P2, N=61, Not yet recruiting, Megan Kruse, MD | Initiation date: Apr 2024 --> Oct 2024

On the other hand, there are some approved drugs, such as pembrolizumab for TMB-H or entrectinib or larotrectinib for NTRK fusion gene, for which there is no stand-alone companion diagnostics and the eligibility for these drugs cannot be judged without the results of CGP test. This paper discusses the current status and issues of companion diagnostics in cancer genomic medicine.

Case Presentation and We report two cases with RAI-resistant lung metastases treated with larotrectinib: 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation)...In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

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.

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

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.

Recent approval of the TRK inhibitor larotrectinib by the Food and Drug Administration (FDA) has brought interest in the study and recognition of NTRK fusions in multiple types of tumors. Trials that assess the response to this drug in cancers carrying NTRK fusions have yielded favorable results. We discuss a rare presentation of an adult-type GBM with epithelioid morphology and a BCR::NTRK2 gene fusion.

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.

P1, N=29, Terminated, Pyramid Biosciences | Phase classification: P1/2 --> P1

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.

One patient was succumbed to the disease at 12 months despite adjunctive treatment with TRK inhibitor larotrectinib after surgery...The final diagnosis relies on molecular assays. Patients with advanced disease may benefit from TRK inhibitor treatment.

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

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

P1/2, N=29, Terminated, Pyramid Biosciences | N=74 --> 29 | Trial completion date: Jun 2024 --> Jul 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Jul 2023; Sponsor terminated development of PBI-200

This is the first report of an MYO5A::NTRK3 fusion in a pediatric GNT. GNT kinase-fused is a provisional methylation class not currently included in the WHO classification of CNS tumors. This case highlights the impact of thorough molecular characterization of CNS tumors, especially with the increasing availability of novel gene targeting therapies.

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.

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

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.

P2, N=13, Recruiting, Children's Hospital of Philadelphia | Not yet recruiting --> Recruiting

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

P2, N=224, Recruiting, AnHeart Therapeutics Inc. | N=154 --> 224

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.

© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Conclusions Laro demonstrated durable responses, extended survival benefit and a favourable safety profile in pts with advanced lung cancer harbouring NTRK gene fusions. These results support the adoption of ctDNA next-generation sequencing panels that include NTRK gene fusions in clinical practice.

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.

An ETV6:NTRK fusion detected in tumor tissue, was treated with larotrectinib; at progression, sequencing of cfDNA identified an NTRK3 G623R alteration as the acquired mechanism of resistance; the patient enrolled in a clinical trial of a second generation TRK inhibitor with clinical benefit. In metastatic PanNENs, cfDNA-based NGS identified tumor-associated mutations in 66% of plasma samples with a high level of plasma-tissue agreement in PanNEN associated genes. Clonal evolution, actionable alterations, and resistance mechanisms were detected through circulating cfDNA genotyping.

P2, N=61, Not yet recruiting, Megan Kruse, MD

P2, N=215, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting

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.

P2, N=32, Active, not recruiting, The University of Sydney | Recruiting --> Active, not recruiting

These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.

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.

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

P2, N=49, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

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.

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.

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.

This case suggests that multimodal therapy dominated by liver transplantation, including preoperative TACE, postoperative adjuvant chemotherapy, and TRK inhibitors, is an effective treatment modality for unresectable primary hepatic YST.

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.

"AnHeart Therapeutics...and Foundation Medicine, Inc., today announced the companies have entered a strategic collaboration for the development and regulatory approval of Foundation Medicine’s tissue-based and liquid-based comprehensive genomic profiling tests, FoundationOne^®CDx and FoundationOne^®Liquid CDx, as companion diagnostics for AnHeart’s investigational next-generation ROS1 inhibitor, taletrectinib, in the United States....Taletrectinib is a potential best-in-class ROS1 inhibitor being evaluated for the treatment of patients with advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC), an underserved group of lung cancer patients in need of new options."

P2, N=13, Not yet recruiting, Children's Hospital of Philadelphia | Initiation date: Nov 2023 --> Feb 2024

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