Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line-Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST).

PURPOSE: The majority of gastrointestinal stromal tumors (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 toward the most relevant KIT mutations, in 4 GIST xenograft models. EXPERIMENTAL DESIGN: 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 (100 mg/kg), sunitinib (20 mg/kg), avapritinib (5 mg/kg), or IDRX-42 (10 mg/kg, 25 mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histologic response, and IHC. The Kruskal-Wallis and Wilcoxon matched-pairs tests were used for statistical analysis, with P < 0.05 considered as significant. RESULTS: IDRX-42 (25 mg/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 with baseline, and tumor growth delay (160.9%) compared with control in UZLX-GIST9. Compared with controls, IDRX-42 (25 mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2-4 histologic response with myxoid degeneration was observed in all IDRX-42 (25 mg/kg)-treated tumors. CONCLUSIONS: 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.

Management of Synovial Sarcoma in a Tertiary Referral Center: A Retrospective Analysis of 134 Patients.

BACKGROUND: Synovial sarcomas (SS) are malignant mesenchymal neoplasms that account for about 10% of all sarcomas. Complete surgical excision is the mainstay of primary treatment for localized disease, but SS have a high tendency for local relapse and metastases. Metastatic disease is commonly treated with systemic chemotherapy. METHODS: We designed a retrospective analysis to describe the clinical presentation, course of treatment, outcome, and prognosis of patients with SS. Univariate and multivariate analyses were performed for potential prognostic factors. RESULTS: We identified 134 patients treated between 1987 and 2018, with a cutoff date of December 2018. Demographics, disease characteristics, treatment, and survival rates were collected and analyzed. The median overall survival (mOS) from the date of diagnosis was 96.7 months. The median progression-free survival was 6.37 months. Disease-free survival was 26 months. Age over 65 years was found to be a prognostic factor with statistically significant value in the univariate analysis regarding mOS (p = 0.015) and mOS after local relapse (p = 0.0228). CONCLUSIONS: Even though our study is limited by the retrospective nature of the analysis, it adds an important amount of clinical data regarding the treatment and outcome of SS.