Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors.

BACKGROUND: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. PATIENTS AND METHODS: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). RESULTS: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C(max) was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days). CONCLUSIONS: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.     

EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer

The incidence of brain metastasis (BM) is high in patients with non-small-cell lung cancer. Available standard therapeutic options, such as whole-brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. Novel agents, such as EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), have now been included in standard non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by a response rate of 70–80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. However, since most of the larger studies on these agents have excluded BM patients from their series, few prospective data are available on the efficacy of these agents in this setting. In recent years, however, several authors have reported a growing number of cases of partial and complete response in BM patients treated with EGFR TKIs. Data from retrospective series and Phase II studies also suggest that a response can be obtained using EGFR TKI treatment for patients with BM, especially those harboring EGFR mutations.     

吉非替尼致问质性肺炎并文献回顾

目的：探讨吉非替尼治疗晚期非小细胞肺癌所致问质性肺炎的临床特点和治疗策略。方法：报告1例吉非替尼治疗晚期非小细胞肺癌所致间质性肺炎的临床资料，并进行系统文献回顾，对吉非替尼所致间质性肺炎的临床特点，机理和治疗进行分析。结果：综合本病例患者特点和国内外文献分析，老年男性、长期吸烟史、吸烟指数高、腺癌、特别是细支气管肺泡癌患者在服用吉非替尼期间更容易发生间质性肺炎，发生时间多在服药后1—2月，临床表现以胸闷、气短、进行性呼吸困难为特点，伴有严重低氧血症，甚至呼吸衰竭。影像学检查以双肺弥漫性浸润性阴影及蜂窝状间质改变为代表，及时判断病因并停药，给予糖皮质激素、吸氧、抗感染等对症处理可缓解。结论：一旦发现吉非替尼所致的间质性肺炎应及时停药，大多数患者病情可缓解，早期可控制的间质性肺炎，不是永久停用吉非替尼的绝对指标，应根据患者的获益和药物治疗相关风险综合考虑。     

A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer

Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naïve patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naïve patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m² d1) and either cisplatin (75 mg/m² d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed–platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations.     

Personalized medicine for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is a heterogeneous illness associated with a high mortality rate. Personalized therapy may improve treatment outcomes by identification of a specific genotypic anomaly and target-specific therapy. The most significant development in recent years was the discovery of activated EGF receptor (EGFR) mutations at exons 19 and 21. Patients with EGFR mutations respond dramatically to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib, resulting in longer progression-free survival. Multiple randomized studies, including the Iressa Pan-Asia Study and WJTOG3405, have confirmed the role of EGFR tyrosine kinase inhibitors as standard first-line therapy for patients with the EGFR mutation. In this article, we summarize the current nonpersonalized therapies and examine the available and investigational personalized therapies for patients with resectable early-stage, unresectable locally advanced, or metastatic disease.     

吉非替尼对肺鳞癌患者免疫功能的影响及其近期临床疗效

目的：研究吉非替尼对肺鳞癌患者免疫功能的影响及其近期临床疗效。方法选取诊断为肺鳞癌的患者84例,随机分为观察组和对照组,每组均为42例,两组患者均给予常规治疗,观察组在常规治疗的基础上给予口服吉非替尼,观察两组患者治疗后体液免疫和细胞免疫功能情况及其近期临床疗效。结果治疗后两组患者血清 CD3、CD4、IgG、IgM、IgA 浓度与 CD4／CD8较治疗前有所降低（P ＜0．05）,CD8较治疗前有所升高（P ＜0．05）;观察组患者血清 CD3、CD4、CD4／CD8、IgG、IgM、IgA 浓度明显高于对照组（P ＜0．05）,观察组 CD8较对照组低（P ＜0．05）;观察组临床疗效优于对照组,治疗后两组均出现恶心、恶心伴呕吐、骨髓抑制,差异无统计学意义（P ＞0．05）。结论在常规治疗的基础上给予口服吉非替尼能改善患者的免疫功能,提高临床疗效,且无严重不良反应。     

金复康口服液对吉非替尼耐药人肺腺癌PC9/R的增敏作用和机制研究

目的 研究金复康口服液对人肺腺癌PC9细胞及耐药PC9/R细胞的吉非替尼增敏作用及机制。方法 金复康口服液20 mg/mL联合不同浓度的吉非替尼（40、20、10、5、2 μmol/L）作用于PC9/R细胞,CCK-8法检测细胞增殖;培养PC9、PC9/R细胞,分为对照组、金复康口服液组、吉非替尼组、联合用药组,流式细胞术检测PC9、PC9/R细胞周期和凋亡。在BALB/c裸鼠右前肢腋窝皮下接种PC9/R细胞建立裸鼠移植瘤模型,观察金复康口服液联合吉非替尼的体内抑瘤作用;对AKT、p-AKT、PTEN、PDCD4蛋白表达的影响和对miRNA-21表达的影响。结果 与吉非替尼（2、5、10、20 μmol/L）组比较,吉非替尼（2、5、10、20 μmol/L）+金复康口服液（20 mg/mL）组的PC9/R细胞抑制率显著增加（P<0.01）;与吉非替尼组比较,联合用药可以通过显著增加早期凋亡细胞比例诱导PC9及PC9/R细胞凋亡,并使PC9、PC9/R细胞停滞在DNA合成前期,从而抑制细胞增殖,差异均具有统计学意义。体内实验表明,与吉非替尼组比较,联合用药显著抑制裸鼠PC9/R移植瘤的生长（P<0.05）,且能显著降低裸鼠PC9/R组织p-AKT表达（P<0.05）,增强PTEN、PDCD4的表达（P<0.05）,联合用药组裸鼠PC9/R瘤组织miRNA-21的表达显著降低（P<0.05）。结论 金复康口服液能提高人肺腺癌PC9/R细胞对吉非替尼的敏感性,其作用的可能机制为通过降低miRNA-21的表达从而增强PTEN、PDCD4的表达以抑制AKT通路活性。     

The therapy of gefitinib towards breast cancer partially through reversing breast cancer biomarker arginine

Background

Breast cancer remains the leading reason of cancer death among women worldwide, and gefitinib is the efficient drug for breast cancer.

Aims

To use targeted metabolomics method to elucidate the therapeutic mechanism of gefitinib through profiling the amino acids.

Methods

Healthy women (n=56) and women with breast cancer (n=60) were enrolled in Affiliated Yuhuangding hospital, medical college of Qingdao University from 2012–2014. API 3200 triple quadrupole mass spectrometer was used to analyze the serum samples.

Results

The concentration of amino acids was compared between healthy women and women with breast cancers. Compared with the healthy women, the concentration of arginine in breast cancer women significantly decreased (p<0.0001). To show the representative capability of arginine towards the pathogenesis of breast cancers, the receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated to be 0.96 ± 0.02, indicating the high predictive capability of arginine for breast cancer . The reversing ability of gefitinib towards the level of arginine was further determined, and 1 month treatment of gefitinib (500 mg/day) significantly reversed the arginine level of breast cancer patients (p<0.0001)

Conclusion

The therapy of gefitinib towards breast cancer through reversing breast cancer biomarker arginine was demonstrated.