北京肿瘤医院肾癌黑色素瘤病区郭军教授等新近刊发在国际权威肿瘤杂志《临床肿瘤学期刊》(Journal of Clinical Oncology)(最新影响因子18.97)上的题为“Phase II, Open-Label, Single-Arm Trial of Imatinib Mesylate in Patients With Metastatic Melanoma Harboring c-Kit Mutation or Amplification”的报告显示:经Ⅱ期临床研究证实,伊马替尼治疗c-Kit基因突变转移性黑色素瘤,可获得较高的总缓解率(23.3%)和疾病控制率(54%)。
郭军教授及其团队在该项II期临床研究中评价了43例患者(均为c-Kit基因突变或扩增的转移性黑色素瘤患者)总体的无疾病进展生存(PFS)、总反应率(ORR)和总生存(OS)。结果显示:6个月的无疾病进展生存率为36.6%,中位无疾病进展生存为3.5个月。1年总生存率为51.0%,中位总生存为14.0个月,PR或SD患者总生存为15个月,疾病进展者为9个月(P=0.036)。相关工作在2010年美国癌症年会上进行了专题讨论,该结果已于近期在JCO杂志正式发表。
此前曾有三位研究者对未经选择的89例转移性黑色素瘤患者使用伊马替尼治疗,结果仅有一例患者疾病缓解。后来证明此例获得缓解的患者是一个c-Kit基因突变的肢端黑色素瘤患者。在郭军教授主持的这项研究中,入组患者均为c-Kit基因突变和(或)c-Kit基因拷贝数扩增患者。与未经选择患者中进行的试验结果相比,这项研究结果非常令人振奋,这些患者多为Ⅳ期、化疗失败患者,目前尚无标准治疗。据此推论,未来可能可以将黑色素瘤患者按分子分型进行分类,之后再根据突变特点选择合适的个体化靶向治疗,如BRAF突变患者可使用PLX4032,c-Kit突变患者可选择伊马替尼,从而逐步地解决整个黑色素瘤的治疗问题。
郭军教授的这一临床试验设计和结果为中国黑色素瘤患者的个体化靶向治疗提供了新的思路,也向其他肿瘤治疗专家及与肿瘤抗争人群展现出了令人振奋的肿瘤治疗前景。(生物谷 Bioon.com)
doi:10.1200/JCO.2010.33.9275
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Phase II, Open-Label, Single-Arm Trial of Imatinib Mesylate in Patients With Metastatic Melanoma Harboring c-Kit Mutation or Amplification
Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, Li H, Sheng X, Cui C, Chi Z, Li S, Han M, Mao L, Lin X, Du N, Zhang X, Li J, Wang B, Qin S.
PURPOSE:Melanomas harbor aberrations in the c-Kit gene. We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with metastatic melanoma harboring c-Kit mutations or amplifications.PATIENTS AND METHODS:Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred. Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d.RESULTS:Forty-three patients were eligible for evaluation, and the median follow-up time was 12.0 months. The median progression-free survival (PFS) was 3.5 months, and the 6-month PFS rate was 36.6%. Rate of total disease control was 53.5%: 10 patients (23.3%; 95% CI, 10.2% to 36.4%) and 13 patients (30.2%; 95% CI, 16.0% to 44.4%) achieved partial response (PR) and stable disease (SD), respectively. Eighteen patients (41.9%) demonstrated regression of tumor mass. Notably, nine of the 10 PRs were observed in patients with mutations in exons 11 or 13. The 1-year overall survival (OS) rate was 51.0%. The median PFS and OS times for patients who had PR or SD versus disease progression were 9.0 months versus 1.5 months (P < .001) and 15.0 months versus 9.0 months (P = .036), respectively. Imatinib 400 mg/d was well tolerated, and only one of the 15 patients who received dose escalation to 800 mg/d achieved SD.CONCLUSION:Imatinib demonstrated significant activity in patients with metastatic melanoma harboring genetic c-Kit aberrations, with an overall response rate of 23.3%. Escalation to 800 mg/d could not restore disease control.