Heinrich Michael C, Joensuu Heikki, Demetri George D, Corless Christopher L, Apperley Jane, Fletcher Jonathan A, Soulieres Denis, Dirnhofer Stephan, Harlow Amy, Town Ajia, McKinley Arin, Supple Shane G, Seymour John, Di Scala Lilla, van Oosterom Allan, Herrmann Richard, Nikolova Zariana, McArthur And Grant
Department of Hematology and Medical Oncology, Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, Oregon 97239-3098, USA.
Clin Cancer Res. 2008 May 1;14(9):2717-25. doi: 10.1158/1078-0432.CCR-07-4575.
To evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases.
This was a phase II, open-label, single arm study. Patients > or = 15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinib-sensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point.
One hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinib-sensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response.
Clinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment.
评估伊马替尼治疗表达一种或多种伊马替尼敏感酪氨酸激酶的晚期、危及生命的恶性肿瘤的活性。
这是一项II期开放标签单臂研究。纳入年龄≥15岁、恶性肿瘤有组织学或分子证据表明伊马替尼敏感酪氨酸激酶表达/激活的患者。血液系统恶性肿瘤和实体瘤患者分别接受400mg/d或800mg/d伊马替尼治疗。治疗持续至疾病进展或出现不可接受的毒性。主要目的是以肿瘤反应为主要终点，确定伊马替尼活性的证据。
186例患有40种不同恶性肿瘤的患者入组（78.5%为实体瘤，21.5%为血液系统恶性肿瘤）。实体瘤患者中8.9%出现确认反应（4例完全缓解，9例部分缓解），血液系统恶性肿瘤患者中27.5%出现确认反应（8例完全缓解，3例部分缓解）。仅在五种肿瘤类型（侵袭性纤维瘤病、隆突性皮肤纤维肉瘤、高嗜酸性粒细胞综合征、骨髓增殖性疾病和系统性肥大细胞增多症）中观察到伊马替尼的显著活性。共对106个肿瘤进行了激活突变筛查：发现5个KIT突变，未发现血小板衍生生长因子受体突变。1例系统性肥大细胞增多症患者对治疗有部分反应，有一个新的伊马替尼敏感KIT突变（D816T）。野生型伊马替尼敏感酪氨酸激酶的表达或激活与临床反应之间没有明确关系。
临床获益主要局限于具有伊马替尼靶激酶激活已知基因组机制的疾病。我们的结果表明肿瘤分子特征对于识别可能从伊马替尼治疗中获益的患者具有重要作用。
