厄洛替尼治疗吉非替尼耐药的进展期非小细胞肺癌的临床观察

目的　评价厄洛替尼对吉非替尼耐药的进展期非小细胞肺癌（ＮＳＣＬＣ）患者的疗效和安全性。方法　回顾性分析２００６年６月至２００９年２月１５例ＮＳＣＬＣ患者,均口服吉非替尼并出现病情进展,改换为厄洛替尼１５０ｍｇ,１次／日,直到病情进展或不良反应不能耐受为止。观察疗效、不良反应以及疗效与临床特征之间的关系。结果　厄洛替尼治疗吉非替尼耐药共１５例进展期ＮＳＣＬＣ患者,１例获得ＰＲ,４例获得ＳＤ,客观有效率为６.７％,疾病控制率为３３.３％。获有效和稳定的５例患者中４例曾吉非替尼治疗获益。厄洛替尼治疗的中位疾病进展期（ＴＴＰ）和中位总生存期（ＯＳ）分别为１１１天和２２３天。厄洛替尼获益的５例患者较未获益的１０例患者获得更长的ＴＴＰ（１１１天ｖｓ．３５.５天,Ｐ＜０.０５）。厄洛替尼最常见的副反应为轻度皮疹和腹泻。结论　厄洛替尼似乎是治疗吉非替尼耐药的进展期ＮＳＣＬＣ的有效药物,尤其是对于曾予吉非替尼治疗可以获益的患者,但厄洛替尼不应作为常规的二线选择,对患者谨慎筛选很有必要。     

晚期非小细胞肺癌化疗和靶向治疗失败后的挽救性化疗

Objective:We conducted a prospective phase Ⅱ trial of single-agent salvage chemotherapy with docetaxel in patients with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy and gefitinib to assess the efficacy and toxicity of docetaxel in this setting.Methods:Patients with histologically confirmed NSCLC who were failure of chemotherapy and gefitinib were given docetaxel 75 mg/m2 intravenously for 30 min every 3 weeks until the toxicity was unacceptable or disease progressed.The response evaluation criteria in solid tumors (RECIST) guidelines were used for the evaluation of antitumor activity.Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0.Results:In total,31 patients were enrolled in this phase Ⅱ trial between February 2004 and December 2006,and 84 cycles (average 2.7 cycles) were given.We observed 4 partial responses (PRs) and 10 stable disease (SD) states in 31 eligible patients.The objective response rate was 12.9%,and the disease control rate was 45.2%.The median survival time (MST) was 10 months (95% Cl,5.05-15.08 months).The 1-year survival rate was 40.6%.The most common toxicities were neutropenia,anemia,and peripheral neuropathy that occurred as follows:45% of the patients experienced grade 3 or 4 neutropenia,29% experienced grade 3 anemia,and 25.8% had grade 3 peripheral neuropathy.No patient terminated docetaxel chemotherapy due to toxicity.Conclusion:Docetaxei is beneficial as salvage chemotherapy in patients with advanced NSCLC after failure of cytotoxic agents and gefitinib.     

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.     

Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection

Background

Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy.

Methods

One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009.

Results

The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months).

Conclusions

Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.     

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.     

吉非替尼一线治疗晚期非小细胞肺癌的临床观察

目的观察吉非替尼一线治疗晚期非小细胞肺癌临床疗效及毒副作用。方法研究2005年11月～2007年5月14例晚期非小细胞肺癌患者,PS≥2,一线口服吉非替尼治疗,250mg/日,观察其近期疗效及毒副作用。结果14例患者中CR 0%(0/ 14),PR 35.7%(5/14),SD 50%(7/14),PD 14.3%(2/14)。临床获益率85.7% (12/14)。毒副作用为唑疮样皮疹42.86%(6/14),皮肤干燥脱屑28.57%(4/14),皮肤瘙痒14.3%(2/14),腹泻35.7(5/14),转氨酶升高14.3%(2/14)。结论吉非替尼一线治疗晚期非小细胞肺癌疗效较好,毒副作用轻微,能明显改善患者的生活质量。     

埃罗替尼在非小细胞肺癌治疗中的研究进展

埃罗替尼（erlotinib）是表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，能与细胞内EGFR分子酪氨酸激酶结构域的ATP结合袋特异性结合，可逆性地抑制EGFR酪氨酸激酶活性，促使肿瘤细胞凋亡，抑制肿瘤细胞的增殖、侵袭、血管新生和转移。该药目前已成功用于晚期非小细胞肺癌（NSCLC）的治疗，可显著延长患者的生存时间和无进展生存时间，显著改善症状，改善患者生活质量。     

埃罗替尼在非小细胞肺癌治疗中的研究进展

埃罗替尼(erlotinib)是表皮生长因子受体(EGFR)酪氨酸激酶抑制剂,能与细胞内EGFR分子酪氨酸激酶结构域的ATP结合袋特异性结合,可逆性地抑制EGFR酪氨酸激酶活性,促使肿瘤细胞凋亡,抑制肿瘤细胞的增殖、侵袭、血管新生和转移。该药目前已成功用于晚期非小细胞肺癌(NSCLC)的治疗,可显著延长患者的生存时间和无进展生存时间,显著改善症状,改善患者生活质量。     

Erlotinib in the treatment of non-small cell lung cancer

Inhibition of the epidermal growth factor receptor is one of the most promising novel therapeutic strategies to be used in the treatment of patients with non-small cell lung cancer. A number of compounds that target the epidermal growth factor receptor are in an advanced stage of clinical development including both antibodies directed against the receptor and small molecule inhibitors of epidermal growth factor receptor tyrosine kinase activity. This drug profile focuses on the development of erlotinib, an orally available inhibitor of epidermal growth factor receptor tyrosine kinase. Results of clinical trials are reviewed, two trials of erlotinib in combination, one with paclitaxel and carboplatin, the other with gemcitabine and cisplatin, and the National Cancer Institute of Canada – Clinical Trials Group BR21, the first study to demonstrate a survival benefit for this class of compound in non-small cell lung cancer. The future role of erlotinib in the management of patients with non-small cell lung cancer is also discussed.     

Erlotinib in the treatment of non-small cell lung cancer

Inhibition of the epidermal growth factor receptor is one of the most promising novel therapeutic strategies to be used in the treatment of patients with non-small cell lung cancer. A number of compounds that target the epidermal growth factor receptor are in an advanced stage of clinical development including both antibodies directed against the receptor and small molecule inhibitors of epidermal growth factor receptor tyrosine kinase activity. This drug profile focuses on the development of erlotinib, an orally available inhibitor of epidermal growth factor receptor tyrosine kinase. Results of clinical trials are reviewed, two trials of erlotinib in combination, one with paclitaxel and carboplatin, the other with gemcitabine and cisplatin, and the National Cancer Institute of Canada--Clinical Trials Group BR21, the first study to demonstrate a survival benefit for this class of compound in non-small cell lung cancer. The future role of erlotinib in the management of patients with non-small cell lung cancer is also discussed.     

Erlotinib, docetaxel, and gefitinib in sequential cohorts with relapsed non-small cell lung cancer

BACKGROUND: Both docetaxel and erlotinib improve overall survival over best supportive care in non-small cell lung cancer (NSCLC). We assessed the effectiveness of erlotinib (E) and gefitinib (G) in patients with relapsed NSCLC in both second- and third-line settings, and compared this with that of docetaxel (D), in our clinical practice. METHODS: Sequential cohorts of patients with relapsed advanced stage NSCLC who had been treated with erlotinib (150 mg), gefitinib (250 mg), or docetaxel (75 mg/m(2)) were retrospectively identified from our database. The primary endpoint was overall survival. Secondary endpoints were response rate and progression-free survival. RESULTS: After adjusting for covariates, there was no significant difference in overall survival between the three drugs in both second-line (median E=24; G=25; D=43 weeks, p=0.17), and third-line (median E=31; G=24; D=29 weeks, p=0.61) settings. Response rates were also not statistically significant between the three drugs across both lines of treatment. CONCLUSIONS: Erlotinib, gefitinib, and docetaxel have similar effectiveness in this non-trial setting.     

A Phase Ⅱ Trial of Gefitinib as Maintenance Therapy after First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer in China

Objective:To investigate the efficacy and safety of gefitinib as maintenance therapy for advanced non-small cell lung cancer (NSCLC) patients who obtained disease control (DC) after first-line chemotherapy in Chinese population. Methods:Chinese patients with advanced NSCLC treated with standard chemotherapy and obtained DC were assigned to receive gefitinib as maintenance treatment. The primary end point was overall survival time (OS), the second end point was disease control rate (DCR) and progression-free survival time (PFS). DCR included complete response (CR) plus partial response (PR) and plus stable disease (SD). The impact of epidermal growth factor receptor (EGFR) mutation status on the treatment as exploratory point was also evaluated by denaturing high-performance liquid chromatography (DHPLC). Results:Among 75 enrolled patients, the overall response rate was 37% and the DCR (CR + PR +SD) was 66%. The median PFS and OS were 17.13 months and 26.13 months respectively, with 1- and 2-year survival rates 89.3% and 34.7%. Patients harboring somatic EGFR mutations obtained a prolonged median PFS and OS compared with EGFR wide type (25.1 vs. 13.0 months, P=0.019 and 33.37 vs. 25.57 months, P=0.014, respectively). In COX regression model, only EGFR mutation status was the independently factor influencing both PFS and OS (P=0.029 and 0.017, respectively), however, rash status was the predictor in terms of PFS (P=0.027).Conclusion:Gefitinib produced encouraging survival when delivered as maintenance therapy in Chinese patients obtaining DC after first-line chemotherapy, especially for patients carrying somatic EGFR mutations. EGFR mutation is an independently predictive factor of survival.     

Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment

Background: Both gefitinib and erlotinib are reversible epidermal growth factor receptor tyrosine kinase inhibitors, but they have somewhat different pharmacological properties. We conducted a phase II study of erlotinib after failure of gefitinib treatment in patients with non-small-cell lung cancer (NSCLC).Patients and methods: Patients with advanced/metastatic NSCLC who had shown disease progression on gefitinib treatment were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity.Results: Between September 2006 and January 2008, a total of 23 patients were enrolled and all were assessable for response and toxicity. All patients were never smokers and all but one had adenocarcinoma. Of these 23 patients, one had a partial response and one stable disease, resulting in an objective response rate of 4.3% and a disease control rate of 8.7%. These two patients benefited from erlotinib for 6.2 months and 7.8 months, respectively; both had also benefited from prior gefitinib therapy. The most common toxic effects were skin rash and diarrhea.Conclusion: Erlotinib should not be given routinely after failure of gefitinib treatment, but can be an option for more highly selected subsets, especially those who had benefited from prior gefitinib treatment. Identification of molecular markers in tumors is important to understand and overcome acquired resistance to gefitinib.     

安罗替尼对比多西他赛用于一线治疗失败后晚期非小细胞肺癌的疗效及安全性研究

目的 评价安罗替尼对比多西他赛用于一线治疗失败的晚期非小细胞肺癌(NSCLC)的疗效及安全性,探讨安罗替尼用于二线治疗晚期NSCLC的可行性.方法 收集2018年1月至2020年3月云南省肿瘤医院干部医疗科收治的60例晚期NSCLC患者,根据临床治疗方案不同均分为3组:安罗替尼组、多西他赛组及联合组,安罗替尼组口服安罗...     

吉非替尼挽救性治疗晚期非小细胞肺癌的初步观察

为了观察吉非替尼（gefitinih）挽救性治疗化疗失败的晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）的疗效和不良反应，给45例化疗失败的晚期NSCLC患者口服吉非替尼250mg／d，直至病情进展或不能耐受毒性（至少30d）。结果 全组总有效率为51．1％（23／45），其中CR3例，PR20例，SD5例，疾病控制率为62．2％（28／45）。中位生存时间为4个月，其中有效者为7个月，无效者则为2个月．1年生存率为21．3％。不良反应主要为Ⅰ～Ⅱ度皮疹（64．4％）、腹泻（31．1％）和恶心呕吐（24．4％）。初步研究结果提示，吉非替尼治疗化疗失败的晚期NSCLC的疗效好，不良反应轻，有望成为晚期NSCLC一线或二线治疗标准。     

Erlotinib usage after prior treatment with gefitinib in advanced non-small cell lung cancer: A clinical perspective and review of published literature

Erlotinib and gefitinib are among the most widely researched, used and available molecularly targeted therapies for treatment of advanced non-small cell lung cancer (NSCLC). They are both tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). In the past decade, there have been reports on clinical benefit from use of erlotinib after gefitinib failure in NSCLC patients. A review of published literature on this focussed topic is provided herein. Pooled analysis of published literature shows that majority of patients were female (60.6%), non-smokers (64.5%), had adenocarcinoma histology (88.3%) and were of East Asian ethnicity (92.3%). Presence of sensitizing EGFR mutation was detected in 48.4% of subjects. Disease control rates with prior gefitinib therapy and with subsequent erlotinib treatment were 79.4% and 45.4% respectively. Based upon our review, the most important predictive factor for clinical benefit from erlotinib identified was previous response to gefitinib. The exact explanations for the potential benefit from erlotinib use in this patient population is still not known and further studies are required to determine the role of molecular mechanisms especially those related to resistance to initial EGFR TKI therapy.     

Changes in angiogenic growth factor levels after gefitinib treatment in non-small cell lung cancer

BACKGROUND: To investigate the changes in angiogenic growth factor expression before and after gefitinib treatment, and the association between this expression and response to gefitinib treatment, we measured circulating levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), matrix metalloproteinase (MMP) -2 and -9, and tissue inhibitors of metalloproteinase (TIMP) -1 and -2 in patients with non-small cell lung cancer (NSCLC). METHODS: Serum and plasma samples were collected from 52 patients before and after gefitinib treatment. The levels of VEGF, bFGF, MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured using a sandwich enzyme immunoassay kit. RESULTS: Of the 52 patients, 17 (32.7%) achieved a partial response, 19 (36.5%) had stable disease and 16 (30.8%) had progressive disease. The levels of VEGF, bFGF, MMP-2, MMP-9, TIMP-1 and TIMP-2 did not change significantly after gefitinib treatment, even in responders. The levels of VEGF in volunteers, responders and non-responders were 384 +/- 86.4, 404 +/- 94.3 and 719 +/- 99.8 pg/ml, respectively. The difference between volunteers and responders was not significant (P = 0.540), while the differences between volunteers and non-responders (P = 0.031), and responders and non-responders (P = 0.028) were significant. CONCLUSIONS: Although our results indicate that gefitinib treatment does not affect circulating levels of angiogenic growth factors even in patients who showed a response to gefitinib treatment, low levels of VEGF may predict response to gefitinib treatment in patients with NSCLC.