Crizotinib治疗EML4-ALK融合基因阳性的NSCLC患者的临床疗效观察

发布时间：2018-05-08 05:37

本文选题：克唑替尼 + 肺肿瘤　；参考：《安徽医科大学》2017年硕士论文

【摘要】：目的Crizotinib在中国患者中的临床疗效及其不良反应尚缺乏大样本临床实验。本研究的研究目的为:1、研究克唑替尼(Crizotinib)对棘皮动物微管结合蛋白样-4-间变性淋巴瘤激酶(echinoderm microtubule-assciated protein-like-4-Anaplastic lymphoma kinase,EML4-ALK)融合基因阳性的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的疗效以及毒副作用。2、对比传统的标准化疗方案,研究Crizotinib对EML4-ALK融合基因阳性的NSCLC患者的疗效和不良反应的严重程度以及耐受情况。3、研究Crizotinib对已经发生脑转移的EML4-ALK融合基因阳性晚期NSCLC患者的临床疗效以及毒副作用。方法1、入组符合本研究要求的45例EML4-ALK融合基因阳性的NSCLC患者,随后给予Crizotinib 250mg/次,2/日,口服治疗,直到病情进展(progressive disease,PD)或者发生不可耐受的毒副反应,随访周期为12个月,观察Crizotinib疗效及其耐受情况。2、筛选符合本研究要求的EML4-ALK融合基因阳性的NSCLC患者86例,Crizotinib组和传统的标准化疗组每组各43例,随访周期为12个月,分析Crizotinib组相较于传统标准化疗组的疗效优劣以及毒副作用的大小。3、入组符合本研究要求的脑转移的EML4-ALK融合基因阳性的晚期NSCLC患者20例,随后给予Crizotinib 250mg/次,2/日,口服治疗,直到病情进展(progressive disease,PD)或者发生不可耐受的毒副反应,随访周期为12个月,观察Crizotinib疗效及其毒副作用。结果1、Crizotinib在EML4-ALK融合基因阳性的NSCLC中的治疗效果45例EML4-ALK融合基因阳性的NSCLC患者给予Crizotinib治疗至少一个月,一个月后给予疗效评价。服用Crizotinib患者部分缓解(partial response,PR)为60%(27/45),疾病稳定(stable disease,SD)为33.3%(15/45),疾病进展为6.7%(3/45),客观缓解率(Objective Response Rate,ORR)为60%(27/45),疾病控制率(disease control rate,DCR)为93.3%(42/45),中位无进展生存期(progression-free survival,PFS)为7.0个月。年龄、性别、吸烟史、EGFR基因状态以及是否一线服用Crizotinib对PFS的影响无显著统计学差异。而入组本实验前已行化疗的患者口服Crizotinib的疗效明显优于入组本实验前未行化疗的患者(中位PFS分别为8个月和5个月,两组差异有统计学意义)。服用Crizotinib的不良反应发生率是40%(18/45),主要不良反应为视觉障碍、恶心、便秘以及谷丙转氨酶升高,本组研究患者中有1例患者在口服Crizotinib治疗期间出现了III度的骨髓抑制,后经对症治疗后血象恢复正常并继续口服Crizotinib,所有入组的患者均能耐受至治疗终止。2、Crizotinib对比化疗在NSCLC患者中的疗效分析Crizotinib组:CR为0,PR为60.5%(26/43),SD为32.6%(14/43),PD为7%(3/43),ORR是60.5%(26/43),DCR是93%(40/43),中位PFS是7.0个月。化疗组:CR为0,PR为25.6%(11/43),SD为20.9%(9/43),PD为53.5%(23/43),ORR是25.6%(11/43),DCR是46.5%(20/43),m PFS(medial progression-free survival,PFS)是3.0个月。Crizotinib组患者的疗效明显要优于传统标准化疗组的患者,P=0.015,两组之间的差异具有统计学意义。Crizotinib组的不良反应发生率是41.8%(18/43),主要的不良反应为视觉障碍、恶心等消化道反应、便秘以及谷丙转氨酶升高,本组研究患者中有1例患者在口服Crizotinib治疗期间出现了III度的骨髓抑制,后经对症治疗血象恢复正常并继续口服Crizotinib,所有患者均能耐受至治疗终止。而标准化疗组的主要不良反应为脱发、恶心、呕吐、腹泻及谷丙转氨酶升高,化疗组有4名患者因为严重的化疗反应不能耐受,从而更改其它方案化疗。1例患者在化疗间歇期猝死。3、Crizotinib对EML4-ALK融合基因阳性的晚期NSCLC患者脑转移的疗效分析20例已经发生脑转移的EML4-ALK融合基因阳性的晚期NSCLC患者给予Crizotinib至少一个月后的疗效分析显示:CR 0例(0%),PR 60%(12/20),SD 45%(9/20),PD 5%(1/20)。ORR为60%(12/20),DCR为95%(19/20)。截止随访时间,有16例患者进展,其中首发进展是颅内进展的为62.5%(10/16)。本组患者未放疗20%(4/20),行放疗或脑转移瘤手术80%(16/20),未行放疗患者SD为75%(3/4),PR为25%(1/4)例,ORR为25%(1/4),DCR为100%(4/4)。在行放疗或脑转移瘤手术的16名患者中,SD 31.2%(5/16)例,PR 62.5%(10/16),PD 6.25%(1/16),ORR为62.5%(10/16),DCR为93.8%(15/16)。本组入组患者中行放疗或者脑转移瘤手术患者的中位无进展生存期为7个月(95%CI 5.70-8.30个月),显著长于于未行放疗及手术治疗患者的3个月(P=0.003)。Crizotinib治疗前接受过脑伽马刀治疗13例患者,包括全脑放疗(Whole brain radiotherapy,WBRT)、立体定向放疗(Stereotactic radiotherapy,SBRT)以及手术,中位PFS为7个月(95%CI4.74-9.26月),服用Crizotinib后放疗3例,m PFS 6个月。服用Crizotinib前后放疗未见明显统计学差异(P=0.951)。Crizotinib不良反应发生率为40%(8/20),主要有视觉障碍、恶心等消化道反应、便秘以及谷丙转氨酶升高,本组研究患者中有1例患者在口服Crizotinib治疗期间出现了III度的骨髓抑制,后经对症治疗血象恢复正常并继续口服Crizotinib,所有患者均能耐受并坚持治疗结束。结论1、Crizotinib作为第一个被国际上批准用于EML4-ALK融合基因阳性的NSCLC患者的靶向治疗药物,具有良好的疗效,不良反应在可耐受范围。2、相较于传统标准的化疗方案,Crizotinib治疗EML4-ALK融合基因阳性的非小细胞患者的疗效显著,可明显延长患者的中位PFS并且提高晚期NSCLC患者的生存质量,毒副作用也明显小于化疗。针对EML4-ALK融合基因阳性的非小细胞患者,应优先考虑行Crizotinib靶向治疗。3、对于已经发生脑转移的EML4-ALK融合基因阳性的NSCLC患者,Crizotinib亦表现出较好的控制率。
[Abstract]:Objective the clinical efficacy and adverse reactions of Crizotinib in Chinese patients are still lacking large sample clinical trials. The purpose of this study was to study the study of kazolinib (Crizotinib) on microtubule binding protein like -4- anakinase (echinoderm microtubule-assciated protein-like-4-Anaplastic lymphoma kinase, EM) in acanthopanzia (EM). L4-ALK) the efficacy and toxic side effects of non-small cell lung cancer (NSCLC) patients with fusion gene positive, and the toxic and side effects.2, compared with the traditional standard chemotherapy scheme, the effect of Crizotinib against EML4-ALK fusion gene positive NSCLC patients and the severity of adverse reactions and tolerance condition.3 were studied, and Crizotinib pairs have been studied. The clinical efficacy and toxic side effects of EML4-ALK fusion gene positive NSCLC patients with positive brain metastases. Method 1, 45 cases of NSCLC patients with EML4-ALK fusion gene positive, followed by Crizotinib 250mg/ times, 2/ day, oral treatment, or intolerance (progressive disease, PD), or intolerance in the disease progression (progressive disease, PD). The follow-up period was 12 months. The efficacy and tolerance of Crizotinib were observed and.2 was observed. 86 cases of NSCLC patients with EML4-ALK fusion gene positive, 43 cases in group Crizotinib and traditional standard chemotherapy group, followed up for 12 months, and the effect of Crizotinib group compared with the traditional standard chemotherapy group was analyzed. And the size of the toxic side effects of.3, 20 cases of advanced NSCLC patients with EML4-ALK fusion gene positive in the brain metastases, followed by Crizotinib 250mg/ times, 2/ day, oral treatment, until the disease progression (progressive disease, PD) or an untolerable toxic and side reaction, the follow-up period was 12 months, observe Crizotinib. Effect and toxic and side effects. Results 1, Crizotinib in EML4-ALK fusion gene positive NSCLC, 45 cases of EML4-ALK fusion gene positive NSCLC patients were given Crizotinib treatment for at least one month, and one month later, the curative effect was evaluated. The partial relief of Crizotinib patients (partial response, PR) was 60% (27/45), and the disease was stable (stabl). E disease, SD) was 33.3% (15/45), the disease progressed to 6.7% (3/45), the objective remission rate (Objective Response Rate, ORR) was 60% (27/45), and the disease control rate (disease control) was 93.3%, and the median progression free survival was 7 months. Age, sex, smoking history, gene state and a first-line dress. There was no significant difference in the effect of Crizotinib on PFS. The efficacy of oral Crizotinib in patients who had undergone chemotherapy before the experiment was significantly better than those who did not undergo chemotherapy before the experiment (median PFS was 8 months and 5 months respectively, and the two groups were statistically significant). The incidence of adverse reactions to Crizotinib was 40% (18/45). The adverse reactions were visual disorder, nausea, constipation, and elevated alanine aminotransferase. In this group, 1 patients had a III degree of bone marrow depression during the oral Crizotinib treatment. After symptomatic treatment, the hematogram returned to normal and continued to take Crizotinib. All the patients in the group were tolerated to terminate.2, Crizotinib The efficacy of chemotherapy in NSCLC patients was analyzed in group Crizotinib: CR was 0, PR was 60.5% (26/43), SD was 32.6% (14/43), PD was 7% (3/43), ORR was 60.5% (26/43), DCR was 93%, 7 months. The effect of ion-free survival, PFS) was 3 months in group.Crizotinib patients better than those in the traditional standard chemotherapy group. P=0.015, the difference between the two groups was statistically significant, the incidence of adverse reactions in group.Crizotinib was 41.8% (18/43), and the main adverse reactions were visual disturbance, nausea and other digestive tract reactions, constipation, and glutamic acid conversion. In this group, 1 patients in this group had a III degree of myelosuppression during the oral Crizotinib treatment. After symptomatic treatment, the hematogram returned to normal and continued to take Crizotinib. All the patients were able to tolerate the termination of the treatment. The main adverse reactions in the standard chemotherapy group were alopecia, nausea, vomiting, diarrhoea and alanine transaminase. High, 4 patients in the chemotherapy group were intolerant of the severe chemotherapy response, thus changing the other regimens in.1 patients with sudden death in the intermission of chemotherapy,.3, and the effect of Crizotinib on the brain metastases of advanced NSCLC patients with positive EML4-ALK fusion gene. 20 cases of advanced NSCLC patients with EML4-ALK fusion gene positive brain metastases were given C. The efficacy analysis of rizotinib at least one month showed: CR 0 cases (0%), PR 60% (12/20), SD 45% (9/20), PD 5% (1/20).ORR 60% (12/20), DCR 95% (19/20). There were 16 patients progressing at the end of the follow-up time, and the first progression was 62.5% (20%). The patients were treated with radiotherapy or brain metastases surgery. SD was 75% (3/4), and PR was 25% (1/4), ORR was 25% (1/4), and DCR was 100% (4/4). In 16 patients undergoing radiotherapy or brain metastases surgery, SD 31.2% (5/16), PR 62.5% (10/16), 62.5% (62.5%), 93.8% (93.8%). The group entered the group with no progress in radiotherapy or brain metastases. The survival period was 7 months (95%CI 5.70-8.30 months), which was significantly longer than 3 months (P=0.003).Crizotinib treatment for 13 patients before the treatment of radiotherapy and surgery, including whole brain radiotherapy (Whole brain radiotherapy, WBRT), stereotactic radiotherapy (Stereotactic radiotherapy, SBRT), and surgery, and median PFS was 7 months ( 95%CI4.74-9.26 months), 3 cases of radiotherapy after taking Crizotinib, m PFS for 6 months. There was no significant difference between radiotherapy and radiotherapy before and after Crizotinib (P=0.951) the incidence of.Crizotinib adverse reaction was 40% (8/20), mainly with visual disturbance, nausea and digestive tract reaction, constipation and elevated alanine transaminase, 1 patients in this group were in oral Cri. Zotinib had a III degree of bone marrow depression during the treatment. After symptomatic treatment, the hematogram returned to normal and continued to take Crizotinib. All patients were able to tolerate and adhere to the end of the treatment. Conclusion 1, Crizotinib is the first targeted therapy for NSCLC patients who have been approved by the world for EML4-ALK fusion gene positive, which has good curative effect. The adverse reaction is in the tolerable range of.2. Compared with the traditional standard chemotherapy regimen, Crizotinib has a significant effect on non small cell patients with EML4-ALK fusion gene positive. It can significantly prolong the patient's median PFS and improve the quality of life of patients with advanced NSCLC, and the toxic and side effects are significantly less than chemotherapy. The negative effect of the EML4-ALK fusion gene is less than that of the chemotherapy. Crizotinib targeting therapy.3 should be given priority in small cell patients. Crizotinib also shows good control rate for patients with NSCLC positive EML4-ALK fusion genes that have undergone brain metastases.

【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2

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