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Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib.

ABSTRACT: Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment. Routine clinical examination classified the tumor as a BRAF-negative pilocytic astrocytoma. Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32-33 leading to breakpoints within the GKAP1 and NTRK2 genes. RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10-16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain. Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705). Subsequently, downstream mediators of the MAPK- and PI3K-signaling pathways were upregulated in GKAP1-NTRK2 cells compared to NTRK2 wild-type; phosphorylated (p)ERK (3.6-fold), pAKT (1.8- fold), and pS6 ribosomal protein (1.4-fold). Following these findings, the patient was enrolled in a clinical trial and treated with the specific TRK-inhibitor larotrectinib, resulting in the arrest of tumor growth. The patient's condition is currently stable and the quality of life has improved significantly. Our findings highlight the value of comprehensive clinical molecular screening of BRAF-negative pediatric low-grade gliomas, to reveal rare fusions serving as targets for precision therapy.

SUBMITTER: Deland L

PROVIDER: S-EPMC8043191 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Background NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors. Methods Patients aged <18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results By July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib. Conclusions In pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.

Project description:BackgroundFusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.MethodsWe enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.ResultsA total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.ConclusionsLarotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

Project description:ObjectiveLarotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).MethodsWe pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.ResultsTwenty-nine patients (median age: 60; range: 6-80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51-87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64-97) for PTC/FTC and 29% (95% CI 4-71) for ATC. Median time to response was 1.87 months (range 1.64-3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1-2.ConclusionIn TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.Significance statementNTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.

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Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib.

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