Understanding rechallenge and resistance in the tyrosine kinase inhibitor era: Imatinib in gastrointestinal stromal tumor

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.