# Imatinib-resistant GIST

Source: https://onco.cc/cancers/gist-imatinib-resistant/  
OnCo record `gist-imatinib-resistant` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Imatinib-refractory GIST; GIST with secondary KIT mutations; Advanced GIST after imatinib; Multidrug-resistant GIST
- Tags: subtype-page
- Group: gastrointestinal
- Burden: 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.
- Subtypes: GIST with KIT exon 13 or 14 secondary mutation (ATP-binding pocket; sunitinib-sensitive); GIST with KIT exon 17 or 18 secondary mutation (activation loop; ripretinib, regorafenib); Polyclonal resistance with multiple secondary KIT mutations; Fourth-line GIST after imatinib, sunitinib and regorafenib (INVICTUS); Isolated progression on imatinib (local treatment)
- Biomarkers: Secondary KIT mutations by circulating tumour DNA (exons 13, 14, 17, 18); Primary KIT or PDGFRA mutation (exon 11 versus 9 versus D842V); Growth within a treated lesion on CT (nodule within a mass); Imatinib plasma level to exclude underdosing; Thyroid function and blood pressure on sunitinib and regorafenib

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/gist-imatinib-resistant/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/gist-imatinib-resistant/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/gist-imatinib-resistant/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/gist-imatinib-resistant/#finding-it [5 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/gist-imatinib-resistant/#treating-it [4 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/gist-imatinib-resistant/#evidence [5 trials, 4 key papers, 5 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/gist-imatinib-resistant/#science [4 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/gist-imatinib-resistant/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/gist-imatinib-resistant/#living-with-it [19 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/gist-imatinib-resistant/coming/ [7 medicines, 4 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/gist-imatinib-resistant/data/ [34 connected records]

## Standard of care

- 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. ([Imatinib](https://onco.cc/drugs/imatinib/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/), [KIT](https://onco.cc/targets/kit/))
- Second line: Sunitinib; ripretinib as an alternative, preferred where the secondary mutation is in exon 17 or 18 (INTRIGUE subgroup; INSIGHT ongoing). ([Sunitinib](https://onco.cc/drugs/sunitinib/), [Ripretinib](https://onco.cc/drugs/ripretinib/), [A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib](https://onco.cc/trials/nct03673501/), [INSIGHT](https://onco.cc/trials/insight-gist/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/))
- Third line: Regorafenib (GRID). ([Regorafenib](https://onco.cc/drugs/regorafenib/))
- Fourth line and beyond: Ripretinib (INVICTUS); imatinib rechallenge; trials of next-generation KIT inhibitors. ([Ripretinib](https://onco.cc/drugs/ripretinib/), [INVICTUS](https://onco.cc/trials/invictus/), [Imatinib](https://onco.cc/drugs/imatinib/), [IDRX-42](https://onco.cc/drugs/idrx-42/), [NB003](https://onco.cc/drugs/nb003/), [Bezuclastinib](https://onco.cc/drugs/bezuclastinib/))

## State of the art

- Four approved kinase inhibitors give sequential control, and continuing some KIT inhibition to the end is standard.
- Circulating tumour DNA genotyping is starting to choose the drug by the resistant clone rather than by line number.
- Broad-spectrum KIT inhibitors in development aim to make resistance a single problem rather than a moving target.

## Open problems

- Polyclonal resistance means no single inhibitor covers every metastasis.
- Each later line adds months, not years, and toxicity accumulates.
- Whether circulating tumour DNA-guided sequencing improves survival is unproven until INSIGHT reports.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Ripretinib
- INVICTUS (Lancet Oncology 2020): https://pubmed.ncbi.nlm.nih.gov/32511981/
- INTRIGUE (JCO 2022): https://pubmed.ncbi.nlm.nih.gov/35947817/
- Wikipedia: https://en.wikipedia.org/wiki/Ripretinib

## Connected records

- cancers: [Gastrointestinal stromal tumour (GIST)](https://onco.cc/cancers/gist/), [KIT exon 11-mutant GIST](https://onco.cc/cancers/gist-kit-exon-11/), [PDGFRA D842V-mutant GIST](https://onco.cc/cancers/gist-pdgfra-d842v/)
- trials: [A Study of IDRX-42 (GSK6042981) Versus (vs) Sunitinib in Participants With Gastrointestinal Stromal Tumors After Imatinib Therapy](https://onco.cc/trials/nct07218926/), [A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib](https://onco.cc/trials/nct03673501/), [GRID](https://onco.cc/trials/grid/), [INSIGHT](https://onco.cc/trials/insight-gist/), [INVICTUS](https://onco.cc/trials/invictus/)
- key papers: [GRID: regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib](https://onco.cc/key-papers/paper-grid-regorafenib-gist-lancet-2013/), [INTRIGUE: ripretinib versus sunitinib in advanced gastrointestinal stromal tumour after imatinib](https://onco.cc/key-papers/paper-intrigue-ripretinib-vs-sunitinib-jco-2022/), [INVICTUS: ripretinib in advanced gastrointestinal stromal tumours after three or more prior kinase inhibitors](https://onco.cc/key-papers/paper-invictus-ripretinib-lancet-oncol-2020/), [Sunitinib in advanced gastrointestinal stromal tumour after failure of imatinib](https://onco.cc/key-papers/paper-demetri-sunitinib-gist-lancet-2006/)
- targets: [KIT](https://onco.cc/targets/kit/)
- drugs: [Bezuclastinib](https://onco.cc/drugs/bezuclastinib/), [IDRX-42](https://onco.cc/drugs/idrx-42/), [Imatinib](https://onco.cc/drugs/imatinib/), [NB003](https://onco.cc/drugs/nb003/), [Regorafenib](https://onco.cc/drugs/regorafenib/), [Ripretinib](https://onco.cc/drugs/ripretinib/), [Sunitinib](https://onco.cc/drugs/sunitinib/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/)
- people: [Sebastian Bauer](https://onco.cc/people/sebastian-bauer/)
- terms: [GIST risk stratification (mitotic count, size, site; Miettinen and modified NIH criteria)](https://onco.cc/terms/gist-risk-stratification/), [SDH deficiency (SDHB immunohistochemistry loss)](https://onco.cc/terms/sdh-deficiency/)

---
JSON: https://onco.cc/api/v1/entities/gist-imatinib-resistant.json