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DRUG:

Rozlytrek (entrectinib)

News alerts, weekly reports and conference planners

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:

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ETV6::NTRK3 Fusion-Positive Wild-Type Gastrointestinal Stromal Tumor (GIST) with Abundant Lymphoid Infiltration (TILs and Tertiary Lymphoid Structures): A Report on a New Case with Therapeutic Implications and a Literature Review. (PubMed, Int J Mol Sci)

The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered...The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.

1 day ago

Clinical • Observational data • Retrospective data • Review • Journal • IO biomarker • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • ETV6 (ETS Variant Transcription Factor 6) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • TFG (Trafficking From ER To Golgi Regulator) • NTRK (Neurotrophic receptor tyrosine kinase) • ANO1 (Anoctamin 1)

NTRK3 fusion • RB1 mutation • PDGFRA mutation • NTRK3 positive • NTRK fusion

Rozlytrek (entrectinib)

Acquired NF2 mutation confers resistance to TRK inhibition in an ex vivo LMNA::NTRK1-rearranged soft-tissue sarcoma cell model. (PubMed, J Pathol)

Drug synergy was seen using trametinib and rapamycin in combination with entrectinib.

5 days ago

Preclinical • Journal

NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NF2 (Neurofibromin 2) • LMNA (Lamin A/C) • NTRK (Neurotrophic receptor tyrosine kinase)

NF2 mutation • NTRK fusion

Mekinist (trametinib) • Rozlytrek (entrectinib) • sirolimus

10d

BFAST: A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)

P2/3, N=1000, Recruiting, Hoffmann-La Roche | Trial completion date: Apr 2024 --> Aug 2028 | Trial primary completion date: Apr 2024 --> Aug 2028

10 days ago

Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases

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)

11d

ETV6-NTRK2 Fusion in a Patient With Metastatic Pulmonary Atypical Carcinoid Successfully Treated With Entrectinib: A Case Report and Review of the Literature. (PubMed, Clin Lung Cancer)

After pursuing other alternative treatments, including chemotherapy (ie, carboplatin, etoposide, capecitabine, temozolomide, and paclitaxel), everolimus, and atezolizumab, she returned with significant progression, including innumerable subcutaneous nodules, left pleura metastasis, multiple bone metastases, and brain metastases. To date, she has maintained sustained benefit for at least 1 year from initiation of entrectinib. Here, we present the first case of a female patient with metastatic AC harboring the ETV6-NTRK2 fusion, and successfully treated with entrectinib, providing evidence for the application of entrectinib in patients with NTRK-positive AC, and underscoring the critical role of molecular profiling for such cases.

11 days ago

Review • Journal • PD(L)-1 Biomarker • Metastases

NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • ETV6 (ETS Variant Transcription Factor 6) • SSTR (Somatostatin Receptor) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK2 fusion • ETV6-NTRK2 fusion • NTRK positive • SSTR Expression

Tecentriq (atezolizumab) • carboplatin • Rozlytrek (entrectinib) • paclitaxel • everolimus • temozolomide • capecitabine • etoposide IV

17d

Lung adenocarcinoma patients with ROS1-rearranged tumors by sex and smoking intensity. (PubMed, Heliyon)

Among patients who exhibited resistance to crizotinib, follow-up treatment of entrectinib and lorlatinib showed remarkable survival benefits. Newer-generation ALK/ROS1-targeted drugs showed efficacy in a cohort of crizotinib resistant ROS1 + patients. These results, when validated, could assist efficiently accruing ROS1 + patients.

17 days ago

Journal

ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)

ROS1 rearrangement

Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib)

25d

If it's a target, it's a pan-cancer target: Tissue is not the issue. (PubMed, Cancer Treat Rev)

Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.

25 days ago

Review • Journal • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • Pan tumor

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • RET (Ret Proto-Oncogene) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • FGFR1 (Fibroblast growth factor receptor 1) • NRG1 (Neuregulin 1) • BRCA (Breast cancer early onset) • NTRK (Neurotrophic receptor tyrosine kinase)

BRAF V600E • TMB-H • KRAS G12C • BRAF V600 • RET fusion • KRAS G12 • NTRK fusion

Keytruda (pembrolizumab) • Mekinist (trametinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Retevmo (selpercatinib) • Jemperli (dostarlimab-gxly) • Pemazyre (pemigatinib)

27d

NAUTIKA1: A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer (clinicaltrials.gov)

P2, N=146, Recruiting, Genentech, Inc. | N=85 --> 146

27 days ago

Enrollment change

PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • 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)

PD-L1 expression • KRAS mutation • KRAS G12C • BRAF mutation • BRAF V600 • NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • RET fusion • ALK fusion • RET mutation • ROS1 fusion • KRAS G12 • ALK-ROS1 fusion

Tecentriq (atezolizumab) • Zelboraf (vemurafenib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Cotellic (cobimetinib) • Gavreto (pralsetinib) • divarasib (RG6330)

Entrectinib in Combination With ASTX727 for the Treatment of Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia (clinicaltrials.gov)

P1, N=12, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Oct 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

1 month ago

Trial completion date • Trial primary completion date • Combination therapy

TP53 (Tumor protein P53) • RUNX1 (RUNX Family Transcription Factor 1) • MAPK1 (Mitogen-activated protein kinase 1) • NTRK (Neurotrophic receptor tyrosine kinase) • MAPK3 (Mitogen-Activated Protein Kinase 3)

TP53 mutation • NTRK expression

Rozlytrek (entrectinib) • Inqovi (decitabine/cedazuridine)

NAUTIKA1: A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer (clinicaltrials.gov)

P2, N=85, Recruiting, Genentech, Inc. | Trial primary completion date: Mar 2024 --> Dec 2025

1 month ago

Trial primary completion date

Tecentriq (atezolizumab) • Zelboraf (vemurafenib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Cotellic (cobimetinib) • Gavreto (pralsetinib) • divarasib (RG6330)

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.

1 month ago

Preclinical • Journal

ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • SLC34A2 (Solute carrier family 34 member 2)

ROS1 rearrangement • ROS1 G2032R • ROS1 S1986Y

Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • Augtyro (repotrectinib)

MyTACTIC: A Study Evaluating Targeted Therapies in Participants Who Have Advanced Solid Tumors With Genomic Alterations or Protein Expression Patterns Predictive of Response (clinicaltrials.gov)

P2, N=252, Completed, Genentech, Inc. | Active, not recruiting --> Completed

1 month ago

Trial completion • Tumor mutational burden • Metastases

Tecentriq (atezolizumab) • Rozlytrek (entrectinib) • paclitaxel • docetaxel • Alecensa (alectinib) • Perjeta (pertuzumab) • Kadcyla (ado-trastuzumab emtansine) • capecitabine • Gavreto (pralsetinib) • Tukysa (tucatinib) • ipatasertib (RG7440) • inavolisib (GDC-0077) • Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) • tiragolumab (RG6058)

Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup? (PubMed, Front Oncol)

Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7). Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to "new drugs" continue to be a challenge in LMICs.

1 month ago

Journal • PD(L)-1 Biomarker • Next-generation sequencing

BRAF (B-raf proto-oncogene) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NTRK (Neurotrophic receptor tyrosine kinase) • STAT6 (Signal transducer and activator of transcription 6) • NAB2 (NGFI-A Binding Protein 2)

BRAF mutation • BRAF K601E • BRAF G469A • BRAF K601

TruSight RNA Pan-Cancer Panel

Keytruda (pembrolizumab) • Mekinist (trametinib) • Tafinlar (dabrafenib) • Rozlytrek (entrectinib)

Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer. (PubMed, NPJ Precis Oncol)

Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

1 month ago

Journal

RET (Ret Proto-Oncogene) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • EML4 (EMAP Like 4) • ETV6 (ETS Variant Transcription Factor 6) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK3 fusion • ALK fusion • RET mutation • ETV6-NTRK3 G623R

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Retevmo (selpercatinib) • Gavreto (pralsetinib)

2ms

Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) PRIME Trial (clinicaltrials.gov)

P1, N=2, Terminated, OHSU Knight Cancer Institute | Active, not recruiting --> Terminated; Low accrual

2 months ago

Trial termination

Keytruda (pembrolizumab) • Opdivo (nivolumab) • Avastin (bevacizumab) • Venclexta (venetoclax) • Lynparza (olaparib) • Mekinist (trametinib) • erlotinib • Gilotrif (afatinib) • Yervoy (ipilimumab) • Ibrance (palbociclib) • dasatinib • Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • carboplatin • Imfinzi (durvalumab) • sorafenib • Rozlytrek (entrectinib) • imatinib • Sutent (sunitinib) • everolimus • Nerlynx (neratinib) • Iclusig (ponatinib) • Kadcyla (ado-trastuzumab emtansine) • Cotellic (cobimetinib) • Lorbrena (lorlatinib) • Lenvima (lenvatinib) • bortezomib • doxorubicin hydrochloride • capecitabine • Verzenio (abemaciclib) • Xtandi (enzalutamide capsule) • Cabometyx (cabozantinib tablet) • albumin-bound paclitaxel • Stivarga (regorafenib) • abiraterone acetate • oxaliplatin • Aliqopa (copanlisib) • Vizimpro (dacomitinib) • Zydelig (idelalisib) • daunorubicin • Zolinza (vorinostat) • Idhifa (enasidenib) • Farydak (panobinostat) • Erivedge (vismodegib) • Nubeqa (darolutamide) • bicalutamide • leucovorin calcium • cabazitaxel • Vesanoid (tretinoin) • fluorouracil topical

2ms

IMPRESS-Norway: Improving Public Cancer Care by Implementing Precision Medicine in Norway (clinicaltrials.gov)

P2, N=3000, Recruiting, Oslo University Hospital | N=1000 --> 3000

2 months ago

Enrollment change

Avastin (bevacizumab) • Herceptin (trastuzumab) • Tecentriq (atezolizumab) • Zelboraf (vemurafenib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Perjeta (pertuzumab) • Zejula (niraparib) • Zykadia (ceritinib) • Jemperli (dostarlimab-gxly) • Erivedge (vismodegib) • Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf)

2ms

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer. (PubMed, Clin Chem)

This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

2 months ago

Journal

MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CD74 (CD74 Molecule) • SLC34A2 (Solute carrier family 34 member 2)

MET amplification • ROS1 fusion • ROS1 positive • ROS1 G2032R • ROS1 mutation

Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib)

2ms

STARTRK-NG: Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options (clinicaltrials.gov)

P1/2, N=69, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Mar 2023 --> Jun 2025

2 months ago

Trial primary completion date • 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)

NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • ROS1 fusion

Rozlytrek (entrectinib)

2ms

A novel EML4-NTRK3 fusion in lung adenocarcinoma with dramatic response to entrectinib. (PubMed, J Cancer Res Ther)

Despite the rare occurrence, these alterations have gained importance owing to approval of drugs like entrectinib and larotrectinib targeting the kinase domain of the gene. Detection of these rests on the use of conventional modalities like Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH); however, accurate characterization requires direct sequencing methods. We report an interesting case of an NTRK fusion-positive NSCLC, exhibiting good response to entrectinib.

2 months ago

Journal

NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • EML4 (EMAP Like 4) • ETV6 (ETS Variant Transcription Factor 6) • SQSTM1 (Sequestosome 1) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK1 fusion • NTRK3 fusion • SQSTM1-NTRK1 fusion • EML4-NTRK3 fusion • NTRK positive • NTRK fusion

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)

2ms

DETERMINE Trial Treatment Arm 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers. (clinicaltrials.gov)

P2/3, N=30, Recruiting, Cancer Research UK | Initiation date: Dec 2023 --> Jun 2024

2 months ago

Trial initiation date

ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)

ROS1 fusion • ROS1 positive

Rozlytrek (entrectinib)

2ms

From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis. (PubMed, Front Pharmacol)

Our analysis provides a broad molecular view of the NTRK family. The real-world adverse drug event analysis of entrectinib and larotrectinib contributes to more refined medication management.

2 months ago

Journal • Adverse events • Real-world evidence • BRCA Biomarker • Real-world

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) • BRCA (Breast cancer early onset) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK expression • NTRK fusion

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)

2ms

Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations. (PubMed, J Pathol)

2 months ago

Journal

EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • CD34 (CD34 molecule) • NTRK (Neurotrophic receptor tyrosine kinase) • CAPZA2 (Capping Actin Protein Of Muscle Z-Line Subunit Alpha 2) • WWP2 (WW Domain Containing E3 Ubiquitin Protein Ligase 2)

EGFR mutation • BRAF mutation • MET fusion • BRAF mutation + EGFR mutation

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Retevmo (selpercatinib)

2ms

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.

2 months ago

Preclinical • Review • Journal

NTRK (Neurotrophic receptor tyrosine kinase)

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib) • selitrectinib (BAY 2731954)

3ms

Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors. (PubMed, Bioorg Med Chem)

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

3 months ago

Journal

NTRK (Neurotrophic receptor tyrosine kinase)

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)

3ms

Tyrosine Kinase Inhibitors for Radioactive Iodine Refractory Differentiated Thyroid Cancer. (PubMed, Life (Basel))

Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway.

3 months ago

Review • Journal • IO biomarker

BRAF (B-raf proto-oncogene) • RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)

BRAF V600E • BRAF V600 • RET fusion • NTRK fusion

Mekinist (trametinib) • Tafinlar (dabrafenib) • sorafenib • Rozlytrek (entrectinib) • Lenvima (lenvatinib) • Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Gavreto (pralsetinib)

3ms

SMMART Adaptive Clinical Treatment (ACT) Trial (clinicaltrials.gov)

P1, N=0, Withdrawn, OHSU Knight Cancer Institute | N=25 --> 0 | Not yet recruiting --> Withdrawn

3 months ago

Enrollment change • Trial withdrawal

HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)

BRCA2 mutation • BRCA1 mutation • HR positive • HER-2 negative • EGFR positive

Avastin (bevacizumab) • Herceptin (trastuzumab) • Lynparza (olaparib) • Tecentriq (atezolizumab) • Ibrance (palbociclib) • Zelboraf (vemurafenib) • carboplatin • Rozlytrek (entrectinib) • Alecensa (alectinib) • Kadcyla (ado-trastuzumab emtansine) • Cotellic (cobimetinib) • capecitabine • Piqray (alpelisib) • Zejula (niraparib) • albumin-bound paclitaxel • fulvestrant • irinotecan • Halaven (eribulin mesylate) • letrozole • vinorelbine tartrate • Herzuma (trastuzumab-pkrb) • anastrozole • Erivedge (vismodegib) • Trazimera (trastuzumab-qyyp) • Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf)

3ms

Taletrectinib for the treatment of ROS-1 positive non-small cell lung cancer: a drug evaluation of phase I and II data. (PubMed, Expert Opin Investig Drugs)

While crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC), unmet needs remain. Taltrectinib has the potential to improve PFS based on its greater potency against ROS1+ tumors and high CNS penetration. By selectively inhibiting ROS1 wild-type and its resistant mutations over TRKB, taltrectinib has a better safety profile with minimal CNS-related AEs compared to other ROS1+ inhibitors.

3 months ago

P1 data • Review • Journal

ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)

ROS1 fusion • ROS1 positive • ROS1 wild-type

Xalkori (crizotinib) • Rozlytrek (entrectinib) • taletrectinib (AB-106)

3ms

A Retrospective and Prospective Real-world Study of Molecular Typing in the Treatment of Advanced Thyroid Cancer (clinicaltrials.gov)

P4, N=200, Recruiting, Fudan University

3 months ago

New P4 trial • Real-world evidence • Real-world • Metastases

Mekinist (trametinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Focus V (anlotinib) • Lenvima (lenvatinib) • Retevmo (selpercatinib) • Gavreto (pralsetinib)

3ms

Lung cancer oncogene-directed therapy, fertility and pregnancy. (PubMed, J Thorac Oncol)

Reproduction may not be out of reach for some patients with advanced NSCLC. Additional explorations of the impact and optimal timing of targeted therapy in egg capture and in pregnancy are needed. Wider scientific and societal discussion about the issues of reproduction in advanced NSCLC are warranted.

3 months ago

Review • Journal

ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)

Xalkori (crizotinib) • Rozlytrek (entrectinib)

4ms

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer. (PubMed, Lung Cancer)

Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

4 months ago

Journal

NTRK (Neurotrophic receptor tyrosine kinase)

NTRK positive • NTRK fusion

Rozlytrek (entrectinib)

4ms

Case report: Successful sequential therapy of crizotinb and entrectinib in ROS1-positive non-small-cell lung cancer with brain metastasis in later-settings. (PubMed, Medicine (Baltimore))

A ROS1-rearranged NSCLC with CNS metastases responded to sequential tyrosine kinase inhibitors treatment of crizotinb followed by entrectinib. This report has potential implications in guiding decisions for the treatment after crizotinib resistance.

4 months ago

Journal • PD(L)-1 Biomarker

EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)

NTRK2 fusion • ALK fusion • ALK mutation • ROS1 fusion • ROS1 positive • ROS1 rearrangement

Opdivo (nivolumab) • Avastin (bevacizumab) • Xalkori (crizotinib) • Rozlytrek (entrectinib) • paclitaxel • Focus V (anlotinib)

4ms

Entrectinib inhibits NLRP3 inflammasome and inflammatory diseases by directly targeting NEK7. (PubMed, Cell Rep Med)

In vivo studies show that ENB has a significant ameliorative effect on mouse models of NLRP3 inflammasome-related diseases, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate (MSU)-induced peritonitis, and high-fat diet (HFD)-induced type 2 diabetes (T2D). These data show that ENB is a targeted inhibitor of NEK7 with strong anti-NLRP3 inflammasome activity, making it a potential candidate drug for the treatment of inflammasome-related diseases.

4 months ago

Journal

NLRP3 (NLR Family Pyrin Domain Containing 3)

Rozlytrek (entrectinib)

4ms

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.

4 months ago

Review • Journal

NTRK (Neurotrophic receptor tyrosine kinase)

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)

4ms

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.

4 months ago

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)

4ms

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.

4 months ago

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)

4ms

Sequential treatments with TRK inhibitors in a patient with NTRK fusion-positive sarcoma: A case report. (PubMed, Medicine (Baltimore))

In the treatment of NTRK fusion-positive tumors, there are cases in which 2 approved first-generation TRK inhibitors can be used sequentially.

4 months ago

Journal

NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK1 fusion • NTRK positive • NTRK fusion

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib)

5ms

A Misleading Case of NTRK-Rearranged Papillary Thyroid Carcinoma. (PubMed, Oncologist)

Between August 2019 and August 2020, the patient received 2 ineffective lines of systemic therapy, including a first line of chemotherapy with cisplatin and pemetrexed, and a second line of immunotherapy with atezolizumab. After palliative partial thyroidectomy that confirmed the diagnosis of papillary thyroid carcinoma, in February 2021, the patient was enrolled in the STARTRK-2 GO40782 basket trial and received entrectinib, an oral pan-TRK inhibitor specifically targeting NTRK-rearranged tumors. After initially experiencing drug-related grade 2 anorexia, dysgeusia, and neurotoxicity and grade 3 asthenia, the dose was reduced, and an excellent and durable objective response was observed.

5 months ago

Journal • PD(L)-1 Biomarker • IO biomarker

NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • TERT (Telomerase Reverse Transcriptase) • NTRK (Neurotrophic receptor tyrosine kinase)

NTRK1 fusion • TERT mutation • NTRK1 mutation

cisplatin • Tecentriq (atezolizumab) • Rozlytrek (entrectinib) • pemetrexed

5ms

Discovery of novel 3-(1H-pyrazol-4-yl)-1H-indazole derivatives as potent type II TRK inhibitors against acquired resistance. (PubMed, Eur J Med Chem)

The solvent front and xDFG mutations induced by larotrectinib and entrectinib result in acquired resistance in advanced-stage patients...In biochemical and cellular assays, 40l showed better inhibitory activity against TRKA than that by the positive control, selitrectinib...In vitro assays indicated that 40l possessed outstanding plasma stability and moderate liver microsomal stability. Based on the above results, compound 40l could be further optimized to overcome the solvent front and xDFG TRK mutations.

5 months ago

Preclinical • Journal

NTRK (Neurotrophic receptor tyrosine kinase)

NTRK fusion

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • selitrectinib (BAY 2731954)

5ms

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.

5 months ago

Review • Journal

NTRK (Neurotrophic receptor tyrosine kinase)

NTRK positive • NTRK fusion

Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Augtyro (repotrectinib)

5ms

Management of Brain Metastases: A Review of Novel Therapies. (PubMed, Semin Neurol)

Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.

5 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene)

EGFR exon 20 insertion

Zelboraf (vemurafenib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Kadcyla (ado-trastuzumab emtansine) • Enhertu (fam-trastuzumab deruxtecan-nxki) • Lumakras (sotorasib) • Retevmo (selpercatinib) • Braftovi (encorafenib) • Alunbrig (brigatinib) • Gavreto (pralsetinib) • Ensacove (ensartinib) • Krazati (adagrasib) • Pozenveo (poziotinib)

5ms

Intrinsic resistance to ROS1 inhibition in a patient with CD74-ROS1 mediated by AXL overexpression. (PubMed, Thorac Cancer)

In summary, we demonstrate that AXL overexpression is a mechanism of intrinsic resistance to ROS1 inhibitors.

5 months ago

Journal

AXL (AXL Receptor Tyrosine Kinase) • CD74 (CD74 Molecule)

ROS1 fusion • ROS1 positive • AXL overexpression • CD74 expression

Xalkori (crizotinib) • Rozlytrek (entrectinib)

5ms

Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma (clinicaltrials.gov)

P1/2, N=6, Terminated, Arkadiusz Z. Dudek, MD | Phase classification: P1b/2 --> P1/2 | Active, not recruiting --> Terminated; This study required dose reductions to the lower dose level (Dose level -1). But this dose level (Dose level -1) was not further explored because of lack of funding.

5 months ago

Phase classification • Trial termination • Metastases

Rozlytrek (entrectinib) • PAC-1

5ms

A Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Participants With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)

P3; N=320 --> 121

5 months ago

Enrollment change • Metastases

PD-L1 (Programmed death ligand 1) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)

RET fusion • ALK fusion • ROS1 fusion

PD-L1 IHC 22C3 pharmDx • VENTANA PD-L1 (SP263) Assay

Imfinzi (durvalumab) • Rozlytrek (entrectinib) • Alecensa (alectinib)