Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Cancer Chemother Pharmacol. 2011 Jan;67 Suppl 1(Suppl 1):S25-43. doi: 10.1007/s00280-010-1526-3. Epub 2010 Nov 30.
Small molecule kinase inhibitors have irrevocably altered cancer treatment. March 2010 marks the 10th anniversary of using imatinib in gastrointestinal stromal tumors (GIST), a cardinal example of the utility of such targeted therapy in a solid tumor. Before imatinib, metastatic GIST was frustrating to treat due to its resistance to standard cytotoxic chemotherapy. Median survival for patients with metastatic GIST improved from 19 to 60 months with imatinib. In treating patients with GIST, two patterns of tyrosine kinase inhibitor resistance have been observed. In the first, ~9-14% of patients have progression within 3 months of starting imatinib. These patients are classified as having primary or early resistance. Median progression-free survival (PFS) on imatinib is approximately 24 months; patients with later progression are classified as having secondary or acquired resistance. Primary studies and a meta-analysis of studies of imatinib in GIST patients have identified prognostic features that contribute to treatment failure. One of the strongest predictors for success of therapy is KIT or PDGFRA mutational status. Patients with KIT exon 11 mutant GIST have better response rates, PFS, and overall survival compared to other mutations. A great deal has been learned in the last decade about sensitivity and resistance of GIST to imatinib; however, many unanswered questions remain about secondary resistance mechanisms and clinical management in the third- and fourth-line setting. This review will discuss the role of dose effects, and early and late resistance to imatinib and their clinical implications. Patients intolerant to imatinib (5%) and those who progress on imatinib are treated with sunitinib. The mechanism of resistance to sunitinib is unknown at this time but is also appears related to growth of clones with secondary mutations in KIT. Third- and fourth-line treatments of GIST and with future treatment strategies are also discussed.
小分子激酶抑制剂已经不可逆转地改变了癌症治疗。2010 年 3 月标志着伊马替尼在胃肠道间质瘤（GIST）中的应用 10 周年，这是此类靶向治疗在实体瘤中应用的一个重要范例。在伊马替尼之前，转移性 GIST 由于对标准细胞毒性化疗的耐药性而难以治疗。转移性 GIST 患者的中位生存期从使用伊马替尼前的 19 个月延长至 60 个月。在治疗 GIST 患者时，已经观察到两种酪氨酸激酶抑制剂耐药模式。在第一种模式中，约 9-14%的患者在开始伊马替尼治疗后 3 个月内出现进展。这些患者被归类为具有原发性或早期耐药性。伊马替尼的中位无进展生存期（PFS）约为 24 个月；随后进展的患者被归类为具有继发性或获得性耐药性。原发性研究和对 GIST 患者伊马替尼研究的荟萃分析已经确定了导致治疗失败的预后特征。治疗成功的最强预测因素之一是 KIT 或 PDGFRA 突变状态。与其他突变相比，KIT 外显子 11 突变的 GIST 患者具有更好的反应率、PFS 和总生存期。在过去的十年中，我们已经了解了 GIST 对伊马替尼的敏感性和耐药性；然而，关于继发性耐药机制和三线及四线治疗的临床管理仍有许多未解决的问题。本文将讨论伊马替尼的剂量效应、早期和晚期耐药及其临床意义。无法耐受伊马替尼（5%）和伊马替尼进展的患者用舒尼替尼治疗。目前尚不清楚舒尼替尼耐药的机制，但似乎也与 KIT 继发性突变克隆的生长有关。本文还讨论了 GIST 的三线和四线治疗以及未来的治疗策略。
