selitrectinib (BAY 2731954) / Bayer, Pfizer - LARVOL DELTA

Activation mevalonate pathway via HMGCS2 introduced resistance to molecular targeted therapy for cancer (AACR 2025) - "We investigated resistance mechanism of cancer harboring NTRK fusion to NTRK-TKI. We established resistant cells to NTRK-TKIs (larotrectinib, entrectinib and selitrectinib) using KM12 harboring NTRK fusion. Activation mevalonate pathway via HMGCS2 overexpression introduced resistance to NTRK-TKI. It found novel resistance mechanism to molecular targeted therapy. Statin showed possibly useful for overcoming resistance mechanism introduced by HMGCS2."

Oncology • Solid Tumor • HMGCS2 • NTRK • PPARA

NTRK Fusion-Positive Thyroid Carcinoma: From Diagnosis to Targeted Therapy. (PubMed, JCO Precis Oncol) - "NTRK1/3 fusions are seen in PTC, PDTC, and ATC, and a follicular growth pattern was observed in a high proportion of cases. In patients treated with larotrectinib, NTRK solvent front mutations are the main resistance mechanism, frequently occurring in PDTC/ATC. Responses to single-agent TRK inhibitor are short-lived in patients with ATC; thus, these drugs should be used with caution in this population."

Journal • Observational data • Retrospective data • Endocrine Cancer • Oncology • Pediatrics • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • NTRK • NTRK1 • NTRK3

SELECTIVE INHIBITION OF NTRK3 ON HEPATIC STELLATE CELLS BY A SMALL MOLECULE (LOXO195) ATTENUATES HCC AND FIBROSIS IN ADVANCED MOUSE MASH AND HUMAN LIVER SLICES (AASLD 2024) - "These findings establish, for the first time, that specific, HSC-directed therapy can attenuate HCC development without directly targeting the tumor. This is a major conceptual advance that introduces the possibility of HSC-directed therapy that antagonizes Ntrk3 for use in human HCC prevention and/or treatment."

Metastases • Preclinical • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Solid Tumor • ACTA2 • COL1A1 • NTRK3

British Journal of Cancer: Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumors with on-target resistance to first-generation agents (Businesswire) - "InnoCare announced British Journal of Cancer...recently published a paper entitled 'Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumors with on-target resistance to first-generation agents'. The journal concluded that zurletrectinib is a novel, highly potent next-generation TRK inhibitor with higher in vivo brain penetration and stronger intracranial activity than other next-generation agents....Zurletrectinib (1 mg/kg BID) inhibited tumor growth in xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib....In an orthotopic mouse glioma xenograft model carrying the TRKA G598R/G670A resistance mutation, zurletrectinib (15 mg/kg) significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively..."

Preclinical • Glioma

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."

Journal • Review • Oncology • Solid Tumor • NTRK • NTRK1 • NTRK2 • NTRK3

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 • Oncology • NTRK

Induction of resistance to neurotrophic tropomyosin-receptor kinase inhibitors by HMGCS2 via a mevalonate pathway. (PubMed, Cancer Med) - "These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HMGCS2 • NTRK • NTRK1 • PPARA • TPM3

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 • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • NTRK • NTRK2 • NTRK3

A recurrent NTRK1 tyrosine kinase domain mutation pair is characteristic in a subset of dedifferentiated liposarcomas. (PubMed, Eur J Cancer) - "We detected (de novo/somatic) missense mutation variants in cis position of the NTRK1 gene in a subset of DDLPS indicating modifying mutations that may contribute to tumorigenesis in a subset of DDLPS. These variants beget resistance to TRK inhibitors indicating an interesting biomarker for other studies with TRK inhibitors."

Journal • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • NTRK • NTRK1 • NTRK2 • NTRK3

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."

Journal • Preclinical • Review • Oncology • Pediatrics • Solid Tumor • NTRK

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."

Journal • Review • Brain Cancer • CNS Tumor • Oncology • Pediatrics • NTRK • NTRK1 • NTRK2 • NTRK3

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."

Journal • Preclinical • Oncology • NTRK

Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update. (PubMed, Expert Opin Ther Pat) - "Challenges remain in accurately diagnosing NTRK gene alterations and integrating screening into routine clinical practice. Trk inhibitors have surpassed their conventional role of inhibition and are now seeing new applications in radiopharmaceutical development and as molecular targeting agents."

Journal • Review • Oncology • NTRK

CLINICO-GENOMIC ANALYSIS OF KIT/PDGFRA/SDH WILD-TYPE GASTROINTESTINAL STROMAL TUMORS IDENTIFIES POTENTIAL DRIVER MUTATIONS (CTOS 2023) - "The patient with ETV6-NTRK3 fusion was treated with larotrectinib for 28.7 months prior to progression, likely due to acquired NTRK3 gatekeeper mutation (F617L) rendering resistance to larotrectinib, then was on a second generation NTRK inhibitor, selitrectinib, for 16.5 months prior to progression. Triple negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy."

Genomic analysis • Omic analysis • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • AURKA • CHEK2 • ETV6 • FGFR1 • KIT • NF1 • NTRK • NTRK3 • PDGFRA • PIK3CA • PTEN • SDHA • SDHB • SDHC • SDHD

The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations. (PubMed, Cancers (Basel)) - "We then assessed the effects of EN variants on these pathways, and showed that the pan NTRK inhibitor Selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis defines the molecular framework in which EN oncofusions operate to promote cancer and provides some mechanisms for therapeutics."

Journal • Oncology • ETV6 • NTF3 • NTRK • NTRK3

TY-2136b, a next generation ROS1/TRK/ALK inhibitor, potently inhibits kinase and cell proliferation activities of tumor cells bearing drug-dependent acquired mutations (AACR 2023) - "Meanwhile, TY-2136b, TPX-0005, and TRK-selective second-generation LOXO-195 inhibitors had similar activity against TRKA G595R and TRKC G623R resistance mutations, but TY-2136b was better than TPX-0005 and LOXO-195 against TRKA G595R/F589L dual mutations in vitro. In vivo studies, TY-2136b showed dose-dependent anti-tumor effect at the dose of 5, 10, and 20 mg/kg, bid, in xenograft tumor models carrying ROS1 G2032R and TRKA G595R mutation, and was more effective than Crizotinib and LOXO-101 at testing dose, and showed better efficacy than TPX-0005 in higher dose...Currently, TY-2136b is under first-in-human clinical investigations in the US and China. * To Whom Correspondence should be addressed to: Jun Li, Chengshan Niu and Yusheng Wu"

Tumor cell • Oncology • ALK • CD74 • NTRK3 • ROS1 • TPM3

Studying novel patient population using integrated real-world data (AACR 2023) - "Highly effective first-generation TRK inhibitors such as Larotrectinib or Entrectinib, are associated with high response rates, and those patients who develop resistance are often given second-generation TRK inhibitors such as LOXO-195. We also compare the results on treatments, procedures, lab tests, and survival with published results from cBioPortal. We will present our findings with preliminary data, describe the data sources used, outline the technologies leveraged, and conclude with lessons learned."

Clinical • Real-world • Real-world evidence • Oncology • BDNF • NTRK • NTRK2 • NTRK3

Interactome analysis identifies signaling pathways activated by ETV6-NTRK3 oncogenic gene fusions (AACR 2023) - "We then assess the effects of EN variants on these pathways, and show that the pan NTRK inhibitor selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis of defines the molecular framework in which EN oncofusions operate to promote cancer."

Late-breaking abstract • Hematological Malignancies • Oncology • Solid Tumor • ETV6 • NTRK • NTRK3

Ropotrectinib is a novel polypharmacology kinase inhibitor against WT and mutant ROS1, TRK and ALK (AACR 2018) - P1/2; "...Moreover, ropotrectinib displays inhibitory activity for SRC/FAK/JAK2, rendering its potential to overcome drug resistance caused by by-passing mechanisms such as EMT.Ropotrectinib is a superb ROS1 inhibitor...Acquired secondary mutations in ROS1 kinase domain is a common drug resistance mechanism in 50-60% patients progressed on crizotinib treatment, with solvent front mutations most frequently observed. Compared to other ROS1 inhibitors, such as lorlatinib, ceritinib, brigatinib and entrectinib, ropotrectinb demonstrated most potent activity against WT and mutant ROS1, especially solvent front mutations such as G2032R in cellular assays and potently inhibited xenograft tumors.Ropotrectinib is the most potent TRK inhibitors in clinic, with IC50s < 1nM in cellular assays. Preclinic in vitro and in vivo studies further demonstrated that ropotrectinib overcomes clinical resistance mutations which occur in patients progressed on TRK inhibitors, such as entrectinib and...

Non Small Cell Lung Cancer

Repotrectinib, a next generation TRK inhibitor, overcomes TRK resistance mutations including solvent front, gatekeeper and compound mutations (AACR 2019) - P1/2; "The anti-proliferative activity of 1st generation (larotrectinib/entrectinib) and next-generation (repotrectinib/LOXO-195) TRKis were compared using engineered Ba/F3 cells expressing WT or mutated TRKs (Table). Tumor regression (-33%) was achieved in a larotrectinib-resistant cholangiocarcinoma patient with LMNA-TRKA G595R and F589L mutations in trans. TRIDENT-1 is currently enrolling NTRK fusion-positive patients with advanced solid tumors."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

[VIRTUAL] Molecular characteristics of repotrectinib that enable potent inhibition of TRK fusion proteins and broad mutant selectivity (AACR 2021) - "In cell proliferation assays, differential potencies against wild type TRKA/B/C fusions were observed: larotrectinib (IC50 23.5 - 49.4 nM), entrectinib (IC50 0.3 - 1.3 nM), selitrectinib (IC50 1.8 - 3.9 nM), and repotrectinib (IC50 < 0.2 nM). Repotrectinib has shown responses in patients with TRK driven tumors with or without resistant mutations in the ongoing global registrational TRIDENT-1 study and has been granted 3 fast track designations. Taken together, the current data characterizes TRK inhibitor potency against resistance mutations and highlights structural characteristics of repotrectinib that enable potent inhibition of TRK proteins and evasion of drug resistance mediated by TRK mutations."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • LMNA • NTRK

Molecular characterization and management of secondary resistance to serial TRK inhibitors. (ASCO 2019) - P=N/A, P2; "Background: TRK inhibitor drugs such as the highly selective larotrectinib (Laro), have proven highly effective in malignancies harboring fusions of NTRK1, 2, or 3...LOXO-195 (L195) is a 2nd generation TRK inhibitor that overcomes these mutations... Resection of oligoclonal PD and continuation of L195 post-PD can be an effective treatment strategy. Oncogenic activation of the KRAS pathway is a possible mechanism of resistance to L195. Our studies indicate that the tumor microenvironment of TRK-fusion sarcomas resistant to TRK inhibitors may increase inflammatory cell infiltrates, which may provide clues for future combination therapy."

Oncology • Sarcoma • Solid Tumor

A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer (clinicaltrials.gov) - P1 | N=81 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Trial completion • Oncology • Pediatrics • Solid Tumor • ETV6 • NTRK • NTRK3

A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer (clinicaltrials.gov) - P1 | N=81 | Active, not recruiting | Sponsor: Bayer | Trial completion date: Jul 2025 ➔ Dec 2022

Trial completion date • Oncology • Pediatrics • Solid Tumor • ETV6 • NTRK • NTRK3

Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy. (PubMed, Eur J Med Chem) - "TRK xDFG mutation-induced acquired resistance of 1 generation inhibitors larotrectinib and entrectinib remains an unmet clinical need...Compared with larotrectinib and selitrectinib, 12d displayed superior inhibitory activity towards Ba/F3 cells harboring CD74-TRKA and ETV6-TRKC with IC values of 2.6 and 6.1 nM, respectively. Moreover, 12d also exhibited potent antiproliferation activity against Ba/F3-ETV6-TRKC and Ba/F3-ETV6-TRKC mutants with IC values of 31.0 and 28.2 nM, respectively. This work provided a new potential type II TRK inhibitor-based lead compound for the treatment of TRK driven cancers."

Journal • Oncology • CD74 • ETV6 • NTRK3