P2, N=215, Completed, Astellas Pharma Europe B.V. | Phase classification: P2a --> P2

P2, N=70, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

P=N/A, N=150, Recruiting, Bayer | N=300 --> 150

P2, N=13, Recruiting, Children's Hospital of Philadelphia | Trial primary completion date: Oct 2024 --> Oct 2026

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.

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.

P2, N=9, Active, not recruiting, National Cancer Institute (NCI) | N=49 --> 9 | Trial completion date: Sep 2024 --> Oct 2025

Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.

Presently, after 22 months of treatment, the patient's complete remission is sustained. Our findings highlight the importance of screening for other oncogenic drivers in BRAF-negative LGGs since rare fusion genes may serve as targets for precision oncology therapy.

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.

Among documented cases of thyroid SC, prognostic factors established for salivary SC have shown broad distributions, including a mitotic activity ranging from < 1 to 10 per 10 high-power fields and variable presence of necrosis, awaiting additional case experience to better elucidate their relevance in thyroid SC. We hereby present a 61-year-old female patient with widely metastatic thyroid SC treated with larotrectinib and provide an updated review of the literature on the molecular pathogenesis and clinicopathologic characteristics of this rare entity.

Patients achieved 1 complete response (12%), 6 partial responses (75%), and 1 stable disease (12%). In this single-institution cohort of patients with NTRK fusion-positive thyroid cancer, NTRK inhibition led to an mPFS of 25 months, with survival surpassing historic benchmarks for ATC and PDTC.

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.

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.

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.

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.

In in vivo xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.

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.

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.

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.

P1/2, N=154, Active, not recruiting, Bayer | Trial primary completion date: Jul 2024 --> Jan 2026

P2, N=52, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting

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.

P1, N=38, Completed, Hoffmann-La Roche | N=24 --> 38

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.

P2, N=52, Not yet recruiting, St. Jude Children's Research Hospital

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.

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.

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.

In conclusion, larotrectinib demonstrated effective antitumor activity against liver metastases of PTC, a relatively rare site of distant metastasis. Furthermore, the efficacy of larotrectinib was maintained, even though the patient had a history of multi-tyrosine kinase inhibitor treatment and a relatively infrequent fusion gene, SQSTM1-NTRK1.

CMN, is a rare pediatric renal tumor that warrant prompt surgical management. A watchful waiting approach may allow for aggressive growth of metastatic disease, as seen in this case of cellular CMN with TPM3::NTRK1 fusion gene, TRK inhibitors can play significant roles in the treatment of CMN with TPM3::NTRK1 fusion gene, but we still need to pay attention to the phenomenon of drug resistance to larotrectinib caused by site mutations of TRKA.

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.

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.

Currently, two drugs, entrectinib and larotrectinib, are approved for use in Japan, and they are planned to be used in this case in the event of recurrence. &lsqb;Summary] Cancer genome profiling was performed on a very rare case of lung metastasis from breast secretory carcinoma, and the ETV6-NTRK fusion gene was confirmed

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

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.

The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 .

Our results indicated that ergotamine, entrectinib, exatecan, dihydroergotamine, and paritaprevir can be used as alternative drugs for colon cancer. The long-term inhibitory effect of the ergotamine led to a decrease in colony size, and the toxicity properties were studied using hemolysis assay. Our study shows the potential of targeting JAK2 as a novel approach to colon cancer treatment, and demonstrate that ergotamine as a promising effects as an anti-cancer drug.

P2, N=65, Active, not recruiting, Jules Bordet Institute | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells...The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.

P2; Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression.

No abstract available