Pleomorphic liposarcoma of the uterus (PLU) is an extremely rare disease with poor prognosis. Limited treatment options exist for these patients, and disease recurrence usually occurs rapidly within months of initial diagnosis. Few case reports of metastatic PLU are available in the literature. We describe a 70-year-old woman who presented with a large uterus and ovarian mass on imaging and negative serum tumor markers and endometrial biopsy. Staging revealed localized disease. Surgical resection revealed PLU on pathology. Immunohistochemistry was negative for smooth muscle actin (SMA), S100, and MDM2, and positive for CD10 and cyclin-D1. She was treated with adjuvant therapy and experienced disease recurrence in the liver at 15 months from surgery. Genetic testing of the metastasis showed IQGAP-NTRK3 gene fusion. She was given entrectinib but continued to show progression in the liver. Right partial hepatectomy was performed, showing positivity for CD10, BCL-1, MDM2, and SMA on tumor staining. Treatment was switched to pazopanib with disease progression in the neck. She was treated with larotrectinib last, showing no disease progression and adequate tolerance of therapy after 18 months of this treatment. This is the first case in the literature of metastatic PLU with NRTK3 fusion treated with sequential first-generation NRTK inhibitors. More case reports are needed to identify commonalities and therapeutic options. Genetic testing in all PLU cases is needed for targeted therapy approaches.

This is an open label, non-randomized study to evaluate the efficacy and safety of the combination of larotrectinib followed by 131I therapy for patients with NTRK fusion differentiated thyroid cancer. The primary Phase II objective will be to evaluate the pulmonary structural response rate at 18 months to the combination of larotrectinib given for 6-months followed by 131I therapy.

BACKGROUND: Increasing knowledge about the genomic changes underpinning cancer development and growth has led to a rapidly expanding number of individualized therapies that specifically target these changes in a patient's tumor. Here we present a case report of a patient with metastatic esophageal carcinoma whose tumor harbored NTRK1 gene amplification and who received targeted systemic therapy with larotrectinib. At initial diagnosis, the patient presented with tumor obstruction of the middle esophagus, simultaneous liver and lung metastases, UICC IV and WHO performance status 3. MATERIALS AND METHODS: The solid tumor genomic profiling test FoundationOne CDx (F1CDx) was used to detect clinically relevant genomic alterations that, in turn, might identify a targeted therapeutic approach if suggested by the findings. The patient was then treated with larotrectinib and had subsequent follow-up biopsies. RESULTS: Simultaneous biopsies of the primary tumor and liver lesions identified a metastatic squamous cell esophageal carcinoma. Comprehensive genomic profiling obtained from liver metastases identified numerous genomic alterations including amplification of NTRK1. Owing to the reduced performance status of the patient, chemotherapy could not be applied and was denied. Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease. The NTRK1 gene amplification was below the limit of detection in a subsequent liver biopsy. CONCLUSION: The use of comprehensive genomic profiling, specifically F1CDx, enabled the selection of a targeted therapy that led to a rapid reduction of the tumor and its metastases according to RECIST criteria. This case suggests that larotrectinib is not only effective in NTRK fusions but may be efficacious in cases with gene amplification. KEY POINTS: Advances in precision medicine have revolutionized the treatment of cancer and have allowed oncologists to perform more individualized therapy. This case shows that larotrectinib could also be effective in cases of NTRK amplification of cancer. Today, there is only limited knowledge about NTRK alterations in squamous epithelial carcinoma of the esophagus. Longitudinal tumor sequencing during the course of the disease may allow for the detection of a molecular genetic cause once the tumor progresses. Additional actionable gene alterations may then be identified, which may provide the rationale for a therapy switch.

PRIMARY OBJECTIVE: I. To determine overall response rate (ORR) to larotrectinib sulfate (larotrectinib) in patients with advanced solid tumors harboring NTRK amplification and pan-TRK expression by immunohistochemistry (IHC), calculated as the proportion of subjects with confirmed complete (CR) or partial response (PR) as best response and as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and Response Assessment in Neuro-Oncology (RANO) criteria in primary central nervous system (CNS) tumor. SECONDARY OBJECTIVES: I. To evaluate the duration of response (DOR) in subjects with CR or PR as best response. II. To estimate the proportion of subjects with any tumor regression as best response. III. To evaluate the growth modulation index (GMI) following initiation of larotrectinib. IV. To evaluate overall (OS) and progression-free survival (PFS) following initiation of larotrectinib. V. To evaluate the clinical benefit rate (CBR) based on the proportion of subjects with best response of CR, PR, or stable disease lasting \>= 16 weeks following initiation of larotrectinib safety. VI. To assess the safety profile and tolerability of larotrectinib. EXPLORATORY OBJECTIVES: I. To characterize NTRK1, NTRK2, and NTRK3 amplification by next-generation sequencing of tumor biopsies. II. To characterize TRKA, TRKB, and TRKC signaling in fresh pre-treatment tumor biopsies, with the aim of elucidating TRK biology and modifiers of response to larotrectinib. III. To characterize concurrently activated oncogenic pathways in fresh pre-treatment tumor biopsies, with the aim of elucidating TRK biology and modifiers of response to larotrectinib. OUTLINE: Patients receive larotrectinib sulfate orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of unacceptable toxicity. Patients who experience disease progression and are deriving clinical benefit from larotrectinib may continue treatment per physician discretion. After completion of study treatment, patients are followed up at 4 weeks, and then every 3 months for 2 years.

INTRODUCTION: Neurotrophic receptor tyrosine kinase fusions cause overexpression or activation of kinase and are believed to confer oncogenic potential in some non-rhabdomyosarcoma soft tissue sarcomas. TRK inhibitors have recently been shown to induce responses in these tumours though current experience with these agents is still limited. CASE REPORT: We report a case of an adolescent with treatment-refractory non-rhabdomyosarcoma soft tissue sarcomas, carrying a novel DCTN1-NTRK1 gene fusion whose progressive disease was treated with multi-kinase and TRK inhibitors.Management and outcome: Our patient was started on pan-TRK inhibitor larotrectinib, as his disease progressed after chemotherapy, radiation therapy and surgery, based on next-generation sequencing test showing DCTN1-NTRK1 gene fusion. He responded quickly to larotrectinib with the improvement of symptoms and reduction of masses. However, this response was short-lived due to the development of acquired solvent front resistance mutation. This patient did not respond to next-generation TRK inhibitor selitrectinib and eventually succumbed to his disease. DISCUSSION: The initial rapid and drastic response of our patient to larotrectinib was not sustained due to the development of acquired resistance. This case emphasizes the need for upfront and periodic next-generation sequencing testing to guide treatment of patients with refractory non-rhabdomyosarcoma soft tissue sarcomas.

Patients with soft tissue sarcomas should be assessed for neurotrophic tropomyosin receptor kinase (NTRK) gene fusions as neoadjuvant treatment with larotrectinib may prevent amputation.

In this pilot study, we will assess the disease control rate (Continued Complete Response-CCR, Complete Response-CR, Partial Response-PR and Stable Disease-SD) as well as survival rate (overall survival- OS and progression free survival- PFS) in children with newly diagnosed HGG with TRK fusion who receive 2 cycles of larotrectinib monotherapy administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule. After 2 monotherapy cycles of larotrectinib, patients with CCR or CR will continue to receive larotrectinib maintenance therapy as monotherapy for a total of 12 cycles. Continuation of treatment beyond 12 cycles, and up to 24 cycles, may be considered for patients on Larotrectinib monotherapy if they are receiving clinical benefit from the study, at the discretion of the treating physician. Patients ≤ 48 months with PR or SD after 2 cycles of larotrectinib will go on to receive combination therapy with standard backbone chemotherapy (BABYPOG or HIT-SKK). Patients \> 48 months of age (or patients ≥ 36 months of age, or patients with DIPG \>18 months of age, at the discretion of the local investigator) will receive focal radiation therapy. A surgical cohort study will be explored whereby patients who have had a tumor biopsy/partial resection at their local institution and are planned to subsequently undergo definitive resection will receive 3-5 days (6-10 doses) of larotrectinib pre-surgery. The study design of this trial requires 15 patients evaluable for disease control and for safety/ toxicity of larotrectinib as monotherapy. The surgical cohort will enroll up to 4 patients and will count towards the total 15 evaluable patients. A minimum of 6 patients will be evaluable for safety toxicity of larotrectinib in combination with standard-of-care chemotherapy or radiotherapy.

BACKGROUND: The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. METHODS: A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. RESULTS: A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. CONCLUSIONS: Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.

Infantile fibrosarcoma (IFS) is a rare pediatric cancer that typically presents early in life. Surgical resection is commonly curative; however, resection is sometimes not possible requiring additional multimodal treatment. IFS commonly harbors a fusion in one of the neurotrophic receptor tyrosine kinase (NTRK) genes. Larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase (TRK), has been shown to be well tolerated and effective in children as young as 1-month old. We report a case of IFS in a newborn treated with larotrectinib. The patient experienced a rapid clinical and radiographic response demonstrating the potential to treat newborns with larotrectinib.

The trial will be conducted in 2 parts: an initial dose escalation phase of larotrectinib in subjects with advanced solid tumors will be followed by an expansion phase in subjects with solid tumors having a NTRK fusion. The objectives of the study are to determine the safety, pharmacokinetic profile, recommended dose and efficacy of orally administered larotrectinib in patients with NTRK fusions.