*Division of Hematology/Oncology, Northwestern University, Chicago, IL †Evidence Scientific Solutions, Part of UBC-Envision Group, Philadelphia, PA.
Am J Clin Oncol. 2014 Aug;37(4):417-22. doi: 10.1097/COC.0b013e31824be3d6.
Disease progression after treatment with a particular therapy, in the traditional view of cancer chemotherapy, indicates resistance to that treatment. However, targeted therapies such as tyrosine kinase inhibitors (TKIs) do not follow these same principles. The purpose of this review is to educate about TKI resistance and rechallenge in oncology, using the TKI imatinib in the treatment of gastrointestinal stromal tumor (GIST). True imatinib resistance does occur; however, in contrast to expectations with traditional chemotherapy, a number of instances of apparent imatinib resistance may not actually be true treatment resistance. For example, clinical evidence indicates that patients with metastatic or unresectable GIST that progressed after cessation of initial imatinib therapy who were rechallenged with imatinib achieved response or stable disease. Also, progression during imatinib treatment may be indicative of noncompliance or a need for dose increase rather than true resistance. The ability to rechallenge with a previously used therapy after progression on or after TKI therapy is relevant to both the adjuvant and the metastatic/advanced settings. Ongoing clinical trials, which are further examining imatinib rechallenge in combination with other agents in patients with GIST who have developed resistance to imatinib and/or another TKI, may impact the treatment paradigm for GIST.
在癌症化疗的传统观点中，治疗后疾病的进展表明对该治疗产生了耐药性。然而，像酪氨酸激酶抑制剂（TKIs）这样的靶向治疗并不遵循这些相同的原则。本综述的目的是通过使用治疗胃肠道间质瘤（GIST）的 TKI 伊马替尼来教育人们了解 TKI 耐药性和再挑战。确实会发生真正的伊马替尼耐药性；然而，与传统化疗的预期相反，许多看似伊马替尼耐药的情况实际上可能不是真正的治疗耐药。例如，临床证据表明，在初始伊马替尼治疗停止后进展的转移性或不可切除 GIST 患者，再次使用伊马替尼治疗可获得缓解或疾病稳定。此外，在伊马替尼治疗期间的进展可能表明不遵守规定或需要增加剂量，而不是真正的耐药性。在 TKI 治疗后进展时或之后能够用先前使用的治疗方法进行再挑战，这与辅助和转移性/晚期治疗都相关。正在进行的临床试验进一步研究了伊马替尼再挑战联合其他药物在对伊马替尼和/或另一种 TKI 产生耐药性的 GIST 患者中的应用，这可能会影响 GIST 的治疗模式。
