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DRUG:

Augtyro (repotrectinib)

i
Other names: TPX-0005, TPX 0005, TPX0005, ZL-2308, BMS-986472, BMS986472, ZL2308, BMS 986472, ZL 2308
Company:
BMS, ZAI Lab
Drug class:
ALK inhibitor, Multi-tyrosine kinase inhibitor, ROS1 inhibitor, Trk inhibitor
Related drugs:
22d
Trial initiation date
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Augtyro (repotrectinib)
29d
Tissue-Agnostic Targeting of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals and Future Directions. (PubMed, Cancers (Basel))
Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases...More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective.
Review • Journal • Pan tumor
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NTRK (Neurotrophic receptor tyrosine kinase)
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NTRK fusion
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Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
1m
Repotrectinib: Redefining the therapeutic landscape for patients with ROS1 fusion-driven non-small cell lung cancer. (PubMed, Clin Transl Med)
The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.
Review • Journal
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ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ROS1 fusion • ROS1 positive • ROS1 rearrangement • ROS1 G2032R
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
1m
ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models. (PubMed, Cell Rep)
Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.
Preclinical • Journal
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NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase)
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NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • NTRK fusion
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Mekinist (trametinib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
2ms
Enrollment open
|
Augtyro (repotrectinib)
2ms
ROS1-rearranged non-small cell lung cancer: Understanding biology and optimizing management in the era of new approvals. (PubMed, Curr Probl Cancer)
Multiple tyrosine kinase inhibitors (TKIs) are now available for the effective treatment of ROS1-rearranged NSCLC in the metastatic setting including crizotinib, entrectinib, and repotrectinib as first-line therapy options. In addition, newer targeted therapies with increased selectivity for ROS1 over other targets are also emerging. As treatment of the disease continues to evolve, understanding the clinical course of patients with ROS1-rearranged NSCLC as well as the data supporting the latest therapy options is key to timely, effective, and longitudinal care.
Review • Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ROS1 rearrangement
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
3ms
Non-Small-Cell Lung Cancer Patients Harboring ROS1 Rearrangement: Real World Testing Practices, Characteristics and Treatment Patterns (ROS1REAL Study). (PubMed, Curr Oncol)
Central nervous system progression was noted in 20% and 25% of the crizotinib and entrectinib/repotrectinib cohorts, respectively. This multi-center study presents real-world treatment patterns of ROS1 NSCLC population, indicating that crizotinib exhibited comparable results to entrectinib/repotrectinib in a first-line setting, although both response rate and survival was numerically longer with treatment with newer agents.
Retrospective data • Journal • Real-world evidence • Real-world
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
3ms
Advances and future directions in ROS1 fusion-positive lung cancer. (PubMed, Oncologist)
The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.
Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
3ms
Pyrazolo[1,5-a]pyrimidine as a Prominent Framework for Tropomyosin Receptor Kinase (Trk) Inhibitors-Synthetic Strategies and SAR Insights. (PubMed, Molecules)
First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively...Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue...This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.
Review • Journal
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NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase)
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Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib) • selitrectinib (BAY 2731954)
3ms
TKI type switching overcomes ROS1 L2086F in ROS1 fusion-positive cancers. (PubMed, NPJ Precis Oncol)
Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib...While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Xospata (gilteritinib) • Cabometyx (cabozantinib tablet) • Augtyro (repotrectinib) • merestinib (LY2801653) • taletrectinib (AB-106)
3ms
L2086F Mutant ROS1-Rearranged NSCLC Resistant to Repotrectinib Responds to Cabozantinib: A Case Report. (PubMed, JTO Clin Res Rep)
Here, we report a case of a patient who was heavily pretreated, with advanced L1951R and L2026M mutated ROS1-rearranged NSCLC, who initially responded to repotrectinib but later developed further on-target resistance with the emergence of an L2086F mutation. The disease then responded to cabozantinib, a separate class of ROS1 TKI with preclinical activity against L2086F.
Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Cabometyx (cabozantinib tablet) • Augtyro (repotrectinib)
4ms
Nonsmall-cell lung cancer treatment: current status of drug repurposing and nanoparticle-based drug delivery systems. (PubMed, Turk J Biol)
First, the molecular mechanisms of Food and Drug Administration (FDA)-approved drugs for NSCLC, including ROS1 tyrosine kinase inhibitors (TKI) like repotrectinib, approved in November 2023, are detailed. Further, in vitro studies employing a combination strategy of drug repurposing and NP-based drug delivery systems as a treatment approach against NSCLC are listed. It includes the latest study on nanoparticle-based drug delivery systems loaded with repurposed drugs.
Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Augtyro (repotrectinib)
4ms
NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors. (PubMed, Acta Neuropathol Commun)
Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.
Journal
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TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • TERT (Telomerase Reverse Transcriptase) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • MDM4 (The mouse double minute 4) • TPM3 (Tropomyosin 3) • TFG (Trafficking From ER To Golgi Regulator) • FKBP15 (FKBP Prolyl Isomerase 15) • KANK1 (KN Motif And Ankyrin Repeat Domains 1) • NTRK (Neurotrophic receptor tyrosine kinase) • SPECC1L (Sperm Antigen With Calponin Homology And Coiled-Coil Domains 1 Like) • GKAP1 (G Kinase Anchoring Protein 1) • KIF5A (Kinesin Family Member 5A)
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carboplatin • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib) • thiotepa
4ms
New P1 trial
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Augtyro (repotrectinib)
5ms
Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents. (PubMed, Br J Cancer)
Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.
Journal
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NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase)
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Vitrakvi (larotrectinib) • Augtyro (repotrectinib) • zurletrectinib (ICP-723) • selitrectinib (BAY 2731954)
5ms
FDA Approval Summary: Repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer. (PubMed, Clin Cancer Res)
The most common (> 20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.
FDA event • Journal • Metastases
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
Augtyro (repotrectinib)
6ms
Enrollment open
|
Augtyro (repotrectinib)
7ms
New P1 trial
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Augtyro (repotrectinib)
8ms
New P2 trial
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
Augtyro (repotrectinib)
8ms
CRISPR/Cas9-edited ROS1 + non-small cell lung cancer cell lines highlight differential drug sensitivity in 2D vs 3D cultures while reflecting established resistance profiles. (PubMed, J Transl Med)
In this study we knock-in for the first time in a ROS1 + patient-derived cell line, three different known resistance-causing mutations using CRISPR/Cas9 in the endogenous translocated ROS1 alleles. Pharmacological assays performed in 2D and 3D cell culture revealed that spheroids are more sensitive to TKIs than cells cultured as a monolayer. This direct comparison between two culture systems could be done thanks to the implementation of normalized growth rates (NGR) to uniformly quantify drug response between 2D and 3D cell culture. Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations.
Preclinical • Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • SLC34A2 (Solute carrier family 34 member 2)
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ROS1 rearrangement • ROS1 G2032R • ROS1 S1986Y
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Augtyro (repotrectinib)
9ms
Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib. (PubMed, Acta Pharm Sin B)
The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.
Preclinical • Review • Journal
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NTRK (Neurotrophic receptor tyrosine kinase)
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Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib) • selitrectinib (BAY 2731954)
10ms
Repotrectinib in a Patient With NTRK Fusion-Positive Pancreatic Carcinoma and Congenital Long QT Syndrome. (PubMed, JCO Precis Oncol)
Repotrectinib in a patient with NTRK fusion-positive pancreatic carcinoma and congenital long QT syndrome.
Journal
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NTRK (Neurotrophic receptor tyrosine kinase)
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NTRK positive • NTRK fusion
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Augtyro (repotrectinib)
10ms
Repotrectinib: First Approval. (PubMed, Drugs)
In addition, preclinical investigation of repotrectinib in multiple myeloma is underway in the USA. This article summarizes the milestones in the development of repotrectinib leading to this first approval for the treatment of locally advanced or metastatic ROS1-positive NSCLC.
Review • Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)
|
ROS1 fusion • ROS1 positive
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Augtyro (repotrectinib)
10ms
Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 fusion • ROS1 positive
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Augtyro (repotrectinib)
10ms
A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations. (PubMed, Front Mol Biosci)
This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.
Journal
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ALK (Anaplastic lymphoma kinase)
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ALK positive • ALK rearrangement • ALK mutation • ALK F1174C • ALK F1174V
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Lorbrena (lorlatinib) • Augtyro (repotrectinib) • TPX-0131
10ms
Phase classification • Combination therapy • Metastases
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation
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Mekinist (trametinib) • Augtyro (repotrectinib)
10ms
Properties of FDA-approved small molecule protein kinase inhibitors: a 2024 update. (PubMed, Pharmacol Res)
Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis)...The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.
FDA event • Review • Journal
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HER-2 (Human epidermal growth factor receptor 2) • FLT3 (Fms-related tyrosine kinase 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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HER-2 positive • FLT3 mutation • ROS1 positive
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Vanflyta (quizartinib) • Torisel (temsirolimus) • Truqap (capivasertib) • Augtyro (repotrectinib) • Fruzaqla (fruquintinib) • Jaypirca (pirtobrutinib) • Cosela (trilaciclib) • Ojjaara (momelotinib) • tofacitinib • Litfulo (ritlecitinib)
10ms
Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. (PubMed, N Engl J Med)
Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).
Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 fusion • ROS1 positive • ROS1 G2032R
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Augtyro (repotrectinib)
10ms
ETV6::NTRK3 gene fusion in a patient with metastatic lung atypical carcinoid successfully treated with repotrectinib: A case report. (PubMed, Lung Cancer)
To the best of our knowledge, we reported the first case demonstrating anti-tumor activity of repotrectinib in a patient with AC carring an ETV6-NTRK3 gene fusion, indicating that repotrectinib may be an efficient therapeutic option for tumors with NTRK gene rearrangements.
Clinical • Observational data • Retrospective data • Review • Clinical Trial,Phase I • Clinical Trial,Phase II • Journal • Metastases
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NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • ETV6 (ETS Variant Transcription Factor 6) • NTRK (Neurotrophic receptor tyrosine kinase)
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NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • ETV6-NTRK3 fusion
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everolimus • Augtyro (repotrectinib) • VC004
11ms
Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • ROS1 fusion
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temozolomide • irinotecan • Augtyro (repotrectinib)
11ms
Enrollment open • Metastases
|
Xalkori (crizotinib) • Augtyro (repotrectinib)
11ms
Targeted therapy for pediatric central nervous system tumors harboring mutagenic tropomyosin receptor kinases. (PubMed, Front Oncol)
In 2017, first-generation TRK inhibitor (TRKi) larotrectinib was granted accelerated approval from the FDA, having demonstrated histologic-agnostic activity against NTRKs fusions tumors. Since this new era has begun, resistance to first-generation TRKi has been described and has opened the development of second-generation molecules, such as selitrectinib and repotrectinib. In this review, we provide a brief overview of the studies on NTRK alterations found in pediatric central nervous system tumors and first and second-generation TRKi useful in clinical practice.
Review • Journal
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NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase)
|
Vitrakvi (larotrectinib) • Augtyro (repotrectinib) • selitrectinib (BAY 2731954)
11ms
Oncogenic Fusions: Targeting NTRK. (PubMed, Crit Rev Oncol Hematol)
Presently, larotrectinib and entrectinib are the only FDA-approved therapies for NTRK-mutated cancers...The treatment landscape for NTRK cancers is still being explored, with numerous new tyrosine kinase inhibitors currently in development or undergoing phase 1 and 2 clinical trials. In this review, we delve into both established and novel therapies targeting NTRK-mutated NSCLC.
Review • Journal
|
NTRK (Neurotrophic receptor tyrosine kinase)
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
11ms
Targeted Therapy for Lung Cancer and Pancreatic Toxicity: Retrospective Study and Recommendations (MTCS 2023)
Crizotinib was the drug most frequently linked to EPE (38%), followed by lorlatinib (26%), ceritinib (12%), entrectinib (8%), dabrafenib/trametinib (6%), repotrectinib (6%) and brigatinib (3%). Despite frequent EPE after TKI introduction, clinical pancreatitis are rare. Based on these results, we conclude that no routine assessment of pancreatic enzyme is required when introducing TKI treatment. To our knowledge, this is the first retrospective study about EPE linked to TKI in NSLC.
Retrospective data
|
BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • NTRK (Neurotrophic receptor tyrosine kinase)
|
Mekinist (trametinib) • Xalkori (crizotinib) • Tafinlar (dabrafenib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • Augtyro (repotrectinib)
11ms
Comprehensive review of ROS1 tyrosine kinase inhibitors (TKIs)-classified by structural designs and mutation spectrum [solvent front mutation (G2032R) and central β-sheet 6 (Cβ6) mutation (L2086F)]. (PubMed, J Thorac Oncol)
Despite ROS1 fusion positive (ROS1+) NSCLC accounting approximately 1-2% of NSCLC, there is a dizzying list of ROS1 tyrosine kinase inhibitor (TKIs) being developed in addition to two approved ROS1 TKIs, crizotinib and entrectinib...Additionally, the less known central β-sheet 6 (Cβ6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target Cβ6 mutation.
Review • Journal
|
FLT3 (Fms-related tyrosine kinase 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 fusion • ROS1 positive • ROS1 G2032R • ROS1 L2086F
|
Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Xospata (gilteritinib) • Cabometyx (cabozantinib tablet) • Augtyro (repotrectinib) • taletrectinib (AB-106) • zidesamtinib (NVL-520)
12ms
Clinical • P1/2 data
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 fusion • ROS1 positive
|
Augtyro (repotrectinib)
12ms
Safety of current treatment options for NTRK fusion-positive cancers. (PubMed, Expert Opin Drug Saf)
The tropomyosin receptor kinase inhibitors (TRKi) larotrectinib and entrectinib are among the first agents with tissue agnostic FDA approvals for cancer treatment, and additional TRKi are undergoing development...There are numerous ongoing studies investigating TRKi as frontline, adjuvant, and salvage therapy. It will be critical to continue to gather long term safety data on the use of these agents, particularly in children.
Review • Journal
|
NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK positive • NTRK fusion
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
12ms
New P3 trial • Metastases
|
Xalkori (crizotinib) • Augtyro (repotrectinib)
12ms
Repotrectinib's Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer. (PubMed, Oncol Ther)
In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.
Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 positive • ROS1 rearrangement • ROS1 G2032R
|
Augtyro (repotrectinib)
1year
TRIDENT-1: A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (clinicaltrials.gov)
P1/2, N=500, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Dec 2024 --> Feb 2028 | Trial primary completion date: Jun 2024 --> Feb 2028
Trial completion date • Trial primary completion date • Metastases
|
ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)
|
NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • ROS1 fusion
|
Augtyro (repotrectinib) • midazolam hydrochloride