**8.3. Alternatives of imatinib in case of resistance or progression of disease with imatinib therapy**

Most patients with advanced GISTs will show improvement with imatinib therapy, although a subgroup of patients will fail to show a response. Resistance to imatinib may be primary or secondary. Primary resistance is defined as continuous growth or growth within 6 months of therapy, and occurs in 15–20% of patients with advanced GIST [109] and occurs frequently in patients with wild-type (WT) GIST or KIT exon 9 mutations or D842V mutation in PDGFRA exon 18 [110]. Unfortunately, most patients develop secondary resistance, which is defined as patients who received treatment with imatinib for longer than 6 months and had an initial response and then developed progressive disease. Secondary KIT mutations occur frequently in KIT exons 13, 14, and 17 and a D842V mutation in PDGFRA exon 18 [111–113].

If a patient develops resistance, escalating imatinib dosage to 800 mg daily or shifting to a second-line therapy like sunitinib may be recommended.

Sunitinib is considered a second-line therapy for patients with advanced GIST refractory to imatinib therapy. Outcomes of a randomized phase III trial versus placebo reported a prolongation of the time to progression from 1.5 to 6.3 months in patients with GIST who progressed on imatinib treatment [114]. It is approved by the EMA and the FDA for the treatment of patients with GIST resistant to imatinib therapy and for patients who are not tolerant to imatinib therapy.

In case of progression on imatinib and sunitinib, regorafenib is considered a third-line therapy [4]. It was recently approved by EMA and FDA for the treatment of patients with unresectable or metastatic GISTs who are resistant or intolerant to imatinib and sunitinib, and it was tested in a phase III randomized trial which included patients with advanced GIST who progressed after imatinib and sunitinib failed. The study reported that regorafenib, when compared to placebo, has significant improvement in PFS [115]. Inadequate data are available for the efficacy of other tyrosine kinase inhibitors (e.g., sorafenib, pazopanib, and ponatinib) for imatinib and sunitinib refractory GISTs [4].
