最常见的不良反应是皮疹和腹泻,发生率分别为73.1%和41.3%.不良反应多为1～2级,3～4级不良反应的发生率仅为6.7%.结论 厄洛替尼治疗晚期NSCLC的疗效确切,患者耐受性良好,可作为化疗失败、不适合或拒绝接受化疗的晚期NSCLC患者的治疗选择.     

Erlotinib therapy in a patient with non-small-cell lung cancer and brain metastases

Brain metastases are a common occurrence and a major cause of mortality in non-small-cell lung cancer, with few systemic treatment options. Although targeting epidermal growth factor receptor-associated tyrosine kinase with erlotinib and gefitinib results in durable responses in some patients, the activity of these drugs against brain metastases has been poorly documented. In particular, few reports have so far reported the activity of erlotinib in this setting. Here we report the case of a male Italian smoker with an adeno-carcinoma of the lung whose lung cancer and brain metastases have both responded to erlotinib.     

甲磺酸奥希替尼治疗EGFR基因突变型非小细胞肺癌脑转移的疗效评价

目的:探讨甲磺酸奥希替尼治疗表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变型非小细胞肺癌(non-small-cell lung cancer,NSCLC)脑转移的临床效果及预后因素.方法:回顾分析2017年5月-2019年12月60 例由蚌埠医学院第一附属医院肿...     

Erlotinib as a single agent in select subsets of patients with advanced non-small-cell lung cancer

Erlotinib is an orally active inhibitor of the epidermal growth factor receptor that is effective for the treatment of non-small-cell lung cancer (NSCLC). Patients with a poor performance status (PS) of 2 constitute up to 40% of advanced NSCLC. This group of patients have a lower life expectancy and are thought to have a greater degree of treatment-related toxicity. The clinical benefit on 238 patients with poor PS included in an open-label, nonrandomized, phase II trial of erlotinib in advanced/metastatic NSCLC was 57.58% defined as complete response plus partial response plus stable disease. Median time to progression was 2.9 months. This review will summarize available data about erlotinib on patients with a PS of 2.     

Molecular predictors of chemotherapy response in non-small-cell lung cancer

Lung cancer is the number one cause of cancer-related mortality. In order to improve the outcome of patients, advances in the understanding of cancer biology and the development of therapeutic modalities that target key proliferation and survival mechanisms are needed. In vitro data have demonstrated that the genes RRM1 and ERCC1 are important components of these mechanisms. Recently, how these genes affect lung cancer therapy has been explored in the clinical setting with the goal of finding customized treatment algorithms to optimize efficacy, improve outcomes and minimize toxicity.     

Inhibiting proliferation of gefitinib-resistant, non-small cell lung cancer

Purpose

Sensitivity to a tyrosine kinase inhibitor (TKI) is correlated with the presence of somatic mutations that affect the kinase domain of epidermal growth factor receptor (EGFR). Development of resistance to TKI is a major therapeutic problem in non-small cell lung cancer (NSCLC). Aim of this study is to identify agents that can overcome TKI resistance in NSCLC.

Methods

We used a carefully selected panel of 12 NSCLC cell lines to address this clinical problem. Initially, the cell lines were treated with a variety of 10 compounds. Cellular proliferation was measured via MTT assay. We then focused on the gefitinib-resistant, EGFR mutant cell lines [H1650: exon 19 and PTEN mutations; and H1975: exons 20 (T790M) and 21 (L858R)] to identify agents that could overcome TKI resistance.

Results

Both 17-DMAG (Hsp90 inhibitor) and belinostat (histone deacetylase inhibitor, HDACi) effectively decreased the growth of almost all NSCLC lines. Also, belinostat markedly decreased the expression of EGFR and phospho-Akt in the cells. Combination of 17-DMAG and belinostat synergistically inhibited in vitro proliferation of these cells. Furthermore, both agents and their combination almost completely prevented TKI-resistant tumor formation (EGFR T790M mutation) in a xenograft model.

Conclusion

These results suggest that the combination of 17-DMAG and belinostat should be examined in a clinical trial for TKI-resistant NSCLC cell.     

Erlotinib in non-small cell lung cancer

Erlotinib and gefitinib are quinazoline derivatives that selectively and reversibly inhibit the tyrosine kinase activity of the EGFR. Activating mutations in the EGFR confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. Erlotinib has been developed in EGFR mutation-positive patients as a firstline treatment, and results from recently completed phase III studies have shown superior progression-free survival and response rates for erlotinib, compared to chemotherapy.     

Erlotinib in patients with advanced non-small-cell lung cancer: impact of dose reductions and a novel surrogate marker

Erlotinib is a relatively well-tolerated treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some patients suffer from severe skin toxicity or diarrhea, making dose reductions or even treatment cessation necessary. Recent clinical trials usually defined a 100 mg daily dose as the lowest acceptable dose, whereas little is known about the efficacy with lower doses. We retrospectively reviewed the files of all patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib. We assessed demographic, disease- and treatment-related information. We tried to correlate tolerability with clinical efficacy. EGF receptor exon 18/19/21 mutations were analyzed in selected patients. Fifty-three patients with advanced non-small-cell lung cancer were treated with erlotinib. In nine patients (17%), the doses had to be reduced to 75 or 50 mg daily due to toxicity. We observed several sustained disease stabilizations in this subgroup. Patients suffering from paronychia with erlotinib had a significantly longer time to progression than did subjects without nail toxicity (P = 0.04). If patients were free from any toxicity, they were at high risk for early tumor progression (P = 0.001) and death. In patients with disease stabilization for 6 months or longer, we observed EGFR 18/19/21 wild type, exon 19 and exon 21 mutations. In conclusion, several patients required dose reductions during treatment with erlotinib. However, in tumors with sensitivity to erlotinib, even daily doses of 50–75 mg can result in sustained disease control. Paronychia represents a favorable surrogate marker for efficacy.     

Treatment of non-small-cell lung cancer

The treatment of non-small-cell lung cancer (NSCLC; including squamous, large-cell anaplastic, and adenocarcinoma) is one of the most frustrating areas in oncology. With the exception of the high cure rates for surgical treatment of truly localized disease, the prognosis for patients with NSCLC is grim. Often rancorous debate has ensued about the best means of exploiting the currently available modalities of radiation therapy and chemotherapy. Recognizing that the effectiveness of the current therapeutic modalities is limited, we will review the treatment results from the past few years that help define where specific treatment options should be used or suggest areas in which to focus future trials. We will also review the implications of current findings in the cell biology of lung cancer as they pertain to the therapy of NSCLC.     

Erlotinib achieved partial response in a non-small cell lung cancer patient with gefitinib-induced interstitial lung disease

Interstitial lung disease (ILD) induced by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a rare but fatal complication of TKI treatment. Transfer to chemotherapy or continuation with TKI of reduced dose are alternative treatment strategies. We report a case of severe ILD in a non-small cell lung cancer patient treated with gefitinib. She experienced partial response with restarted low-dose EGFR-TKI erlotinib and corticosteroid treatment.     

Follow-up in non-small-cell lung cancer

The major impetus for structured follow-up after primary treatment of localized non-small-cell lung cancer is both early detection and re-treatment of recurrent disease with a curative intent, and early detection and treatment of a secondary primary tumor. In patients with lung cancer, the significance of intensive follow-up is still under debate.