抗非小细胞肺癌药物奥希替尼研究进展

年3月22日中国食品药品监督管理局(CFDA)批准表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)奥希替尼(Osimertinib)用于治疗EGFR T790M基因突变阳性的局部晚期或转移性非小细胞肺癌(NSCLC)。奥希替尼是第三代EGFR-TKI,治疗效果显著,副作用更小,尤其适用于对第一、二代EGFR-TKI耐药或者脑转移的病人。与含铂类治疗药物的二联化学疗法相比,奥希替尼可使NSCLC病人中位无进展生存期(PFS)延长5.7个月,疾病进展风险下降70%。该文就奥希替尼的作用机制、研究历程、药效学、药动学、不良反应,耐药机制进行综述,为临床使用提供参考。     

Therapeutic efficacy of gefitinib and erlotinib in patients with advanced lung adenosquamous carcinoma

BackgroundAdenosquamous carcinoma (ASC) of the lung is a rare subtype of nonsmall-cell lung cancer (NSCLC). To date, the efficacious targeted therapy for advanced ASC remains unclear and the epidermal growth factor receptor (EGFR) mutation rate is not well known.MethodsWe retrospectively reviewed clinical information of patients with ASC who were treated with gefitinib or erlotinib at Zhejiang Cancer Hospital between January 2007 and December 2011. Survival analysis was evaluated by the Kaplan-Meier method. EGFR mutations were assessed in part using direct sequencing methods.ResultsIn total, 49 patients with a median age of 57 years were used in this study. Thirteen patients achieved a partial response and 19 had disease stabilization. The objective response rate was 26.5%, and the disease control rate was 65.3%. The median progression-free survival and overall survival were 4.3 and 17.6 months, respectively. In 21 patients with adequate specimens for molecular analysis, 7 (33.3%) had EGFR mutations (4 with deletions within exon 19 and 3 with L858R messenger mutation in exon 21). EGFR mutations were significantly more frequent in women (4/9, 44.4%) than men (3/12, 25%), never-smokers (6/15, 40%), and smokers (1/6, 16.7%).ConclusionEGFR-tyrosine kinase inhibitor (TKI) is an effective treatment for ASC. The frequency of EGFR mutation and clinical characteristics of the EGFR mutants in ASC are similar to those of Asian patients with adenocarcinoma.     

EGFR-TKI治疗晚期非小细胞肺癌的临床疗效和安全性观察

目的 评价表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）对局部晚期或转移性非小细胞肺癌（NSCLC）患者临床疗效与安全性.方法 对经病理确诊的初治或经治的29例晚期NSCLC的患者,予吉非替尼250mg/d或厄洛替尼150mg/d 口服,至肿瘤进展或发生不可耐受的毒副作用.结果 29例患者的总有效率为48.3%,疾病控制率为72.4%,中位疾病进展时间为7.7个月;随访结束时11例患者死亡,死亡患者的中位生存期为8个月;主要的的毒副作用是皮疹和腹泻,均可耐受.结论 EGFR-TKI制剂治疗NSCLC,具有较好的疗效和耐受性.     

A multicenter phase II study of sorafenib monotherapy in clinically selected patients with advanced lung adenocarcinoma after failure of EGFR-TKI therapy (Chinese Thoracic Oncology Group,CTONG 0805)

Objectives

Aim of the study was to investigate efficacy and safety of sorafenib in patients with advanced lung adenocarcinoma after failure of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy.

Patients and methods

Patients who were diagnosed with stage IIIB or stage IV lung adenocarcinoma, and benefited from one prior EGFR-TKI therapy and then failed, were eligible. No more than one previous chemotherapy regimen was permitted. Patients received oral sorafenib 400 mg twice daily continuously until disease progression or intolerable toxicity. Primary endpoint was disease control rate (DCR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). For patients who agreed to provide peripheral blood or tumor tissue, we analyzed the genotype of Bcl-2-interacting mediator of cell death (BIM) deletion polymorphism and EGFR mutation status.

Results

Of 65 enrolled patients, 64 were evaluable. The DCR was 32.8%, which did not meet the predefined statistical hypothesis of 38.4%. The median PFS and OS were 3.7 months [95% (confidence interval), 3.5–3.9 months] and 7.4 months (95% CI, 5.7–9.2 months), respectively. Logistic regression analysis showed no correlation between DCR and age, gender, smoking status and performance status. Hand-foot syndrome (HFS) was the predominant toxicity occurring in 71.9% of patients. Fourteen patients (21.9%) had ≥grade 2 dermatologic reactions that resulted sorafenib dose reduction in three patients (4.7%). Of 36 patients, the BIM deletion polymorphism was found in 3, and no response to sorafenib was observed. In 30 tumor tissues, 22 EGFR active mutations were found. The DCR had no significant difference between mutation-positive and wild-type patients (31.8% vs. 42.9%, respectively; HR, 0.622; p = 0.665).

Conclusion

Sorafenib monotherapy did not achieve positive result in patients defined in our trial and we need better biomarker to determine the population who can benefit from sorafenib treatment (ClinicalTrials.gov number: NCT00922584).     

EGFR-TKI治疗晚期非小细胞肺癌——肿瘤个体化治疗的典范

肺癌是目前发病率和病死率最高的恶性肿瘤,在世界范围内每年因肺癌导致的死亡超过100万人。根据临床和组织病理学特征,肺癌可以大致分为非小细胞肺癌(non-small cell lung cancer,NSCLC)和小细胞肺癌(small cell lung cancer,SCLC)两种类型,其中非小细胞肺癌约占全部肺癌的85%[1]。仅有一小部分的NSCLC患者可以通过积极的治疗得以治愈。约75%[2]的患者在就诊时已是局     

姑息化疗EGFR-TKI治疗失败后晚期非小细胞肺癌临床疗效观察

目的观察晚期非小细胞肺癌EGFR-TKI治疗失败后姑息化疗的疗效及不良反应。方法姑息化疗EGFR-TKI治疗失败的晚期非小细胞肺癌患者16例,其中10例采取联合化疗,6例采取单药化疗。结果 16例患者中PR 1例,SD 10例,疾病控制率为68.8%;联合化疗组中位生存期13月,1年生存率60.0%;单药化疗组中位生存期8月,1年生存率33.3%,两组比较差异无统计学意义（P〉0.05）。两组不良反应轻微,均可耐受。结论对于EGFR-TKI治疗失败而且体力状况较好的晚期NSCLC患者,可尝试采取姑息化疗。     

影响表皮生长因子受体酪氨酸激酶抑制剂治疗晚期非小细胞肺癌疗效的临床因素分析

目的 探讨影响表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)患者疗效的临床因素.方法 对2005年1月至2006年12月接受EGFR-TKI治疗的166例晚期NSCLC患者的临床资料进行回顾性分析,其中ⅢB期62例,Ⅳ期104例,均有可测量的临床病灶.结果 166例NSCLC患者中,119例取得临床获益,疾病控制率(DCR)为71.7%.患者的性别、年龄、吸烟情况、病理类型、应用EGFR-TKI时是否存在骨脑转移、应用EGFR-TKI治疗的时机以及诊断时血清乳酸脱氢酶(LDH)水平不影响EGFR-TKI的治疗效果.在126例有血清癌胚抗原(CEA)水平的NSCLC患者中,84例患者CEA高于正常水平,诊断时血清CEA水平高者和正常者的DCR分别为79.8%和59.5%(P=0.016).在临床获益患者中,吸烟状态和诊断时CEA水平影响无进展生存期(PFS),其中不吸烟者的PFS为(9.57±6.75)个月,轻度吸烟者为(4.86±3.44)个月,重度吸烟者为(5.25±4.34)个月(P=0.007);诊断时CEA水平高者的PFS为(9.45±7.48)个月,CEA水平正常者为(6.52±4.46)个月(P=0.036).结论 EGFR-TKI治疗晚期NSCLC是安全有效的,CEA水平高的患者更易从EGFR-TKI治疗中获益.

Abstract：

Objective To explore the clinical factors affecting the sensitivity of EGFR-TKI treatment in advanced non-small cell lung cancer. Methods Clinical data were retrospective analyzed to determine the clinical factors affecting the outcome of 166 patients with advanced non-small cell lung cancer who received EGFR-TKI treatment in our hospttal from January of 2005 to December of 2006. Results One hundred and nineteen patients benefited from EGFR-TKI treatment in the total of 166 patients and the disease control rate was 71.7%. Among the factors analyzed, sex, age, smoking, pathological type, brain and bone metastasis or not when EGFR-TKI was used, the time using EGFR-TKI and the level of LDH at the time of diagnosis had no significant effect on the clinical benefit rate. Among the 126 patients with serum CEA assayed at diagnosis, 84 cases had a higher serum CEA level. Compared with the patients with normal serum CEA level, the patients with a higher serum CEA level benefited more easily from EGFR-TKI therapy, with a disease control rate of 79.8% and 59.5%, respectively (P = 0. 016). Among the patients who got benefits from EGFR-TKI treatment, smoking and the CEA level at diagnosis had effects on the duration of progression-free survival. The progression free survivals were 9.57 ± 6.75 months in non-smokers, 4.86 ±3.44 months in light-smokers and 5.25 ± 4.34 months in heavy-smokers (P = 0.007 ). The progression free survival was 9.45 ± 7.48 months in the group with a higher serum CEA level and 6.52 ± 4.46 months in the group with normal serum CEA level (P = 0.036). Conclusions In patients with advanced non-small cell lung cancer, EGFR-TKIs treatment is safe and effective. The patients with high CEA level are prone to benefit from it.     

EGFR-TKI治疗非小细胞肺癌的耐药机制进展研究

肺癌的发病率和死亡率已居我国恶性肿瘤的第一位。以表皮生长因子受体,酪氨酸激酶为靶点的酪氨酸激酶抑制剂(EGFR-TKI)治疗肺癌已广泛引起关注。但部分患者在服用EGFR-TKI初期即出现原发耐药,有些患者在服用EGFR-TKI一段时间后产生继发性耐药,本文综述EGFR-TKl分子耐药机制的研究现状,探讨EGFR-TKl分子耐药机制重要的临床意义。      

埃克替尼二、三线治疗48例晚期非小细胞肺癌

[目的]探讨埃克替尼二、三线治疗非小细胞肺癌（NSCLC）的疗效及安全性。[方法]回顾性分析48例NSCLC患者的资料。治疗方法：埃克替尼片,口服．每次125mg．每133次。分析患者的近期疗效及不良反应。[结果]治疗1个月后客观有效率（ORR）35．4％,疾病控制率（DCR）70．8％;治疗3个月后0RR60．4％,DCR79．2％;治疗6个月后0RR45．8％．DCR70．8％：治疗1年后ORR27．1％,DCR58.3％。对治疗3个月后不同临床特征患者的疗效分析显示,腺癌、无吸烟史及ECOG2分是埃克替尼治疗获益的优势因素。不良反应主要是皮疹（47．9％）和腹泻（22．9％）。[结论]埃克替尼二、三线治疗晚期NSCLC具有较好的近期疗效及安全性．     

Therapeutic potential of tyrosine kinase inhibitors in breast cancer

Despite recent advances in the treatment of breast cancer, survival rates for patients with metastatic breast cancer remain poor, and new treatments are still required for both hormone-dependent and hormone-independent disease. The epidermal growth factor receptor (EGFR) is a promising new target for anticancer therapy because it is commonly highly expressed in breast cancer and is implicated in the control of many aspects of tumor biology. Because expression of EGFR is inversely related to expression of the estrogen receptor (ER) and is associated with resistance to currently available breast cancer therapies, EGFR-targeted therapies may be valuable in the treatment of ER-negative tumors and endocrine-resistant, ER-positive tumors. Furthermore, the novel mechanism of action of EGFR-targeted therapies may complement the antitumor activity of existing treatment with cytotoxic agents, radiotherapy, or hormones. In this article, the small-molecule inhibitors of the tyrosine kinase activity of EGFR are discussed, with particular emphasis on the potential use of such agents at each stage of breast cancer, including a potential role in chemoprevention.