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DRUG:

Rozlytrek (entrectinib)

i
Other names: RXDX-101, NMS-E628, RXDX101, RXDX 101, NMS E628, RG6268, RG 6268, NMSE628, RG-6268
Company:
Nerviano Medical Sciences, Roche
Drug class:
ALK inhibitor, TrkB receptor inhibitor, TrkC kinase inhibitor, TrkA receptor inhibitor, ROS1 inhibitor, JAK2 inhibitor, TNK2 inhibitor
Related drugs:
5d
Young-Onset, ROS1-Rearranged Adenocarcinoma of the Lung With Cardiac Tamponade: A Case Report. (PubMed, Cureus)
Oral administration of entrectinib was highly effective, and his serum carcinoembryonic antigen (CEA) level improved from 247 to 10.8 ng/mL. The present case has clinical significance because a pathological and genetic diagnosis was made from the pericardial effusion fluid, and the clinical manifestations of cardiac tamponade due to lung cancer were well controlled by the administration of entrectinib.
Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CEACAM5 (CEA Cell Adhesion Molecule 5)
|
ROS1 rearrangement
|
Rozlytrek (entrectinib)
5d
New trial • Real-world evidence • Real-world • Metastases
|
Xalkori (crizotinib) • Rozlytrek (entrectinib)
6d
Entrectinib versus crizotinib in Asian patients with ROS1-positive non-small cell lung cancer: A matching-adjusted indirect comparison. (PubMed, Lung Cancer)
The outcomes in this MAIC study including Asian patients with ROS1-positive NSCLC showed a trend for greater clinical benefit with entrectinib versus crizotinib. These findings may contribute to better-informed treatment decisions.
Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 positive
|
Xalkori (crizotinib) • Rozlytrek (entrectinib)
6d
New P2 trial
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • cisplatin • Tagrisso (osimertinib) • Tecentriq (atezolizumab) • Ibrance (palbociclib) • Zelboraf (vemurafenib) • Imfinzi (durvalumab) • gemcitabine • Rozlytrek (entrectinib) • imatinib • 5-fluorouracil • Tyvyt (sintilimab) • Alecensa (alectinib) • Nerlynx (neratinib) • Loqtorzi (toripalimab-tpzi) • AiRuiKa (camrelizumab) • Tevimbra (tislelizumab-jsgr) • Irene (pyrotinib) • Balversa (erdafitinib) • albumin-bound paclitaxel • irinotecan • Orpathys (savolitinib) • epirubicin • vinorelbine tartrate • Partruvix (pamiparib) • Epkinly (epcoritamab-bysp) • Enweida (envafolimab) • Hetronifly (serplulimab) • Vumon (teniposide) • Ariely (adebrelimab)
9d
Redefining pancreatic cancer management with tumor-agnostic precision medicine. (PubMed, Carcinogenesis)
Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.
Journal • BRCA Biomarker • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Pan tumor
|
HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • RET (Ret Proto-Oncogene) • FGFR2 (Fibroblast growth factor receptor 2) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase)
|
TP53 mutation • KRAS mutation • BRCA2 mutation • BRCA1 mutation • MSI-H/dMMR • KRAS G12C • HER-2 overexpression • BRAF mutation • BRAF V600 • RET fusion • FGFR2 mutation • FGFR2 fusion • ALK fusion • NRG1 fusion • KRAS G12 • NTRK positive • NTRK fusion
|
Keytruda (pembrolizumab) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Jemperli (dostarlimab-gxly) • Augtyro (repotrectinib)
23d
Targeted Therapy in Salivary Gland Cancer: Prevalence of a Selected Panel of Actionable Molecular Alterations in a German Tertiary Referral Center Patient Cohort. (PubMed, Mol Diagn Ther)
Our data indicate that targeted therapy using e.g., trastuzumab deruxtecan, bicalutamide, pembrolizumab, cetuximab, entrectinib or sacituzumab govitecan might be a promising option especially for a relevant subset of patients with RM-SGC not suitable for salvage surgery. However, evidence from clinical studies regarding response rates to these therapies remains sparse, which underlines the need of multicenter clinical trials.
Journal • PD(L)-1 Biomarker • IO biomarker
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • AR (Androgen receptor) • NTRK (Neurotrophic receptor tyrosine kinase) • TACSTD2 (Tumor Associated Calcium Signal Transducer 2)
|
HER-2 overexpression • HER-2 amplification • HER-2 expression • EGFR overexpression • TROP2 overexpression • HER-2 elevation • NTRK1 translocation
|
Keytruda (pembrolizumab) • Erbitux (cetuximab) • Rozlytrek (entrectinib) • Enhertu (fam-trastuzumab deruxtecan-nxki) • Trodelvy (sacituzumab govitecan-hziy) • bicalutamide
23d
Enrollment closed
|
BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden)
|
Avastin (bevacizumab) • cisplatin • Tecentriq (atezolizumab) • Zelboraf (vemurafenib) • carboplatin • gemcitabine • Rozlytrek (entrectinib) • docetaxel • Alecensa (alectinib) • Cotellic (cobimetinib) • pemetrexed • divarasib (RG6330)
29d
Gene-expression profile analysis to disclose diagnostics and therapeutics biomarkers for thyroid carcinoma. (PubMed, Comput Biol Chem)
Then we detected 6 repurposable drug molecules (Entrectinib, Imatinib, Ponatinib, Sorafenib, Retevmo, and Pazopanib) by molecular docking with KGs-mediated receptor proteins, ADME/T analysis, and cross-validation with the independent receptors. Therefore, these findings might be useful resources for wet lab researchers and clinicians to consider an effective treatment strategy against THCA.
Journal • Gene Expression Profile
|
TOP2A (DNA topoisomerase 2-alpha) • TIMP1 (Tissue inhibitor of metalloproteinases 1) • RUNX2 (RUNX Family Transcription Factor 2)
|
KIM1 expression • TIMP1 expression
|
sorafenib • Rozlytrek (entrectinib) • imatinib • Iclusig (ponatinib) • pazopanib • Retevmo (selpercatinib)
1m
Targeted and cytotoxic inhibitors used in the treatment of lung cancers. (PubMed, Pharmacol Res)
On the order of 20% of NSCLCs bear activating mutations in EGFR and are treated with osimertinib and other kinase antagonists...Local treatment options to control thoracic disease include radiotherapy and surgery. In patients with extensive-stage disease, a platinum agent (cisplatin or carboplatin) combined with etoposide and an anti-PDL1 inhibitor (atezolizumab or durvalumab) for four cycles followed by anti-PDL1 maintenance therapy is the recommended first-line regimen.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
|
EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
|
EGFR mutation • BRAF mutation • ALK translocation
|
Mekinist (trametinib) • cisplatin • Tagrisso (osimertinib) • Tecentriq (atezolizumab) • Tafinlar (dabrafenib) • carboplatin • Imfinzi (durvalumab) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Retevmo (selpercatinib) • pemetrexed • etoposide IV • Tabrecta (capmatinib)
1m
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
|
NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK fusion
|
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
|
ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 fusion • ROS1 positive • ROS1 rearrangement • ROS1 G2032R
|
Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
2ms
Response to Crizotinib After Entrectinib Resistance in ROS1-Rearranged, MET-Amplified Lung Adenocarcinoma. (PubMed, JCO Precis Oncol)
Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.
Journal
|
MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
MET amplification • ROS1 rearrangement • ROS1 amplification
|
Xalkori (crizotinib) • Rozlytrek (entrectinib)
2ms
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
|
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 • NTRK fusion
|
Mekinist (trametinib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
2ms
Real-Life Experience with Entrectinib in Neurotrophic Tyrosine Receptor Kinase Fusion-Positive Solid Tumors: A Multicenter Retrospective Trial. (PubMed, Target Oncol)
In this retrospective study, we aimed to obtain real-world data concerning the use of entrectinib in patients with solid tumors harboring NTRK fusion genes. Although our findings are partially similar to the results of clinical studies, prospective studies in larger patient groups with more diverse tumor types and different demographic characteristics are needed to confirm the findings.
Retrospective data • Journal
|
NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK positive • NTRK fusion
|
Rozlytrek (entrectinib)
2ms
TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer (clinicaltrials.gov)
P2, N=3791, Recruiting, American Society of Clinical Oncology | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Jun 2026
Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases
|
BRAF (B-raf proto-oncogene)
|
FoundationOne® CDx
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Lynparza (olaparib) • Tecentriq (atezolizumab) • Yervoy (ipilimumab) • Ibrance (palbociclib) • Zelboraf (vemurafenib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • sunitinib • Perjeta (pertuzumab) • Cotellic (cobimetinib) • Talzenna (talazoparib) • Verzenio (abemaciclib) • Stivarga (regorafenib) • Lytgobi (futibatinib) • Tukysa (tucatinib) • Torisel (temsirolimus) • Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf)
2ms
Current Landscape of NTRK Inhibition for Pediatric CNS Tumors. (PubMed, CNS Drugs)
The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.
Journal
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NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK positive • NTRK fusion
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)
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
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 rearrangement
|
Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
2ms
Unusual presentation of ROS1 rearranged metastatic non-small cell lung cancer. (PubMed, Respir Med Case Rep)
The patient was ultimately diagnosed with ROS1 rearranged lung adenocarcinoma and achieved a dramatic response with entrectinib. This case highlights the variable presentation of non-small cell lung cancer (NSCLC) and the importance of comprehensive molecular testing for newly diagnosed metastatic NSCLC.
Journal • Metastases
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
ROS1 rearrangement
|
Rozlytrek (entrectinib)
3ms
Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-type Non-Small Cell Lung Cancer. (PubMed, Cancer Res)
Notably, suppression of the NTRK1 pathway by knockdown or Entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models...RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating crosstalk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcomes immunotherapy resistance in NTRK1 wild-type NSCLC patients.
Journal • Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker
|
NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • NTRK (Neurotrophic receptor tyrosine kinase)
|
Rozlytrek (entrectinib)
3ms
Identification of STAM-binding protein as a target for the treatment of gemcitabine resistance pancreatic cancer in a nutrient-poor microenvironment. (PubMed, Cell Death Dis)
Pancreatic cancer (PC) is a highly malignant solid tumor whose resistance to gemcitabine (GEM) chemotherapy is a major cause of poor patient prognosis. High-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified the FDA drug entrectinib as a potent GEM sensitizer and STAMBP inhibitor, augmenting the antitumor effect of GEM in a patient-derived xenograft (PDX) model. Overall, we established a novel mechanism, via the STAMBP-E2F1-PDK1 axis, by which PC cells become chemoresistant in a nutrient-poor tumor microenvironment.
Journal
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E2F1 (E2F transcription factor 1)
|
gemcitabine • Rozlytrek (entrectinib)
3ms
Identification of Hub of the Hub-Genes From Different Individual Studies for Early Diagnosis, Prognosis, and Therapies of Breast Cancer. (PubMed, Bioinform Biol Insights)
Finally, we suggested hHubGs-guided top-ranked 10 candidate drug molecules (SORAFENIB, AMG-900, CHEMBL1765740, ENTRECTINIB, MK-6592, YM201636, masitinib, GSK2126458, TG-02, and PAZOPANIB) by molecular docking analysis for the treatment against BC. The literature review also supported our findings much more for BC compared with the results of individual studies. Therefore, the findings of this study may be useful resources for early diagnosis, prognosis, and therapies of BC.
Journal
|
EGFR (Epidermal growth factor receptor) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • CCND1 (Cyclin D1) • TOP2A (DNA topoisomerase 2-alpha) • CCNA2 (Cyclin A2) • CDK1 (Cyclin-dependent kinase 1) • CCNB1 (Cyclin B1)
|
sorafenib • Rozlytrek (entrectinib) • pazopanib • omipalisib (GSK2126458) • AMG 900 • zotiraciclib (TG02) • Kinaction (masitinib)
3ms
Long-Term Tumor Stability After First-Line Treatment With Larotrectinib in an Infant With NTRK2 Fusion-Positive High-Grade Glioma. (PubMed, J Natl Compr Canc Netw)
Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.
Journal
|
ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK2 fusion • ALK fusion • ROS1 fusion • MET fusion • NTRK positive • NTRK fusion
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)
3ms
DELINOR: A Study to Learn About the Effectiveness of Cancer Medicines in Patients With Metastatic Non-small Cell Lung Cancer in Norway. (clinicaltrials.gov)
P=N/A, N=1, Completed, Pfizer | Recruiting --> Completed | N=20605 --> 1 | Trial completion date: Feb 2025 --> Jan 2024 | Trial primary completion date: Feb 2025 --> Jan 2024
Trial completion • Enrollment change • Trial completion date • Trial primary completion date • Metastases
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Avastin (bevacizumab) • Xalkori (crizotinib) • Tagrisso (osimertinib) • Tecentriq (atezolizumab) • erlotinib • Gilotrif (afatinib) • carboplatin • gefitinib • Rozlytrek (entrectinib) • paclitaxel • docetaxel • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Alunbrig (brigatinib) • Vizimpro (dacomitinib)
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
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
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
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
Xalkori (crizotinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)
3ms
CRAFT: Entrectinib as a Single Agent in Upfront Therapy for Children <3 Years of Age With NTRK1/2/3 or ROS1-FUSED CNS Tumors (clinicaltrials.gov)
P2, N=52, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting
Enrollment open
|
carboplatin • Rozlytrek (entrectinib) • cyclophosphamide • etoposide IV • Neulasta (pegfilgrastim) • Neupogen (filgrastim)
4ms
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&lsqb;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 &lsqb;1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.
Review • Journal
|
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) • Rozlytrek (entrectinib) • Augtyro (repotrectinib) • selitrectinib (BAY 2731954)
4ms
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
|
FLT3 (Fms-related tyrosine kinase 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Xospata (gilteritinib) • Cabometyx (cabozantinib tablet) • Augtyro (repotrectinib) • merestinib (LY2801653) • taletrectinib (AB-106)
4ms
Identification of Key Genes and Signaling Pathways in Entrectinibresistant Non-small Cell Lung Cancer Using Bioinformatic Analysis and Experimental Verification. (PubMed, Curr Med Chem)
We have identified core genes associated with non-small cell resistance to entrectinib, including CHI3L2, ZEB2, and S100A12. ZEB2 is a core gene associated with acquired resistance to entetinib in NSCLC.
Journal
|
CELF2 (CUGBP Elav-Like Family Member 2) • PDK4 (Pyruvate Dehydrogenase Kinase 4) • MIR1293 (MicroRNA 1293) • SEMA5A (semaphorin 5A) • ZEB2 (Zinc Finger E-Box Binding Homeobox 2) • S100A12 (S100 Calcium Binding Protein A12)
|
Rozlytrek (entrectinib)
4ms
KOSMOS-II: KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II (clinicaltrials.gov)
P=N/A, N=1000, Recruiting, Seoul National University Bundang Hospital | Trial completion date: Sep 2025 --> Mar 2027 | Trial primary completion date: Sep 2025 --> Sep 2026
Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases
|
Avastin (bevacizumab) • Herceptin (trastuzumab) • Tecentriq (atezolizumab) • erlotinib • Zelboraf (vemurafenib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Perjeta (pertuzumab) • Kadcyla (ado-trastuzumab emtansine) • Gavreto (pralsetinib)
4ms
The landscape of cancer-associated transcript fusions in adult brain tumors: a longitudinal assessment in 140 patients with cerebral gliomas and brain metastases. (PubMed, Front Oncol)
This study provides data on the incidence of NTRK gene fusions in brain tumors, which could strongly support the relevance of innovative clinical trials with specific targeted therapies (larotrectinib, entrectinib) in this population of patients. FGFR3 (17)::TACC3 (11) rearrangement was detected in breast carcinoma BM with the possibility of using some specific targeted therapies and TMPRSS (2)::ERG (4) rearrangements occur in a subset of patients with, prostatic carcinoma BM, endometrium BM, and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted, where there are yet no approved ERG-directed therapies.
Journal
|
EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR3 (Fibroblast growth factor receptor 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • TACC3 (Transforming acidic coiled-coil containing protein 3) • ETV6 (ETS Variant Transcription Factor 6) • NTRK (Neurotrophic receptor tyrosine kinase)
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)
4ms
New P2 trial
|
carboplatin • Rozlytrek (entrectinib) • cyclophosphamide • etoposide IV • Neulasta (pegfilgrastim) • Neupogen (filgrastim)
4ms
TRKing down drug resistance in NTRK fusion-positive cancers†. (PubMed, J Pathol)
Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents.
Journal
|
NF2 (Neurofibromin 2) • NTRK (Neurotrophic receptor tyrosine kinase)
|
Rozlytrek (entrectinib)
4ms
Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development. (PubMed, Cancers (Basel))
Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017...Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting...Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.
Review • Journal • Tumor mutational burden • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Pan tumor
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HER-2 (Human epidermal growth factor receptor 2) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
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Keytruda (pembrolizumab) • Mekinist (trametinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Enhertu (fam-trastuzumab deruxtecan-nxki) • Retevmo (selpercatinib) • Jemperli (dostarlimab-gxly)
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Discovery of novel indazole derivatives as second-generation TRK inhibitors. (PubMed, Eur J Med Chem)
NTRK fusion-positive cancers can be treated with the first-generation TRK inhibitors, larotrectinib and entrectinib...And the inhibitory effect against TRKAG667C (IC50 = 9.9 nM) was better than that of selitrectinib (IC50 = 113.1 nM). Further, compound B31 exhibited moderate kinase selectivity and excellent plasma stability (t1/2 > 480 min). In vivo pharmacokinetic studies in Sprague-Dawley rats showed that B31 had acceptable pharmacokinetic properties.
Journal
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NTRK (Neurotrophic receptor tyrosine kinase)
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Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • selitrectinib (BAY 2731954)
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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
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Discovery of a first-in-class protein degrader for the c-ros oncogene 1 (ROS1). (PubMed, Bioorg Chem)
The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.
Journal
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CD74 (CD74 Molecule) • SLC34A2 (Solute carrier family 34 member 2) • SDC4 (Syndecan 4)
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • taletrectinib (AB-106)
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Efficacy and safety of NTRK inhibitors in patients with NTRK fusion-positive lung and thyroid cancers. (PubMed, Clin Adv Hematol Oncol)
Larotrectinib and entrectinib also produce robust and durable responses in NTRK fusion-positive thyroid cancer that is refractory to radioactive iodine. Second-generation TRK inhibitors that have been designed to overcome acquired resistance are under investigation.
Review • Journal • IO biomarker
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NTRK (Neurotrophic receptor tyrosine kinase)
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Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)
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Clinical characteristics and treatment patterns of patients with NTRK fusion-positive solid tumors: A multisite cohort study at US academic cancer centers. (PubMed, J Manag Care Spec Pharm)
Currently, there are 2 US Food and Drug Administration-approved targeted therapies for NTRK gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies. This study reports on contemporary real-world NTRK testing patterns and use of TRKis in solid tumors, including time between NTRK testing and initiation of TRKi therapy and duration of TRKi therapy.
Retrospective data • 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)
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New P2 trial • Metastases
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Mekinist (trametinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • sorafenib • Rozlytrek (entrectinib) • Focus V (anlotinib) • everolimus • Lenvima (lenvatinib) • AiTan (rivoceranib) • Cabometyx (cabozantinib tablet) • Gavreto (pralsetinib) • Caprelsa (vandetanib) • Zepsun (donafenib)
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Current status of gene panel testing in our department and a case report (JBCS 2024)
Gemcitabine+Carboplatin therapy was administered while waiting for the test results to come out, and it was highly effective. In such a situation, for patients with NTRK fusion genes, which are companion diagnostics for Entrectinib, and PALB2 gene mutations, which are suggested to be sensitive to Olaparib, early use of CGP testing contributes to improving prognosis, so the significance of early implementation of CGP testing is also being questioned. In one case experienced in our department, it is possible that better Carboplatin response and Olaparib sensitivity could have been maintained if CGP had been performed early
Clinical • Case report • PARP Biomarker • BRCA Biomarker • BRCA Companion diagnostic • PARP Companion diagnostic
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • BRCA2 (Breast cancer 2, early onset) • PALB2 (Partner and localizer of BRCA2) • NTRK (Neurotrophic receptor tyrosine kinase)
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BRACAnalysis CDx™ • FoundationOne® Liquid CDx
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Lynparza (olaparib) • carboplatin • gemcitabine • Rozlytrek (entrectinib)