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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.
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.
Almost every patient with metastatic GIST eventually progresses on imatinib, most within two to three years, through secondary mutations in KIT; three further kinase inhibitors are approved for this stage, each adding months rather than years.
Squamous cancers sit in the upper and middle oesophagus, adenocarcinomas at the junction and in the stomach; the stomach wall also gives rise to GIST from its pacemaker cells.
Same organ: Gastric & gastro-oesophageal junction cancer, HER2-positive gastric cancer, Claudin 18.2-positive gastric cancer, PD-L1-high gastric cancer, Microsatellite-unstable (MSI-high) gastric cancer, Early gastric cancer, Oesophageal squamous cell carcinoma, Oesophageal and junctional adenocarcinoma, Oesophageal cancer, Gastrointestinal stromal tumour (GIST), KIT exon 11-mutant GIST, PDGFRA D842V-mutant GIST
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Also on OnCo: Symptoms and red flags · Early detection roadmap.
Confirm adherence and plasma level; dose escalation to 800 mg (especially exon 9); local therapy for isolated progression while continuing imatinib.
Sunitinib; ripretinib as an alternative, preferred where the secondary mutation is in exon 17 or 18 (INTRIGUE subgroup; INSIGHT ongoing).
Ripretinib (INVICTUS); imatinib rechallenge; trials of next-generation KIT inhibitors.
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Sunitinib remains the standard second-line treatment, with ripretinib as a better-tolerated alternative, and mutation-guided choice by circulating tumour DNA is being tested prospectively in INSIGHT.
Ripretinib is the approved fourth-line treatment for GIST and is being tested earlier in mutation-selected patients (INSIGHT).
Regorafenib is the standard third-line treatment for GIST after imatinib and sunitinib.
Sunitinib is the standard second-line kinase inhibitor for GIST, with particular activity against KIT exon 9 and exon 13/14 secondary mutations.
Query for this cancer: (TITLE:"Imatinib-resistant GIST" OR ABSTRACT:"Imatinib-resistant GIST" OR TITLE:"Imatinib-refractory GIST" OR ABSTRACT:"Imatinib-refractory GIST" OR TITLE:"GIST with secondary KIT mutations" OR ABSTRACT:"GIST with secondary KIT mutations" OR TITLE:"Advanced GIST after imatinib" OR ABSTRACT:"Advanced GIST after imatinib" OR TITLE:"Multidrug-resistant GIST" OR ABSTRACT:"Multidrug-resistant GIST") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Imatinib-resistant GIST, not a curated reading list.
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Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Take with a meal and a large glass of water.
Take with a low-fat breakfast (under 30% fat).
Avoid grapefruit.
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
See all on the product pages:ImatinibRegorafenibRipretinibSunitinib·Printable cards in the navigator
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