bezuclastinib (PLX9486)

The introduction of imatinib, a selective tyrosine kinase inhibitor (TKI), revolutionized the management of advanced GIST...Current approaches emphasize molecular subtype-guided first-line therapy, ctDNA-driven sequencing of subsequent lines, and the use of novel TKIs (e.g., avapritinib, ripretinib, bezuclastinib) tailored to specific resistance mutations. Furthermore, we explore emerging modalities such as boron neutron capture therapy (BNCT), which offers a kinase-independent mechanism to target resistant disease, and combination strategies that integrate immunotherapy, epigenetic modulators, and pathway-specific inhibitors. Advances in liquid biopsy and molecular profiling are enabling real-time adaptation of therapy, moving GIST management toward a dynamic, personalized paradigm aimed at overcoming resistance and improving patient outcomes.

P3, N=442, Active, not recruiting, Cogent Biosciences, Inc. | Trial primary completion date: Jul 2025 --> Sep 2025

P2, N=40, Active, not recruiting, Sarcoma Alliance for Research through Collaboration | Recruiting --> Active, not recruiting

P2, N=237, Active, not recruiting, Cogent Biosciences, Inc. | Trial primary completion date: Sep 2025 --> May 2025

Sunitinib, regorafenib, and ripretinib are currently approved as standard second-, third-, and fourth-line therapies, each demonstrating efficacy against distinct mutational profiles. Avapritinib, notably effective against PDGFRA D842V mutations, represents a milestone for previously untreatable subgroups. Several alternative agents-such as nilotinib, masitinib, sorafenib, dovitinib, pazopanib, and ponatinib-have shown varying degrees of success in refractory cases or specific genotypes. Investigational compounds, including crenolanib, bezuclastinib, famitinib, motesanib, midostaurin, IDRX-42, and olverembatinib, are under development to address resistant or wild-type GISTs...Future strategies include precision medicine approaches such as ctDNA-guided therapy, rational drug combinations, and novel drug delivery systems to optimize bioavailability and reduce toxicity. Ongoing research will be crucial for refining treatment sequencing and expanding therapeutic options, especially for rare GIST subtypes.

Despite the considerable therapeutic progress in recent years, systemic mastocytosis is an incurable disease. In the last 20 years, the management of systemic mastocytosis has transformed from a one-size-fits-all approach, characterized by nonspecific cytoreductive drugs, to a tailored strategy focused on increasingly precise molecular targets, with the most notable example being the KIT inhibitors. Recently, the FDA and EMA have approved two drugs for treating systemic mastocytosis: avapritinib and midostaurin. Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results.

P3, N=442, Active, not recruiting, Cogent Biosciences, Inc. | Recruiting --> Active, not recruiting

P=N/A, N=0, Available, Cogent Biosciences, Inc.

P=N/A, N=0, Available, Cogent Biosciences, Inc.

P1/2, N=51, Completed, Cogent Biosciences, Inc. | Phase classification: P1b --> P1/2

P2, N=207, Active, not recruiting, Cogent Biosciences, Inc. | Recruiting --> Active, not recruiting

P2, N=207, Recruiting, Cogent Biosciences, Inc. | N=138 --> 207