KIT exon 13 mutation

55% (42/77) of liquid samples with a KIT -driver mutation had a co-occurring imatinib-resistant alteration, and a minority of cases harbored non- KIT mechanisms of resistance such as FGFR2 fusion, BRAF or EGFR alterations... Known driver and TKI-resistant mutations are identified in liquid biopsies of patients with GIST, with high concordance to tissue in the presence of elevated TF. Liquid biopsy may be valuable in the molecular classification of GIST during the medical management of advanced disease.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

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.

While KIT ATP-BP mutations were associated with clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of KIT mutations to predict the clinical benefit of second-line therapy in pts with advanced GIST. These data were presented in part at the Jan 2023 ASCO plenary session.

P2, N=48, Recruiting, University of Miami | Trial completion date: Jul 2028 --> Dec 2028 | Trial primary completion date: Jul 2026 --> Dec 2026

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.

This study represents a one of the most comprehensive analyses of the genomic landscape and integration of genomic features with clinicopathologic attributes and survival outcome in GIST.

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.

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.

IDRX-42 showed significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity and had antiproliferative effects. In models with KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.

In liquid, 58% (39/67) of samples with a KIT-driver mutation had a co-occurring imatinib-resistant KIT alteration... Known driver and TKI-resistant mutations of both somatic and potential germline origin are identified in peripheral blood ctDNA of GIST patients. Liquid biopsy shows high concordance to tissue in identifying driver mutations in the presence of elevated TF and may exhibit TKI-resistant specific alterations. This study indicates that liquid biopsy may be useful in the molecular classification of GIST during the medical management of advanced GIST patients.

Anlotinib showed moderate antitumor activity in drug-resistant GIST cell lines in vitro, and good PFS and better tolerance in second-line therapy study.

P2, N=48, Recruiting, University of Miami | Trial completion date: Apr 2028 --> Jul 2028 | Initiation date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2026 --> Jul 2026

P2, N=15, Completed, Grupo Espanol de Investigacion en Sarcomas | Recruiting --> Completed | N=39 --> 15

P2, N=48, Recruiting, University of Miami | Trial completion date: Jan 2028 --> Apr 2028 | Initiation date: Jan 2023 --> Apr 2023 | Trial primary completion date: Jan 2026 --> Apr 2026

P1/2, N=39, Completed, Asan Medical Center | Recruiting --> Completed

Ripretinib has acceptable tolerability, with the most common drug-related grade 3 or 4 adverse events being lipase increases, hypertension, fatigue and hypophosphataemia. Ripretinib is therefore a valuable additional line of therapy available for the management of gastrointestinal stromal tumours.

There remains a high unmet need for more effective and better tolerated second- and later-line treatments for patients with GIST. Phase 1/2 bezuclastinib data in advanced solid tumors, including GIST, were encouraging and support further clinical investigation of co-targeting the complementary conformational states of the same kinase with bezuclastinib and sunitinib. The Peak Study aims to assess the efficacy and safety of bezuclastinib in combination with sunitinib as second-line treatment in adult patients with imatinib-resistant, or intolerant, GIST.

Standard treatment for metastatic or unresectable GISTs includes tyrosine-kinase inhibitors (TKIs) such as imatinib as first-line therapy followed by sunitinib, regorafenib and ripretinib as second-, third- and fourth-line therapies, respectively (2). This case report is a microcosm of the latest GIST treatments. It provides the evidence that combination therapy of ripretinib with sunitinib or imatinib can be an efficacious therapeutic option for arresting GIST progression in selective patients, who are refractory to current standard therapies.

They also function as predictive markers for response to imatinib... Overall Ckit mutation rate was lower (73%) than reported in literature, thus concluding that incidence of ckit muta-tions could be lower in Indian population. Ckit exon 9 mutations had consistent duplication while deletions and substitutions were found in in exon 11. Exon 9 mutations guided treatment decisions.

P2, N=48, Recruiting, University of Miami | Not yet recruiting --> Recruiting

Mice were treated daily with vehicle (control), imatinib (100mg/kg), avapritinib (5mg/kg), sunitinib (20mg/kg), or M4205 (10mg/kg, 25mg/kg). Conclusions M4205 has significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induces volumetric responses, decreases mitotic activity, has antiproliferative effects and in models with KIT exon 13 mutation leads to characteristic myxoid degeneration.

These data confirm that c-KIT exon 11 mutations occur frequently in canine GISTs, and identify the presence of a PDGFRA mutation similar to human GISTs. This study also suggests a potential association of c-KIT mutation with more aggressive biological behavior.

Targeted NGS can simultaneously and efficiently detect nine GIST-related gene mutations and provide reference for clinicians' individualized diagnosis and treatment. Our results have important implications for clinical management.

P2, N=48, Not yet recruiting, University of Miami

Molecular detection is an indispensable technique for diagnosing cellular EMCs. The KIT mutations noted in this case report may offer fresh insights into EMCs treatment options.

Pts with KIT resistance mutations received 2L+ therapy with avapritinib, dose-escalated imatinib, nilotinib, pazopanib, ponatinib, regorafenib, ripretinib, or sunitinib. ctDNA is a noninvasive tool for detecting driver and resistance mutations in pts with advanced GIST. GIST pts with KIT exon 13 V654 resistance mutations had superior outcomes in the 2L+ setting with sunitinib. Regorafenib was not superior to other 2L+ TKIs in pts with KIT exon 17 resistance mutations, possibly due to their own activity against exon 17 resistance alterations.

Background: The majority of GISTs are driven by constitutively activated KIT/PDGFRA kinases and susceptible to treatment with tyrosine kinase inhibitors such as imatinib, sunitinib and regorafenib...Mice were treated daily with vehicle (control), imatinib (100mg/kg), avapritinib (5mg/kg), sunitinib (20mg/kg), or M4205 (10mg/kg, 25mg/kg)... M4205 has significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induces volumetric responses, decreases mitotic activity, has antiproliferative effects and in models with KIT exon 13 mutation leads to characteristic myxoid degeneration. * Cornillie et al.

Gene phenotypes of mucosal melanoma in different locations has differences. Lesions in the nasal cavity and paranasal sinus should be assessed separately from other parts such as the nasopharynx.

Herein, we report a patient presenting with a primary small bowel spindle cell GIST and concurrent peritoneal and liver metastases displaying an imatinib-sensitive KIT exon 11 in-frame deletion. We present the first report of a multi-drug resistant GIST patient who developed an FGFR2 gene fusion as a secondary genetic event to the selective pressure of various TKIs. This case also highlights the heterogeneous escape mechanisms to targeted therapy across various tumor nodules, spanning from both KIT-dependent and KIT-independent off-target activation pathways.

We demonstrated the mechanism by which KIT secondary mutations on exon 13/17 cause Imatinib resistance to GIST, and validated that several novel TKIs were valuable therapeutic options against Imatinib-resistance for both secondary- and primary-KIT mutations.

P2, N=122, Recruiting, First Affiliated Hospital of Zhejiang University | Not yet recruiting --> Recruiting

P1/2, N=41, Recruiting, Asan Medical Center | Trial completion date: Aug 2020 --> Aug 2022 | Trial primary completion date: Aug 2020 --> Aug 2022

P2, N=122, Not yet recruiting, First Affiliated Hospital of Zhejiang University

On the other hand, non-resectable or advanced stage GISTs display a good response to tyrosine kinase inhibitors (TKI) such as imatinib or sunitinib. Notably, 33.3% of our patients required a WT clinical approach even after the mutational analysis, increasing the use of first-line sunitinib. Future NGS studies on WT GISTs could reveal novel molecular alterations.

It is extremely rare to see giant congenital primary nodular MM in utero in neonates. The pathogenesis, treatment and prognosis of congenital MM need further research. The diagnosis mainly depends on histopathology and immunohistochemistry, and it needs to be differentiated from malignant lymphoma and primitive neuroectodermal tumor. The current treatment strategy for MM relies on the surgical excision of the mass. Research directed at molecular detection for genetic mutations would contribute to targeted therapy and better prognosis.

P2, N=39, Recruiting, Grupo Espanol de Investigacion en Sarcomas | Trial completion date: Nov 2020 --> Dec 2024 | Trial primary completion date: Nov 2020 --> Dec 2023