NTRK positive

Larotrectinib is highly active in patients with newly diagnosed NTRK fusion-positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion-positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

Notably, the phase 1/2 TRIDENT-1 study showed impressive progression-free survival and intracranial activity in both TKI-naïve and pretreated patients. With its high response rates and manageable side effects, repotrectinib is set to play a significant role in treating ROS1+ and NTRK+advanced solid tumors, highlighting the ongoing need for research and clinical application.

NTRK fusion tumors present heightened migratory and invasive potential in clinical settings. Further experiments confirmed the significant inhibitory effects of TRK inhibitors on the migration and invasion abilities of these cells. There is a complex relationship between ECM1, NOVA1 and NTRK fusion; however, further research is needed to determine whether NTRK fusion promotes tumor metastasis through these two genes.

Moreover, several bacterial species were similarly modulated upon Larotrectinib in faecal and saliva samples. Our results suggest a parallel dynamism of microbiota profiles in both body matrices possibly useful to identify microbial biomarkers as contributors to precision medicine in cancer therapies.

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.

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.

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.

Metastases beyond the ipsilateral axillary lymph nodes are rare, with the most common sites involving the lung and liver. Except for the potential addition of targeted drug therapy for NTRK fusion-positive tumors, the treatment approach is otherwise similar to invasive breast carcinomas of similar receptor status.

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.

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.

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.

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

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

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.

Repotrectinib in a patient with NTRK fusion-positive pancreatic carcinoma and congenital long QT syndrome.

We also advocate the use of molecular techniques in rare tumors of uncertain type or differentiation, to increase understanding and possibilities of reproducible classification of these rare neoplasms. Pathologists and oncologists should recognize this entity, which leads to a direct approach for detecting NTRK fusion for appropriate treatment.

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

The intake of high calorie food decreased the absorption rate and increased the T of VC004, while the AUC values were similar in both groups. No serious adverse event was reported. In conclusion, food does not alter the pharmacokinetics and safety profile of VC004 in a clinically meaningful manner.

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

The concordance rate between IHC and RNA-based NGS was 33.4%, and between immunohistochemistry and nCounter was 40%. Our findings indicate that NTRK fusions in Brazilian NSCLC patients are relatively rare (1.3%), and RNA-based nCounter methodology is a suitable approach for NRTK fusion identification in small biopsies.

P1/2, N=74, Active, not recruiting, Pyramid Biosciences | Recruiting --> Active, not recruiting

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.

DNA- and RNA-based screening systems may be useful for detecting tyrosine kinase fusion genes in specific fusion-negative sarcomas and identifying key therapeutic targets, leading to possible breakthroughs in the treatment of bone and soft tissue sarcomas. Given that current DNA sequencing misses fusion genes, RNA-based screening systems should be widely considered as a worldwide test for sarcoma. If standard treatments such as chemotherapy are not effective, or even if the sarcoma is of bone, RNA sequencing should be considered to identify as many therapeutic targets as possible.

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.

P1/2, N=75, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Mar 2025 --> Sep 2027 | Trial primary completion date: Mar 2025 --> Sep 2026

P=N/A, N=46621, Completed, Bayer | Active, not recruiting --> Completed

Patients with NTRK+ solid tumors who were treated with repotrectinib generally experienced stable HRQoL as measured by the QLQ-C30. These results compliment the efficacy and safety profile of repotrectinib as a treatment option for patients with NTRK+ solid tumors.

IHC for Pan-TRK was positive in all eight NTRK-fusion positive tumors tested and negative in two tumors with other kinase fusions. Clinical follow-up was too limited to allow general conclusions.

Adjuvant single-agent Doxorubicin had been applied until in September 2020 a CT scan had revealed extensive multifocal recurrent disease. Thus, second line Docetaxel and Gemcitabine had been initiated before rapid progressive disease after two cycles prompted salvage surgery... We report the case of a patient with uterine sarcoma harboring a newly described NTRK3 gene fusion partner IGDCC3 that shows a rapid clinical response to treatment with LARO.

Larotrectinib reduced tumor size in TRK fusion‐positive pediatric PTC. Improved radioiodine uptake occurred in 3/4 patients, but therapeutic 131I did not cause additional tumor response in the two patients treated. Stopping larotrectinib did not result in rapid disease progression in all patients, suggesting that it can be safely stopped in this population.

No abstract available

Conclusion Clinical efficacy of larotrectinib for the TSO Comp NTRK fusion positive population (97 patients, ORR=78.4%, 95% CI [69%, 86%]) was similar to the efficacy of larotrectinib in the total extended primary efficacy analysis population (164 patients, ORR=73%, 95%CI [65%, 79%]). Study results support the use of the TSO Comp (EU) assay to aid clinicians in identifying cancer patients with NTRK gene fusions who may be eligible for treatment with larotrectinib.

The prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile.

These data lead to suggest that IHC with VENTANA pan-TRK antibody can be a reliable screening tool for the identification of patients potentially bearing NTRK rearranged tumours.

FISH or RNA-based NGS is a reliable detection approach. NTRK rearrangement can be precisely, rapidly, and economically detected based on the developed optimal algorithm.

P1/2, N=155, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2025 --> Jul 2024

Repotrectinib safety at RP2D was manageable, consistent with prior reports. Table: 1372P Repotrectinib in NTRK+ solid tumors

Of all pts with treatment-related adverse events (TRAEs; n=265), 57% had grade 1–2 TRAEs; dose reduction, interruption and discontinuation occurred in 24%, 34% and 6% of all pts, respectively. Table: 666P Conclusions In this updated analysis, entrectinib was well tolerated and continued to induce clinically meaningful responses in pts with NTRK-fp solid tumours.

TRKi could be considered at diagnosis for CNS NTRK-fusion positive tumors, some IFS and Other-MT. not adapted.

An individual therapy for surgical treatment of IIFS is recommended. This comprises marginal resection in instead of the golden standard "wide resection" in selected cases.