# 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

## 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

- 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/)
- trials: [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/), [INVICTUS](https://onco.cc/trials/invictus/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/)
- cancers: [Gastrointestinal stromal tumour (GIST)](https://onco.cc/cancers/gist/)

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