PDGFRA D842V

P2, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Dec 2025 --> Jun 2026

APB and encorafenib (ECB as the internal standard) were separated using an isocratic mobile phase approach on an Agilent SB-C18 (reversed-phase) column. The metabolic stability characteristics including the intrinsic clearance and the in vitro half-life of APB were determined to be 22.11 mL min-1 kg-1 and 36.67 min, respectively. In silico analysis suggests that minor structural changes to the methyl pyrazole moiety in drug design may improve the metabolic stability and safety relative to APB.

In advanced or metastatic disease, standard care involves sequential treatment with tyrosine kinase inhibitors, including imatinib, sunitinib, and regorafenib. The expanding range of targeted therapies, such as avapritinib for the PDGFRA D842V mutation, underscores the importance of molecular profiling in guiding optimal treatment strategies. This review aims to summarize current knowledge on the diagnosis and treatment of GIST, with a focus on the role of molecular-genetic profiling, the therapeutic value of individual tyrosine kinase inhibitors, and emerging options for advanced disease, with particular emphasis on ripretinib.

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.

It covers the role of tyrosine kinase inhibitors (TKIs), specifically imatinib, and further treatment options, such as sunitinib, regorafenib, and ripretinib, as well as avapritinib for platelet-derived growth factor receptor alpha D842V mutations. In addition, this review emphasizes individualized treatment strategies within multidisciplinary expert teams, including surgery and other locoregional therapies, together with the importance of mutation-guided approaches, particularly for wild-type GISTs. Finally, it explores the potential of next-generation KIT inhibitors, combination therapies, and other investigational approaches.

Avapritinib extends PFS and OS among patients with PDGFRA D842V-mutant GIST in real-world practice, mirroring pivotal trial outcomes. Its substantial activity supports its use as a first-line therapy for this subgroup. The manageable safety profile reinforces avapritinib viability for routine use. Given the rarity of these cases, it is advised to consult sarcoma-expert units.

Regorafenib was introduced but failed immediately owing to tumor penetration. Although based on a single case, this report demonstrates a significant metabolic response to pimitespib in PDGFRA-mutant GIST. More cases are required to fully elucidate the efficacy of this therapy against such rare tumors.

P2, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2025 --> Dec 2025 | Trial primary completion date: Jul 2025 --> Dec 2025

P1, N=9, Terminated, Blueprint Medicines Corporation | N=67 --> 9 | Trial completion date: Dec 2025 --> Mar 2025 | Active, not recruiting --> Terminated; Terminated - alignment of strategic priorities

P1, N=67, Active, not recruiting, Blueprint Medicines Corporation | Recruiting --> Active, not recruiting | Phase classification: P1/2 --> P1 | Trial completion date: Nov 2029 --> Dec 2025 | Trial primary completion date: Nov 2029 --> Jan 2025

In this cohort study of patients with PDGFRA-mutant GISTs, the D842V-mutant GISTs were associated with an overall lower [18F]FDG uptake compared with other GIST subgroups. Therefore, the role of functional imaging with [18F]FDG-PET in this subset of GISTs may be limited and should be further explored for its potential prognostic and predictive value.

One model is characterized by a primary, imatinib-resistant PDGFRA exon 18 p.D842V mutation. Our established platform of well-characterized GIST PDX models, covering the most relevant driver mutations, serves as an excellent tool for preclinical drug testing and tumor biology studies.