KIT exon 9 mutation

Baseline body composition parameters, particularly myosteatosis, effectively predict the adverse events and DFS in patients taking imatinib. Personalized treatment, such as targeted nutritional and exercise interventions, and close monitoring of patients with myosteatosis or sarcopenia can enhance compliance and improve survival rates.

90Y-SIRT is a potent treatment for patients with liver metastases of GIST resistant to TKI therapy. In patients with 'q-wt' GIST, SIRT is an option for first-line use.

Molecular testing revealed a KIT exon 9 mutation and CDKN2A/B gene alterations, indicating aggressive tumor behavior and resistance to standard treatment. This case underscores the importance of recognizing atypical metastatic sites in GIST.

The SC formulation also significantly reduced tumor volumes and demonstrated dose-dependent histological responses, nearly eradicating tumor tissue in 11 days with the highest dose. These findings suggest that the SC slow-release formulation maintains stable drug concentrations during treatment, potentially improving therapeutic efficacy at the target site.

Moreover, mutations in Kit exon 9 and 11 are actionable, due to their response to imatinib, while mutations in PDGFRA respond to sunitinib and/or avapritinib. This allows the clinician to have an accurate picture of the genetic changes of the tumor over time. In this work, we aimed to discuss the implications of mutational testing in clinical outcomes, the methods to test ctDNA and the future challenges in the establishment of alternatives of personalized medicine.

P2, N=23, Active, not recruiting, Asan Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2024

Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ³4 line settings.

Our results suggest that short read NGS-based assays may miss a significant number of clinically actionable KIT variants, and that follow-up of KIT and PDGFRA NGS-negative cases by alternative testing modalities should be considered.

As sunitinib and regorafenib are only effective against certain secondary mutations, ripretinib can broadly inhibit a wide range of primary and secondary KIT mutations. The proportion of secondary mutations in KIT Exon 11 primary mutations is significantly higher than that in KIT Exon 9 primary mutations following progression on first-line imatinib treatment. Furthermore, the main resistance mechanism of KIT Exon 11 mutant GISTs continues to rely on complex secondary mutations in KIT signaling. Differences in resistance mechanisms among various primary mutations imply that subsequent treatment should take into account both the patient 's primary and resistance mutations.

uPARAP is highly expressed in several GIST xenograft models across multiple passages of ex-mouse tumors. Considering its preferential expression in GIST and other mesenchymal tumors and the recycling character of this molecular target, uPARAP may serve as a powerful emerging target for systemic treatment of GIST beyond traditional kinase inhibitors or in combination with the latter. uPARAP positive xenograft models can be used for in vivo evaluation of such anti-uPARAP treatment.

Different KIT mutation types and signaling pathways atlerations were detected in progression samples of KIT-mutant GISTs after avapritinib or ripretinib failure compared with baseline, which may be associated with mechanism of resistance.

Approximately 70% and 77% of patients develop secondary resistance to first-line imatinib or at least three lines of treatment. The prevalence of secondary mutations among patients with primary exon 11 mutations seemes higher than those with exon 9 mutations. Ripretinib demonstrated promising mPFS and mOS benefit for patients with both primary and secondary KIT mutations, which was numerically superior to previously reported mPFS for sunitinib and regorafenib in patients with any secondary mutations.