Ibtrozi (taletrectinib)

The following ten drugs received FDA approval in 2025 - avutometinib (inhibiting MEK1/2 in serous ovarian carcinomas), defactinib (blocking FAK in low grade serous ovarian carcinomas), delgocitinib (antagonizing the JAK family in hand eczema), mirdametinib (inhibiting MEK1/2 in type I neurofibromatosis), remibrutinib (blocking BTK in chronic spontaneous urticaria), rilzabrutinib (antagonizing BTK in chronic immune thrombocytopenia), sunvozertinib (blocking mutant exon 21 insertion EGFR NSCLC), taletrectinib (inhibiting mutant ROS1 in NSCLC), vimseltinib (blocking CSF1R in tenosynovial giant cell tumors), and zongertinib (antagonizing mutant HER2 in NSCLC). This article summarizes the physicochemical properties of all 94 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 45 of the 94 FDA-approved drugs have a least one Lipinski rule of five violation.

P2, N=14, Terminated, Nuvation Bio Inc. | N=40 --> 14 | Recruiting --> Terminated; The study was discontinued early by the Sponsor for business reasons on 06 Dec 2024

Current first-generation tyrosine kinase inhibitors (TKIs) such as crizotinib and entrectinib provide meaningful benefit but are limited by poor central nervous system (CNS) penetration and the development of resistance mutations, particularly G2032R. While its approval represents a significant advance for ROS1+ NSCLC, challenges remain, including resistance mechanisms such as L2086F, limited global access, and the absence of phase III confirmatory trials. Ongoing research into sequencing strategies, resistance profiling, and novel combination regimens will be essential to optimize patient outcomes.

First-generation tyrosine kinase inhibitors (TKIs) such as crizotinib displayed significant early reactions but faced challenges due to restricted central nervous system (CNS) penetration and mutation resistance, while entrectinib and larotrectinib expanded treatment options but also experienced resistance...Safety data shows an acceptable toxicity profile, mainly featuring gastrointestinal and hepatic adverse effects, with fewer neurocognitive side effects compared to lorlatinib...Current trials and regulatory activities in China, the U.S., and other locations demonstrate taletrectinib's growing clinical significance. Taletrectinib's well-rounded pharmacological attributes of systemic action, intracranial effectiveness, resistance range, and tolerability render it an intriguing enhancement to the framework of precision oncology.

Crizotinib first demonstrated substantial clinical benefit, but its limitations, including poor central nervous system (CNS) penetration and acquired resistance, highlighted the need for next-generation inhibitors. Several agents have since been developed, including entrectinib, lorlatinib, repotrectinib, taletrectinib, and zidesamtinib, each offering improved intracranial (IC) activity and efficacy against resistance mutations, notably ROS1^G2032R. Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape.

Findings show that taletrectinib has a promising anticancer impact, good CNS penetration, and a solid safety record, especially in patients with brain metastases. These results imply that ROS1-positive cancers may benefit from taletrectinib as a treatment.

P2, N=217, Active, not recruiting, Nuvation Bio Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jun 2027 --> Dec 2027

P=N/A, N=50, Not yet recruiting, Innovent Biologics (Suzhou) Co. Ltd.

Systemic SAEs exhibited greater variability across agents, ranging from 29% to 47%: crizotinib, 43% (95% CI, 36%-49%); ceritinib, 41% (95% CI, 37%-45%); lorlatinib, 39% (95% CI, 25%-55%); entrectinib, 32% (95% CI, 28%-36%); repotrectinib, 29% (95% CI, 24%-33%); iruplinalkib, 44% (95% CI, 38%-50%); and unecritinib, 47% (95% CI, 38%-56%)...Taletrectinib and unecritinib were notably associated with hepatotoxicity...These findings will guide drug selection and safety monitoring, emphasizing the necessity of considering patients' health status, potential risk factors, and the characteristics of ROS1-TKI-related adverse reactions. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024551353, identifier CRD42024551353.

P3, N=180, Recruiting, Nuvation Bio Inc.