KIT K642E

P2, N=40, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P2, N=40, Recruiting, National Cancer Institute (NCI) | Initiation date: Sep 2023 --> Dec 2023

P2, N=40, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

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.

P2, N=40, Recruiting, National Cancer Institute (NCI) | Initiation date: Jun 2023 --> Sep 2023

P2, N=40, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Dec 2022 --> Jun 2023

This multicenter study highlights KIT-alterations sensitive to imatinib and augments evidence for imatinib in subsets of KIT-altered melanoma.

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.

AMs are uncommon tumors with dismal survival, usually occurring in the elderly in various gross and microscopic appearances. In terms of molecular profile, BRAF and KIT mutations are rarely detected. Profiling of larger cohorts is required to elucidate the pathogenesis and to identify potential molecular indicators that may contribute to the development of individualized targeted therapies.

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.

Patient was then started on nivolumab/ipilimumab with rapid progression on immunotherapy. He was found to have KIT mutation (exon 13K642EMT), and started on imatinib, but he continued to have progression. He was switched to temozolomide with no response...Lower expression of MS4A1/CD20 is known to be associated with poor prognosis in melanoma and other solid tumors.3 We demonstrated that a concurrent KIT mutation in melanoma with lower expression of MS4A1/CD20 contributes to poor prognosis in melanoma. Therefore, this small subset of aggressive tumors may need combination strategies involving targeting driver pathways with a kinase and immune checkpoint inhibitor.

Patient was then started on nivolumab/ipilimumab with rapid progression on immunotherapy. He was found to have KIT mutation (exon 13K642EMT), and started on imatinib, but he continued to have progression. He was switched to temozolomide with no response...Lower expression of MS4A1/CD20 is known to be associated with poor prognosis in melanoma and other solid tumors.3 We demonstrated that a concurrent KIT mutation in melanoma with lower expression of MS4A1/CD20 contributes to poor prognosis in melanoma. Therefore, this small subset of aggressive tumors may need combination strategies involving targeting driver pathways with a kinase and immune checkpoint inhibitor.