506 Phase (Ph) 1/2a study of TSR-011, a potent inhibitor of ALK and TRK, in advanced solid tumors including crizotinib-resistant ALK positive non-small cell lung cancer

Sachdev, Jasgit C.; Arkenau, Hendrick-Tobias; Infante, J. R.; Mita, Mitsuo; Anthony, S. P.; Natale, Ronald B.; Ejadi, Samuel; Wilcoxen, Keith; Kansra, Vikram; Laken, Haley; Hughes, Lindsey D.; Martell, R.; Weiss, Glen J.

doi:10.1016/s0959-8049(14)70632-x

Cited by 9 publications

(4 citation statements)

References 1 publication

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“…Currently, there are still some ALK inhibitors under clinical investigation, such as the pan-TKIs entrectinib, 31 belizatinib, 32 and repotrectinib, 33 which target oncogenic rearrangements in ALK, ROS, and tropomyosin receptor kinase (TRK). 34 Among them, entrectinib was approved for the treatment of TRK fusion solid tumors in 2019.…”

Section: Receptor Tyrosine Kinase Inhibitors Alk Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

852

490

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Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

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Section: Receptor Tyrosine Kinase Inhibitors Alk Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

852

490

View full text Add to dashboard Cite

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“…Two publications reported the baseline characteristics and study design of a Phase I/IIa open-label trial assessing the efficacy and safety of oral belizatinib in patients with advanced solid tumors and lymphomas (NCT02048488) [30,33]. Preliminary dose-finding results from these studies were published as an abstract in 2014 [36] and an update on the enrolled patients with an ALK + mutation was published in 2015 [42]. One publication reported on the efficacy of LOXO-195 in two patients with TRK-fusion-positive cancers who developed acquired resistance mutations to larotrectinib.…”

Section: Current Evidence For Other Treatmentsmentioning

confidence: 99%

Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy

et al. 2020

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Aim: To conduct a systematic review and meta-analysis feasibility of clinical, quality of life and economic evidence for neurotrophic tropomyosin-related receptor tyrosine kinases ( NTRK) inhibitors in patients with NTRK gene fusion-positive tumors. Materials & methods: Databases were searched for studies on NTRK inhibitors in adult and pediatric patients. Results: 27 publications reported clinical data for seven interventions. Efficacy/safety data were available for two interventions only. Four trials each reported data for larotrectinib and entrectinib with pooled analyses reporting objective response rates of 75% (95% CI: 61–85) and 57.4% (43.2–70.8), respectively. No publications reported economic or quality of life evidence. Conclusion: Preliminary data demonstrate that NTRK inhibitors are well tolerated and show impressive clinical benefit; corroboration of existing studies and real-world data are required.

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“…Finally, different substitutions were introduced to the 4-fluoro phenyl ring; however, these derivatives either decreased selectivity or suffered from compromised cellular activity against ALK . When 5-3 was screened against a kinase panel, 5-3 was found to have potent pan-TRK activity (IC 50 for TRKA/B/C < 0.003 μM) . Currently, 5-3 is under a Phase 1/2 study in patients with advanced solid tumors and lymphomas (NCT02048488).…”

Section: Trk Inhibitorsmentioning

confidence: 99%

“…152 When 5-3 was screened against a kinase panel, 5-3 was found to have potent pan-TRK activity (IC 50 for TRKA/B/C < 0.003 μM). 153 Currently, 5-3 is under a Phase 1/2 study in patients with advanced solid tumors and lymphomas (NCT02048488).…”

Section: ■ Trk Inhibitorsmentioning

confidence: 99%

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

et al. 2018

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The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.

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506 Phase (Ph) 1/2a study of TSR-011, a potent inhibitor of ALK and TRK, in advanced solid tumors including crizotinib-resistant ALK positive non-small cell lung cancer

Cited by 9 publications

References 1 publication

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

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