NTRK fusion

The best TRK inhibitor 5c had IC50 values of 0.75 and 0.96 nM against TRKAG595R and TRKAG667C, showing better potency than drugs larotrectinib (approximately 87- and 46-fold improvement) and selitrectinib (approximately 10- and 13-fold improvement). More importantly, 5c demonstrated favorable in vivo pharmacokinetic properties and antitumor efficacy (tumor growth inhibition (TGI) of 91% at 30 mg/kg and 115% at 60 mg/kg with 4 of 6 partial regression) in a BaF3-TMP3-TRKAG667C xenograft mouse model, which is greatly superior to that of selitrectinib (TGI of 2% at 30 mg/kg). Compound 5c exhibits significant potential to overcome clinical acquired multiple resistance to TRK inhibitors.

Targeted tyrosine kinase inhibitors (TKIs) have transformed GIST management, with imatinib as the foundational first-line therapy and subsequent agents, sunitinib, regorafenib, avapritinib, and ripretinib, addressing primary or secondary resistance driven by diverse mutational patterns. Emerging therapeutic directions include next-generation kinase inhibitors, heat shock protein inhibitors, immunotherapy, metabolic and epigenetic targeting, and biomarker-driven individualized treatment strategies. This review synthesizes contemporary advances in the histopathological, molecular, and therapeutic landscape of GISTs, emphasizing an integrated diagnostic approach and highlighting ongoing efforts to overcome therapeutic resistance and optimize personalized care.

P1/2, N=42, Recruiting, Cullgen (Shanghai),Inc

The rarity of patients with NTRK gene fusion-positive cancer and number of eligible CGDBs/clinical sites present challenges for the identification of sufficient RWD sources that can be used in comparative effectiveness studies to contextualize results from single-arm trials. This approach provides a potential solution to identify fit-for-purpose RWD to support precision medicine for patients with cancer harboring rare genomic alterations.

These results support the use of repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116 .

This case highlights the role of TPR::NTRK1 fusion in driving abnormal melanocyte proliferation and the potential contribution of MCL1 amplification to tumor progression. These findings provide insights into the genetic underpinnings of APN in CMN and suggest potential therapeutic targets for high-risk lesions.

Larotrectinib evoked broad and durable antitumor activity in a plethora of solid tumors with NTRK fusions. Safety profile was consistent with that of clinical trials, even after long-term administration. While NGS use is increasing, broader access is needed.

P1, N=21, Not yet recruiting, Shanghai Tongji Hospital, Tongji University School of Medicine

P2, N=52, Not yet recruiting, West China Hospital of Sichuan University; West China Hospital of Sichuan University

P1/2, N=120, Recruiting, Shanghai East Hospital; Novatim Immune Therapeutics (Zhejiang) Co., Ltd.

P1, N=48, Not yet recruiting, West China Hospital of Sichuan University; West China Hospital of Sichuan University

P1, N=500, Not yet recruiting, Sun Yat-sen University Cancer Center; Sichuan Baili Pharmaceutical Co., Ltd.