Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

Halalsheh, Hadeel; McCarville, M. Beth; Neel, Michael D.; Reynolds, Mark; Cox, Michael C.; Pappo, Alberto S.

doi:10.1002/pbc.27271

Cited by 24 publications

(14 citation statements)

References 16 publications

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“…4). For example, the ETV6–NTRK3 fusion is considered practically pathognomonic in secretory breast carcinoma, MASC, congenital mesoblastic nephroma (cellular or mixed subtypes), and infantile fibrosarcomas, with a prevalence of >90% in select series of patients 83,91–94 . Second, other cancer types in which NTRK fusions are found at much lower frequencies (5–25% or <5%), including rare subsets of some common tumours (such as breast, lung, and colorectal cancers, and melanoma).…”

Section: Ntrk Fusion Frequency and Diagnosismentioning

confidence: 99%

NTRK fusion-positive cancers and TRK inhibitor therapy

2018

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NTRK gene fusions involving either NTRK1, NTRK2, or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB, and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.

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Section: Ntrk Fusion Frequency and Diagnosismentioning

confidence: 99%

NTRK fusion-positive cancers and TRK inhibitor therapy

2018

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“…Generell ist jedoch zu berücksichtigen, dass sowohl bei der CMN als auch beim IFS der chirurgische Eingriff die wesentliche Therapieoption darstellt [22,23,34]. Bei fortgeschrittenen Tumoren kann eine Chemotherapie mit einem relativ geringen Risiko für Spätfolgen sinnvoll sein [45].…”

Section: Trk-inhibitoren: Anwendung Bei Kindern Und Heranwachsendenunclassified

Diagnosis and therapy of tumors with NTRK gene fusion

et al. 2020

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ZusammenfassungNTRK-Genfusionen sind seltene genetische Alterationen, die tumorentitätenübergreifend vorkommen können. Während sie in den meisten soliden Tumoren nur sehr niederfrequent vorkommen, lassen sie sich in bestimmten Tumoren wie dem infantilen Fibrosarkom, dem kongenitalen mesoblastischen Nephrom und dem sekretorischen Mamma- oder Speicheldrüsenkarzinom jedoch häufig nachweisen. NTRK-Genfusionen bzw. TRK-Fusionsproteine gelten als starke onkogene Treiber. Bei Nachweis von NTRK-Genfusionen können TRK-Inhibitoren unabhängig von der Tumorentität eingesetzt werden. Vertreter sind Entrectinib und Larotrectinib. Bislang ist nur Larotrectinib in der Europäischen Union zugelassen. Für beide wurden Wirksamkeit und Verträglichkeit in Phase-I- und Phase-II-Studien gezeigt. Die Seltenheit der TRK-Fusionstumoren stellt diagnostische und klinische Prozesse vor große Herausforderungen: Einerseits sollen alle Patienten mit TRK-Fusionstumoren identifiziert werden, andererseits sind epidemiologische und histologische Aspekte sowie Ressourcen zu berücksichtigen. Basierend auf diesen Punkten möchten wir einen Diagnosealgorithmus für TRK-Fusionstumoren vorschlagen, außerdem stellen wir aktuelle Daten zu den TRK-Inhibitoren vor.

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“…NTRK fusions have been identified in tumors of more than 20 histologies [5]. Certain NTRK fusions, like ETV6-NTRK3, are represented in > 90% of secretory breast carcinomas [6], mammary analog of secretory carcinomas (MASC) [7], congenital mesoblastic nephroma [8,9], and infantile fibrosarcomas [10,11]. These fusions are also found at lower incidences (5-25%) in tumors such as breast, lung, colon, and melanoma [2], leading to the 2018 basket trial in which 55 NTRK-fusion-positive patients with 17 different cancer types were treated with the first-generation TRK inhibitor larotrectinib [12].…”

Section: Introductionmentioning

confidence: 99%

Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an NTRK-fusion inhibitor

et al. 2020

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Background: Lipofibromatosis-like neural tumors (LPF-NT) are a newly identified class of rare mesenchymal neoplasms. Current standard of care therapy is surgical resection alone; there are no chemotherapies or molecular targeted therapies that have been shown to be effective in patients who are not surgical candidates due to either tumor bulk or location. Most LPF-NT harbor NTRK fusions, although the therapeutic significance of these fusions has not been previously demonstrated in this malignancy. Here, we present the first case of a patient with surgically-unresectable LPF-NT successfully treated with medical therapy, specifically the TRK fusion-protein inhibitor entrectinib. Case presentation: The patient is a 21 year old man with no co-morbidities who presented for evaluation due to intermittent abdominal pain and was found to have a mass spanning from T12-L2. Biopsy revealed a mesenchymal spindle cell neoplasm and S100 positivity pointed to possible nerve sheath origin. The sample was ultimately found to have an LMNA-NTRK1 fusion, confirming the diagnosis of LP-NFT. Unfortunately, due to the bulk and location of the tumor, surgery was felt to be exceptionally morbid and the patient was treated in a clinical trial with the NTRK inhibitor entrectinib. Surprisingly, he had such a robust clinical response that he was ultimately deemed a surgical candidate and he was successfully taken to surgery. Post-operative pathology revealed > 95% necrosis, demonstrating exceptional sensitivity to the targeted therapy. The patient remains NED and on entrectinib 12 months post-operatively. Conclusions: The exceptional treatment response of this patient suggests that NTRK fusions are true drivers of the disease. Thus, all patients should be evaluated for NTRK fusions using sensitive methodologies and treatment with TRK fusion-protein inhibitors should be considered in patients who are not candidates for oncologic resection.

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Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

Cited by 24 publications

References 16 publications

NTRK fusion-positive cancers and TRK inhibitor therapy

NTRK fusion-positive cancers and TRK inhibitor therapy

Diagnosis and therapy of tumors with NTRK gene fusion

Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an NTRK-fusion inhibitor

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