Clinical practice guidelines for molecular tumor markers, 2nd edition review part 1.

With advances in gene and protein analysis technologies, many target molecules that may be useful in cancer diagnosis have been reported. Therefore, the "Tumor Marker Study Group" was established in 1981 with the aim of "discovering clinically" useful molecules. Later, the name was changed to "Japanese Society for Molecular Tumor Marker Research" in 2000 in response to the remarkable progress in gene-related research. Currently, the world of cancer treatment is shifting from the era of representative tumor markers of each cancer type used for tumor diagnosis and treatment evaluation to the study of companion markers for molecular-targeted therapeutics that target cancer cells. Therefore, the first edition of the Molecular Tumor Marker Guidelines, which summarizes tumor markers and companion markers in each cancer type, was published in 2016. After publication of the first edition, the gene panel testing using next-generation sequencing became available in Japan in June 2019 for insured patients. In addition, immune checkpoint inhibitors have been indicated for a wide range of cancer types. Therefore, the 2nd edition of the Molecular Tumor Marker Guidelines was published in September 2021 to address the need to revise the guidelines. Here, we present an English version of the review (Part 1) of the Molecular Tumor Marker Guidelines, Second Edition.

Dramatic response to entrectinib in a patient with malignant peripheral nerve sheath tumor harboring novel SNRNP70-NTRK3 fusion gene.

Neurotropic tropomyosin receptor kinase (NTRK) gene rearrangements have been reported in limited cases of sarcomas; however, to date, there has been only one report of such rearrangements in malignant peripheral nerve sheath tumors (MPNSTs). Herein, we describe a 51-year-old male patient with a buttock tumor arising from the sciatic nerve, which was diagnosed as MPNST with positive S-100 staining, negative SOX10 staining, and loss of trimethylation at lysine 27 of histone H3 (H3K27me3) confirmed by immunohistochemistry. Soon after the resection of the primary tumor, the patient was found to have pulmonary and lymph node metastases. Chemotherapy with eribulin and trabectedin showed limited effects. However, the patient responded rapidly to pazopanib, but severe side effects caused discontinuation of the treatment. RNA panel testing revealed a novel fusion gene between Small Nuclear Ribonucleoprotein U1 Subunit 70 (SNRNP70) gene and NTRK3 gene. Furthermore, loss of NF1, SUZ12, and CDKN2A genes was confirmed by DNA panel testing, which is compatible with a histological diagnosis of MPNST. SNRNP70 possesses a coiled-coiled domain and seems to induce constitutive activation of NTRK3 through dimerization. In fact, immunohistochemistry revealed diffuse staining of pan-TRK within tumor cells. Treatment with entrectinib, which is an NTRK inhibitor, showed a quick and durable response for 10 months. Although NTRK rearrangements are very rare in MPNST, this case highlights the importance of genetic testing in MPNST, especially using an RNA panel for the detection of rare fusion genes.

China special issue on gastrointestinal tumors-NTRK fusion in a large real-world population and clinical utility of circulating tumor DNA genotyping to guide TRK inhibitor treatment.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are rare oncogenic drivers and targets of TRK inhibitors in solid tumors. Little is known about NTRK fusion in Chinese patients with pan-cancer. Our study investigated the prevalence and genomic features of NTRK1/2/3 gene fusions in 67 883 Chinese patients with pan-cancer using next-generation sequencing (NGS) data and circulating tumor DNA (ctDNA) NGS to guide TRK inhibitor treatment and resistance monitoring. The prevalence of NTRK fusion (tissue NGS) in the pan-cancer population was 0.18%, with 46 unique NTRK-fusion partner pairs, of which 33 were not previously reported. NTRK2 breakpoint occurred more frequently in intron 15 than intron 12. In colorectal cancers (CRCs), compared to NTRK-negative tumors, NTRK-positive tumors displayed higher tumor mutational burden (TMB) levels (54.6 vs 17.7 mut/Mb, P < .0001). In microsatellite instability-high (MSI-H) CRC, patients with NTRK fusion had a significantly lower TMB than NTRK-negative cases (69.3 vs 79.9 mut/Mb, P = .012). The frequency of NTRK fusion in a ctDNA NGS cohort of 20 954 patients with cancer was similar to that of the tissue NGS cohort. In eight NTRK fusion ctDNA-positive patients, larotrectinib induced objective response in 75% of patients and median progression-free survival was 16.3 months. Blood samples collected from a patient with disease progression after larotrectinib treatment revealed NTRK3 G623R as the potential resistance mechanism. Our study revealed previously unreported NTRK fusion partners, associations of NTRK fusion with MSI and TMB, and the potential utility of ctDNA to screen candidates for TRK inhibitors and monitor drug resistance.

NTRK Fusion in a Cohort of BRAF p. V600E Wild-Type Papillary Thyroid Carcinomas.

Owing to the availability of a potent tropomyosin receptor kinase (TRK) inhibitor, it is necessary to develop an effective strategy to identify an enriched population of NTRK fusions in papillary thyroid carcinoma (PTC) in routine diagnostic practice. The reported prevalence of NTRK fusion in a large cohort of PTC is ∼3%. We performed an analysis to refine the characteristic histologic features of PTCs harboring NTRK fusions and further validate the diagnostic utility of pan-TRK immunohistochemistry as a screening tool. In this study, 450 PTCs known to harbor no BRAF p. V600E mutations were screened by pan-TRK immunohistochemistry, and the cases with TRK expression were confirmed by RNA-based next-generation sequencing assay. Eleven NTRK fusion cases were detected (2.4%), and all PTCs were classical subtypes. NTRK1 and NTRK3 were involved in the fusion with 9 different partner genes. Most cases showed similar characteristic histologic findings. Nodular permeative border, multinodular growth with a predominantly follicular pattern, extensive lymphatic invasion, and prominent internodular and intratumoral fibrosis were the characteristic histologic features of NTRK-rearranged PTCs. The ill-defined margins in the ultrasonography findings, which could not be clearly distinguished from the adjacent nontumorous thyroid tissue, were nodular permeative margins in histologic findings. Therefore, preoperative ultrasonographic findings in nodule margins were consistent with the final histologic findings. NTRK1/3 fusion in PTCs showed an overall sensitivity of 100% (95% CI, 71.51%-100%) and specificity of 100% (95% CI, 71.51%-100%) in the 22 cases examined, as confirmed with next-generation sequencing. Our study provides an integrative report of the preoperative ultrasonographic, histologic, immunohistochemical, and molecular features of NTRK-rearranged PTCs. Based on these findings, we propose an algorithmic approach for the stepwise assessment of NTRK fusions in PTCs.

Mammary-analog secretory carcinoma in children: Surgery or TRK inhibitors first?

We report two cases of pediatric mammary-analog secretory carcinoma (MASC), a male operated on at age 8 and a female operated on at 12, who are in remission 2 years after surgery. The diagnosis of MASC was challenging and established by identifying the ETV6::NTRK3 fusion transcript in both cases. Given the excellent results of TRK inhibitor treatments in adult MASC and pediatric tumors expressing an ETV6::NTRK3 fusion, they should probably be prescribed as first-line treatment in cases requiring surgery with foreseeable serious sequelae or metastatic disease.

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors.

BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

A Unique Case Report of Infant-Type Hemispheric Glioma (Gliosarcoma Subtype) with TPR-NTRK1 Fusion Treated with Larotrectinib.

Herein, we present a rare case of a nine-month-old boy diagnosed with infant-type hemispheric glioma (gliosarcoma subtype) at the left frontal lobe. Following subtotal resection, the patient started chemotherapy with the BABY POG protocol. We describe the clinical diagnosis, histological characteristics, radiological features, molecular aspects, and management of this tumor. A comprehensive molecular analysis on the tumor tissue showed a TPR-NTRK1 gene fusion. The patient was treated with a TRK inhibitor, larotrectinib, and exhibited a stable disease with residual lesion following 8 months of target therapy. The present study is the first report of an infantile gliosarcoma harboring NTRK1 rearrangement treated with larotrectinib.

Dermal lipofibromatosis-like neural tumor.

BACKGROUND: Lipofibromatosis-like neural tumor (LPF-NT) is a rare soft tissue typically occurring in the subcutis, characterized by a cellular proliferation of CD34- and S100-protein positive spindle-shaped tumor cells with an infiltrative growth pattern. OBJECTIVE: To describe five cases arising mainly in the dermis in order to expand their morphologic spectrum. METHODS: H&E slides were reviewed, and all cases were stained for CD34, SOX10, S100, ALK, and NTRK1 and some of them with additional staining. RESULTS: Patients were three males and two females with a mean age of 44.8 years (14-68 years). Histopathologically, all cases were characterized by a dense dermal infiltration by monomorphous, mildly atypical, plump to spindle-shaped tumor cells, staining diffusely positive for CD34, S100, and NTRK1 but were negative for S100, EMA, NKIC3, MNF116, SMA, ALK, and desmin. LIMITATIONS: Limited clinical information. CONCLUSION: LPL-NT can be located mainly in the dermis. Sixty percent of our cases showed typical areas of LPL-NT intermingled with more plump cells like the ones in fibrous hamartoma of infancy. We recommend a panel of CD34, S100, and NTRK1 antibodies not only in subcutaneous spindle cell neoplasms but also in the ones predominantly involving the dermis in order to make an accurate diagnosis.

Canadian consensus on TRK-inhibitor therapy for NTRK fusion-positive sarcoma.

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.

NTRK fusions are extremely rare in bone tumours.

AIMS: Because of the efficacy of tropomyosin receptor kinase (Trk) inhibitor therapy in tumours with rearrangements of the neurotrophic tyrosine kinase receptor genes (NRTK genes), there has been a surge in demand for NTRK fusion screening. To date, most studies involving mesenchymal tumours have focused on soft tissue tumours, and data on bone tumours are sparse. Hence, we aimed to explore the frequency of NTRK fusions in a large series of primary bone tumours. METHODS AND RESULTS: Immunohistochemical expression of pan-Trk was successfully assessed in 354 primary bone tumours by the use of tissue microarrays. In a selection of positive cases, additional molecular analysis for NTRK fusions was performed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Positivity was found in 19 cases (5%), which comprised Ewing sarcoma (n = 6, 33%), osteosarcoma (n = 11, 13%), and giant-cell tumour of bone (n = 2, 3%). In all except one case, cytoplasmic staining was observed. Weak staining was most often observed (n = 13), although five cases showed moderate staining and one case showed focal strong staining. Molecular analysis was successful in six cases, all of which were negative for NTRK fusions. CONCLUSION: The likelihood of finding an NTRK fusion in bone tumours in clinical practice is extremely low. This may imply that, if more comprehensive large-scale molecular studies confirm this, routine predictive NTRK testing in bone tumour patients with advanced disease may be reconsidered.

NTRK fusion-positive colorectal cancer in Japanese population.

ALK, ROS1 and NTRK fusions are involved in the tumorigenesis of various organs, including colorectal cancer. This study aims to clarify the prevalence of these fusions in colorectal cancer in the Japanese population. Immunohistochemical analysis of 1012 specimens of colorectal cancer revealed two NTRK-positive cases (0.2%) whereas no ALK- or ROS1-positive cases were identified. Reverse transcription polymerase chain reaction (RT-PCR) detected an LMNA-NTRK1 fusion in a case of adenosquamous carcinoma and a TPM3-NTRK1 fusion in a case of tubular adenocarcinoma. Both NTRK1 fusion-positive cases lacked activating mutations in KRAS and BRAF and were mismatch repair-deficient with loss of MLH1 and PMS2 expression and MLH1 promoter methylation. Our results show that receptor tyrosine kinase fusions are rare but present in colorectal cancers in Japanese patients, with a prevalence similar to that reported in other countries.

A novel NCOR2-NTRK1 fusion detected in a patient of lung adenocarcinoma and response to larotrectinib: a case report.

BACKGROUND: The identification of NTRK fusions in tumours has become critically important due to the actionable events predictive of response to TRK inhibitor. It is not clear whether the NTRK breakpoint location is different for response to targeted therapy and NTRK fusions affects the efficacy of immunotherapy. CASE PRESENTATION: Here we reported a 60-year-old female diagnosed with advanced lung adenocarcinoma. NGS-based molecular profiling identified a novel NCOR2-NTRK1 fusion and high tumor mutational burden (TMB) (58.58 mutations/Mb) in this case. Additionally, program death-ligand 1 (PD-L1) expression was detected in 20-30% of the tumor cells by immunohistochemical (IHC) staining. The patient received treatment with anti-PD-1 immune checkpoint inhibitor of camrelizumab. After two cycles of treatment, the CT scan showed some tumor nodules were still enlarged, indicating disease progression. She was then changed to TRK inhibitor larotrectinib. One month later, the CT scan showed the volume of some lesions started to decrease, and no metastasis lesions were found. The patient then continued the administration of larotrectinib, and some lesion sizes were significantly reduced or even disappeared in the next few months. Currently, this patient is still alive. CONCLUSIONS: Altogether, this report provided a new driver of lung adenocarcinoma expanded the mutational spectrum of NTRK1 fusion variants and suggested using larotrectinib as the targeted therapy is more effective than anti-PD-1 inhibitor in lung adenocarcinoma harboring with NTRK fusion, positive PD-L1 expression, and high TMB simultaneously.

NTRK testing: First results of the QuiP-EQA scheme and a comprehensive map of NTRK fusion variants and their diagnostic coverage by targeted RNA-based NGS assays.

Gene fusions involving the three neurotrophic tyrosine receptor kinase genes NTRK1, NTRK2, or NTRK3 were identified as oncogenic drivers in many cancer types. Two small molecule inhibitors have been tested in clinical trials recently and require the detection of a NTRK fusion gene prior to therapeutic application. Fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (tNGS) assays are commonly used for diagnostic profiling of gene fusions. In the presented study we applied an external quality assessment (EQA) scheme in order to investigate the suitability of FISH and RNA-/DNA-based tNGS for detection of NTRK fusions in a multinational and multicentric ring trial. In total 27 participants registered for this study. Nine institutions took part in the FISH-based and 18 in the NGS-based round robin test, the latter additionally subdivided into low-input and high-input NGS methods (regarding nucleic acid input). Regardless of the testing method applied, all participants received tumor sections of 10 formalin-fixed and paraffin-embedded (FFPE) tissue blocks for in situ hybridization or RNA/DNA extraction, and the results were submitted via an online questionnaire. For FISH testing, eight of nine (88.8%) participants, and for NGS-based testing 15 of 18 (83.3%) participants accomplished the round robin test successfully. The overall high success rate demonstrates that FISH- and tNGS-based NTRK testing can be well established in a routine diagnostic setting. Complementing this dataset, we provide an updated in silico analysis on the coverage of more than 150 NTRK fusion variants by several commercially available RNA-based tNGS panels.

Characterization of on-target adverse events caused by TRK inhibitor therapy.

BACKGROUND: The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. PATIENTS AND METHODS: Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. RESULTS: Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. CONCLUSIONS: TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

TRK Inhibitors in Non-Small Cell Lung Cancer.

OPINION STATEMENT: Care should be taken to ensure that the diagnostic strategy for a recently diagnosed advanced non-small cell lung cancer includes NTRK fusion testing. RNA sequencing is the gold standard method of detection of NTRK fusion; however, pan-TRK immunohistochemistry could be used as a screening method with good sensitivity. Larotrectinib and entrectinib are approved therapies for TRK fusion-positive lung cancers as first or subsequent lines of therapy. TRK inhibition has demonstrated clinically meaningful, deep, and durable systemic and central nervous system responses. Larotrectinib and entrectinib have a manageable safety profile, including some TRK-related adverse events, such as dizziness and weight gain. At disease progression on first-generation TRK inhibitors, enrollment on a clinical trial should be encouraged, as new-generation TRK inhibitors are being tested.

Japan society of clinical oncology/Japanese society of medical oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese society of pediatric hematology/oncology.

BACKGROUND: The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 15 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.

Changing the Therapeutic Landscape in Non-small Cell Lung Cancers: the Evolution of Comprehensive Molecular Profiling Improves Access to Therapy.

Targeting genomic alterations has led to a paradigm shift in the treatment of patients with lung cancer. In an effort to better identify potentially actionable alterations that may predict response to FDA-approved and or investigational therapies, many centers have migrated towards performing targeted exome sequencing in patients with stage IV disease. The implementation of next-generation sequencing (NGS) in the evaluation of tumor tissue from patients with NSCLC has led to the discovery of targetable alterations in tumors that previously had no known actionable targets by less comprehensive profiling. An improved understanding of the molecular pathways that drive oncogenesis in NSCLC and a revolution in the technological advances in NGS have led to the development of new therapies through biomarker-driven clinical trials. This review will focus on the advances in molecular profiling that continue to fuel the revolution of precision medicine, identifying targets such as MET exon 14 skipping alterations and select recurrent gene alterations with increasing frequency.

LMNA::NTRK1 Fusion-positive Leiomyosarcoma: Discrepancy between DNA-based Comprehensive Genomic Profiling and RNA Sequencing.

A 26-year-old man presented with a tumor in the left soleus muscle. The tumor was diagnosed as a locally advanced leiomyosarcoma. The patient was treated with irradiation followed by wide resection. One year after surgery, the patient presented with multiple lung metastases. Despite aggressive sequential chemotherapy, systemic metastatic tumors continued to develop. To explore therapeutic options for the patient, we performed DNA-based CGP with FoundationOne® CDx (F1). F1 identified an out-of-strand rearrangement of the NOS1AP::NTRK1 gene, which has not been previously reported. In contrast, RNA sequencing revealed an in-frame LMNA::NTRK1 gene, which is an oncogenic fusion gene.

Larotrectinib efficacy for liver metastases in papillary thyroid carcinoma patient harboring SQSTM1-NTRK1 fusion.

BACKGROUND: Pooled data analysis from three phase I/II larotrectinib clinical trials revealed that larotrectinib demonstrated rapid and durable disease control and a favorable safety profile for patients with neurotrophic-tropomyosin receptor kinase (NTRK) fusion positive thyroid carcinoma. Herein, we report the case of a patient with papillary thyroid carcinoma (PTC) and liver metastases who demonstrated a durable response to treatment with larotrectinib. CASE PRESENTATION: A 50-year-old female with PTC was referred to our hospital for postoperative observation. Computed tomography (CT) scan was performed to screen for distant metastasis, since thyroglobulin concentration increased gradually, and revealed multiple distant metastases, including multiple liver metastases. Radioactive iodine was administered at a dose of 100 mCi. However, uptake was observed only in the thyroid bed, and distant metastases had no avidity. As liver metastases progressed, lenvatinib (24 mg/day) was initiated after confirmation of liver metastases by liver biopsy 9 years and 1 month after the initial referral to our hospital. Since the multiple metastases became refractory for lenvatinib, the OncoGuide™ NCC Oncopanel System was performed, and the SQSTM1-NTRK1 gene fusion was confirmed. Larotrectinib was subsequently administered at a dose of 200 mg/day. The CT before the initiation of larotrectinib showed multiple liver metastases with a maximum diameter of 48 mm. The first CT evaluation at 1 month after the initiation of larotrectinib treatment showed that the tumor volume was reduced by 28% in the RECIST 1.1 criteria. After 3 months of larotrectinib treatment, a 38% reduction in the tumor volume was achieved as the best clinical response. The only side effect was grade 1 myalgia. At 12 months after the initiation of larotrectinib treatment, none of the lesions had progressed. CONCLUSIONS: 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.