Imatinib-resistant GIST

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.

Ripretinib, a switch-control inhibitor that locks KIT in the inactive conformation regardless of the secondary mutation, was tested fourth line in INVICTUS (Lancet Oncology 2020): median progression-free survival rose from 1.0 to 6.3 months and overall survival from 6.6 to 15.1 months, and the FDA approved it in May 2020. In INTRIGUE it was not superior to sunitinib in the second line overall, but patients with exon 11 primary and exon 17 or 18 secondary mutations did better on ripretinib and those with exon 13 or 14 mutations better on sunitinib, so the INSIGHT trial now tests mutation-directed choice, the first prospective genotype-guided sequencing in GIST. Next-generation KIT inhibitors, IDRX-42, NB003 and bezuclastinib with sunitinib, aim to cover all the secondary mutations at once.