Anti-tumor efficacy of the novel KIT inhibitor IDRX-42 (formerly M4205) in patient- and cell line-derived xenograft models of gastrointestinal stromal tumor (GIST)

Background: The majority of GIST are driven by constitutively activated KIT/PDGFRA kinases and are susceptible to treatment with tyrosine kinase inhibitors. During treatment, most of these tumors will develop secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective KIT inhibitor with high activity towards the most relevant KIT mutations, in 4 GIST xenograft models.

Methods: NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT:p.K642E) and the cell-line derived model GIST882 (KIT:p.K642E). Mice were treated daily with vehicle (control), imatinib (100mg/kg), sunitinib (20mg/kg), avapritinib (5mg/kg), or IDRX-42 (10mg/kg, 25mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histological response and immunohistochemistry. The Kruskal-Wallis and Wilcoxon Matched Pairs tests were used for statistical analysis, with p<0.05 considered as significant.

Results: IDRX-42 (25mg/kg) caused tumor volume shrinkage in UZLX-GIST25, GIST882 and UZLX-GIST2B, with a relative decrease to 45.6%, 57.3% and 35.1% on the last day as compared to baseline, and tumor growth delay (160.9%) compared to control in UZLX-GIST9. Compared to controls, IDRX-42 (25mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2-4 HR with myxoid degeneration was observed in all IDRX-42 (25mg/kg)-treated tumors.

Conclusion: 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.

 

Comments:

The study described evaluated the efficacy of a novel selective KIT inhibitor called IDRX-42 in four different xenograft models of gastrointestinal stromal tumors (GIST). GISTs are typically driven by constitutively activated KIT or PDGFRA kinases, and while treatment with tyrosine kinase inhibitors (TKIs) is effective initially, the development of secondary mutations often leads to drug resistance.

In this study, patient-derived xenograft models (UZLX-GIST9, UZLX-GIST2B, and UZLX-GIST25) and a cell-line derived model (GIST882) were used. Each model had specific mutations in the KIT gene. NMRI nu/nu mice were transplanted with these GIST models and treated with different agents: vehicle (control), imatinib, sunitinib, avapritinib, or IDRX-42 at varying doses.

The efficacy of IDRX-42 was assessed based on tumor volume evolution, histopathology, grading of histological response, and immunohistochemistry. Statistical analysis was performed using the Kruskal-Wallis and Wilcoxon Matched Pairs tests.

The results showed that IDRX-42, particularly at a dose of 25mg/kg, caused tumor volume shrinkage in UZLX-GIST25, GIST882, and UZLX-GIST2B models. The relative decrease in tumor volume compared to baseline was 45.6%, 57.3%, and 35.1%, respectively, on the last day of treatment. In the UZLX-GIST9 model, IDRX-42 induced tumor growth delay of 160.9% compared to the control group. Treatment with IDRX-42 at 25mg/kg also resulted in a significant decrease in mitosis compared to the control group.

Furthermore, in the UZLX-GIST25 and GIST882 models, IDRX-42 induced histopathological changes characterized by grade 2-4 histological response (HR) with myxoid degeneration in all tumors treated with IDRX-42 at 25mg/kg.

In conclusion, IDRX-42 demonstrated significant antitumor activity in both patient-derived and cell line-derived xenograft models of GIST. The novel KIT inhibitor led to tumor volume shrinkage, reduced mitotic activity, and exhibited antiproliferative effects. Additionally, in models with a specific KIT exon 13 mutation, IDRX-42 induced characteristic myxoid degeneration. These findings suggest that IDRX-42 holds promise as a potential therapeutic option for GIST, especially in cases with specific KIT mutations.

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c-Kit PDGFR