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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
Imatinib-resistant GIST is disease that has grown through the first drug, usually because the tumour has acquired a second KIT mutation that imatinib cannot block. Sunitinib, regorafenib and ripretinib are given in turn; ripretinib, in the INVICTUS trial, extended progression-free survival from 1 to 6 months in patients who had exhausted the other three.
Primary resistance to imatinib, progression within six months, is rare in KIT exon 11 disease and mostly seen in PDGFRA D842V and KIT or PDGFRA wild-type tumours. Secondary resistance is the rule in metastatic disease: after a median of around two years, clones with a second KIT mutation emerge, either in the ATP-binding pocket encoded by exons 13 and 14 or in the activation loop encoded by exons 17 and 18, and different metastases often carry different mutations. Tissue biopsy of one lesion therefore under-represents the disease, and circulating tumour DNA has become the way to map the resistant clones. Isolated progression in a single lesion can be treated with surgery, ablation or embolisation while imatinib continues.
Sunitinib, which inhibits KIT, PDGFRA and VEGF receptors, was approved in 2006 after a placebo-controlled trial in which it extended time to progression from 6 to 27 weeks; it works best against exon 13 and 14 secondary mutations and poorly against activation loop mutations. Regorafenib followed in 2013 after the GRID trial, extending progression-free survival from 0.9 to 4.8 months in the third line. Imatinib rechallenge (RIGHT) and continuation beyond progression slow growth because sensitive clones persist. Toxicity, hand-foot skin reaction, hypertension, fatigue and hypothyroidism, accumulates through the sequence.
| Setting | Approach | Guideline |
|---|---|---|
| Progression on imatinib 400 mg | Confirm adherence and plasma level; dose escalation to 800 mg (especially exon 9); local therapy for isolated progression while continuing imatinib. | not mapped |
| Second line | Sunitinib; ripretinib as an alternative, preferred where the secondary mutation is in exon 17 or 18 (INTRIGUE subgroup; INSIGHT ongoing). | not mapped |
| Third line | Regorafenib (GRID). | not mapped |
| Fourth line and beyond | Ripretinib (INVICTUS); imatinib rechallenge; trials of next-generation KIT inhibitors. | not mapped |