scholarly journals RARE-45. ACTIVITY OF LAROTRECTINIB IN TRK FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi231-vi231 ◽  
Author(s):  
Francois Doz ◽  
Birgit Geoerger ◽  
Steven G DuBois ◽  
Juneko E Grilley-Olson ◽  
Cornelis M van Tilburg ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Disease Control ◽  
Objective Response ◽  
Cns Tumors ◽  
Clinical Activity ◽  
Molecular Testing ◽  
Low Grade ◽  
Gene Fusions ◽  
Duration Of Treatment

Abstract BACKGROUND TRK fusions are oncogenic drivers of a variety of tumors, many of which can involve the central nervous system (CNS). Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion cancers (Drilon et al., NEJM 2018). Here we report on the clinical activity of larotrectinib in an expanded set of TRK fusion-positive primary CNS tumors. METHODS Patients with primary CNS tumors harboring a TRK fusion treated with larotrectinib on two clinical trials (NCT02637687 and NCT02576431) were identified by local molecular testing. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). Data cutoff: February 19, 2019. RESULTS 18 patients with various histological types of glial tumors (11 high-grade, 4 low-grade, 3 unknown) were identified. The patients had gene fusions involving NTRK2 (n=13), NTRK1 (n=2) and NTRK3 (n=2); one was not determined. Median age was 10 years (range 1–79); 14 patients were pediatric (< 18). In 14 evaluable patients, the objective response rate was 36% (2 CR, 3 PR), with responses seen in high- and low-grade disease and across histologies. Nine patients had SD. The 24-week disease control rate was 71%. The duration of treatment ranged from 0.03+ to 16.6+ months. One patient (3.7 years old) with glioblastoma progressed after 5.5 months on larotrectinib. Sequencing revealed a solvent front mutation and the patient was subsequently enrolled in compassionate use protocol for BAY2731954 (formerly known as LOXO-195). CONCLUSION Larotrectinib is active in patients with TRK fusion cancer with intracranial disease. Confirmed responses and durable disease control were seen in primary CNS tumors of various grades and histologies. These results further support expanded testing for NTRK gene fusions in patients with primary CNS tumors.

scholarly journals EPCT-08. ACTIVITY OF LAROTRECTINIB IN PEDIATRIC TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii305-iii305
Author(s):  
Hiroaki Goto ◽  
Birgit Geoerger ◽  
Steven G DuBois ◽  
Juneko E Grilley-Olson ◽  
Cornelis M van Tilburg ◽  
...  
Keyword(s):  
Disease Control ◽  
Pediatric Patients ◽  
Objective Response ◽  
Progression Free Survival ◽  
Disease Status ◽  
Cns Tumors ◽  
Clinical Activity ◽  
Molecular Testing ◽  
Gene Fusions ◽  
Duration Of Treatment

Abstract BACKGROUND TRK fusions are oncogenic drivers in a variety of tumors, many involving the CNS. Larotrectinib, a selective FDA- and EMA-approved TRK inhibitor, demonstrated a 79% objective response rate (ORR) and a 35.2-month median duration of response (DoR) in adult and pediatric patients with various non-CNS solid tumors harboring NTRK gene fusions. We report the clinical activity of larotrectinib in pediatric patients with primary TRK fusion CNS tumors. METHODS Patients aged &lt;18 years with primary CNS tumors harboring an NTRK gene fusion detected by local molecular testing who were treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). RESULTS As of February 2019, 14 pediatric patients with primary TRK fusion CNS tumors were identified. Gene fusions involved NTRK2 (n=10), NTRK1 (n=2), and NTRK3 (n=2). Median age was 7.0 years (range 1.3–16.7). ORR was 45% (95% CI 17–77%) among 11 evaluable patients. Two patients had complete responses (pending confirmation), three had confirmed partial responses, and six had stable disease. 24-week disease control rate was 73%. DoR ranged from 2.6+ to 5.5+ months and progression-free survival ranged from 0.03+ to 13.9+ months. Duration of treatment ranged from 0.03+ to 16.6+ months. Treatment-emergent adverse events were mainly grade 1–2. CONCLUSIONS Larotrectinib resulted in objective responses and durable disease control in pediatric patients with primary TRK fusion CNS tumors. These results support expanded testing for NTRK gene fusions in patients with CNS tumors.

Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2002-2002
Author(s):  
Sébastien Perreault ◽  
Cornelis Martinus van Tilburg ◽  
Birgit Geoerger ◽  
Karsten Nysom ◽  
Ingrid Ora ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Disease Control ◽  
Pediatric Patients ◽  
Disease Control Rate ◽  
Cns Tumors ◽  
Low Grade ◽  
Gene Fusions ◽  
Receptor Kinase

2002 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types, including central nervous system (CNS) tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across 175 adult and pediatric patients with various non-CNS cancers (McDermott et al, ESMO 2020). We report data on patients with TRK fusion-positive primary CNS tumors. Methods: Patients 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: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified: 19 high-grade gliomas (HGG), 8 low-grade gliomas (LGG), 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, and 1 small round blue cell tumor. The patients had gene fusions involving NTRK2 (n = 24; 73%), NTRK1 (n = 5; 15%), and NTRK3 (n = 4; 12%). Median age was 8.9 years (range 1.3–79.0); 26 patients were pediatric ( < 18 years). Patients were heavily pre-treated with 45% having 2 or more prior lines of systemic therapy. The ORR in all patients was 30% (95% CI 16–49): 3 complete responses (all in pediatric patients), 7 partial responses (2 pending confirmation), 20 stable disease (including 15 pts > 6 months), and 3 progressive disease. The ORR in patients with HGG and LGG were 26% (95% CI 9–51) and 38% (95% CI 9–76), respectively. In all patients, the 24-week disease control rate was 73% (95% CI 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The median time to response was 1.9 months. Median duration of response (DoR) was not reached (95% CI 3.8–not estimable [NE]) at a median follow-up of 12.0 months. The 12-month DoR rate was 75% (95% CI 45–100). Median PFS was 18.3 months (95% CI 6.7–NE) at a median follow-up of 16.5 months. Median overall survival (OS) was not reached (95% CI 16.9–NE) at a median follow-up of 16.5 months, with a 12-month OS rate of 85% (95% CI 71–99). Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events (TRAE) were reported by 20 patients and were Grade 3–4 in 3 patients (9%). There were no treatment discontinuations due to TRAEs. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile. These results support testing for NTRK gene fusions in patients of all ages with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

scholarly journals RARE-07. EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i42-i42
Author(s):  
Sébastien Perreault ◽  
François Doz ◽  
Birgit Geoerger ◽  
Karsten Nysom ◽  
Ingrid Øra ◽  
...  
Keyword(s):  
Disease Control ◽  
Pediatric Patients ◽  
Objective Response ◽  
High Grade Glioma ◽  
Disease Control Rate ◽  
Cns Tumors ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
High Grade ◽  
Gene Fusions

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 &lt;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.

Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2006-2006 ◽  
Author(s):  
Alexander E. Drilon ◽  
Steven G. DuBois ◽  
Anna F. Farago ◽  
Birgit Geoerger ◽  
Juneko E. Grilley-Olson ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Metastases ◽  
Disease Control ◽  
Objective Response ◽  
Response To Therapy ◽  
Cns Tumors ◽  
Tumor Shrinkage ◽  
Age Range ◽  
Fusion Type

2006 Background: TRK fusions are oncogenic drivers of a variety of cancers, many of which can involve the central nervous system (CNS). Larotrectinib is an FDA-approved selective TRK inhibitor for the treatment of TRK fusion cancer (Drilon et al, NEJM 2018). While larotrectinib has been shown to cross the blood–brain barrier (Ziegler et al, Br J Cancer 2018), its clinical activity in a series of TRK fusion cancers with primary or metastatic intracranial disease has not been described. Methods: Patients (pts) with non-primary CNS solid tumors with brain metastases, or primary CNS tumors harboring a TRK fusion treated with larotrectinib in 2 clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression (PD), withdrawal, or unacceptable toxicity. Disease status was investigator-assessed (RANO and RECIST). Data cutoff: July 30, 2018. Results: 14 pts were identified: 5 non-primary CNS solid tumors (3 lung cancer, 2 thyroid cancer; fusion type: 2 ETV6-NTRK3, 2 SQSTM1-NTRK3, 1 EPS15-NTRK1; age range 25–79 y) and 9 primary CNS tumors (3 glioma, 2 glioblastoma, 1 astrocytoma, 3 NOS; fusion type: 3 BCR-NTRK2, 2 KANK-NTRK2, 1 each of AFAP1-NTRK1, AGTPBP1-NTRK2, ETV6-NTRK3, SPECC1L-NTRK2; age range 2–79 y). In the 5 pts with non-primary CNS tumors, the best objective response to therapy was PR in 3 (60%, 1 pending confirmation), SD in 1 (20%), and not evaluable (NE) in 1 (20%). Duration of response ranged from 9+ to 13 mo. In the 9 pts with primary CNS tumors, disease control was achieved in all evaluable pts (primary PD not observed; 1 pt required dose increase). The best objective response to therapy was PR in 1 (11%; pending confirmation, −55% tumor shrinkage, ongoing at 3.7 mo), SD in 7 (78%; tumor shrinkage range −1% to −24% for pts with measurable disease, 5 had SD > 4 mo), and NE in 1 (11%). Duration of treatment ranged from 2.8–9.2+ mo. Conclusions: Larotrectinib is active in pts with TRK fusion cancers with intracranial disease. Confirmed responses and durable disease control were seen in metastatic disease and primary CNS tumors of various histologies. These results further support expanded testing for TRK fusions across all cancers, including primary CNS tumors. Clinical trial information: NCT02637687 and NCT02576431.

scholarly journals QOL-36. USE OF CANNABINOIDS IN THE PEDIATRIC CENTRAL NERVOUS SYSTEM TUMOR POPULATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii438-iii438
Author(s):  
Kathleen Dorris ◽  
Jessica Channell ◽  
Ashley Mettetal ◽  
Molly Hemenway ◽  
Natalie Briones ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Central Nervous System ◽  
Nervous System ◽  
Cell Activity ◽  
Cns Tumors ◽  
Low Grade ◽  
Tumor Type ◽  
Central Nervous System Tumor ◽  
The Impact

Abstract BACKGROUND Cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are a class of compounds found in marijuana. Numerous studies in adults have examined cannabinoid use in management of cancer-related symptoms such as nausea, anorexia, and pain. Less is known about the use in the pediatric oncology population. METHODS A prospective observational study has been ongoing since 2016 at Children’s Hospital Colorado to evaluate cannabinoids’ impact using PedsQL™ modules on quality of life of pediatric patients with central nervous system (CNS) tumors who are 2–18 years old. Laboratory assessments of T-cell activity and pharmacokinetics of CBD, THC and associated metabolites are in process. Diaries with exploratory information on cannabinoid use patterns are being collected. RESULTS Thirty-three patients (14:19; male:female) have been enrolled with a median age of 6.4 years (range, 2.9–17.7 years). The most common tumor type in enrolled patients is embryonal tumors (13/33; 39%). Nine (27%) patients have low-grade glial/glioneuronal tumors, and eight (24%) had high-grade/diffuse midline gliomas. The remaining patients had ependymoma or craniopharyngioma. The median time on cannabinoids is 9 months. Most (n=20) patients have used oral products with CBD and THC. One patient continues on cannabinoid therapy in follow up. Preliminary immune function analyses identified impaired neutrophil superoxide anion production and chemotaxis in patients taking cannabinoids at early time points on therapy. CONCLUSIONS Families of children with various CNS tumors are pursuing cannabinoid therapy for both antitumor and supportive care purposes. Analysis of the impact of cannabinoids on patients’ quality of life is ongoing.

Chromosome abnormalities in low grade central nervous system (CNS) tumors

1991 ◽  
Vol 56 (1) ◽  
pp. 127
Author(s):  
P.P. Long ◽  
B.S. Carson ◽  
H. Brem ◽  
S. Grossman ◽  
C.A. Griffin
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Chromosome Abnormalities ◽  
Cns Tumors ◽  
Low Grade

scholarly journals Incidence trends in pediatric central nervous system tumors in Canada: a 15 years report from Cancer and Young People in Canada (CYP-C) registry

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Valérie Larouche ◽  
Annie-Kim Toupin ◽  
Benoît Lalonde ◽  
David Simonyan ◽  
Nada Jabado ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Young People ◽  
Pediatric Patients ◽  
Incidence Rates ◽  
Cns Tumors ◽  
Benign Tumors ◽  
Low Grade ◽  
Age Group ◽  
Cns Tumor

Abstract Background The aim of this study is to present a national surveillance report on pediatric central nervous system (CNS) tumors in Canada during the period between 2001 and 2015. Methods All pediatric patients with a diagnosis of primary CNS tumors were collected by the Cancer in Young People in Canada (CYP-C) surveillance system that includes every patient less than 15 years of age with a tumor seen in one of the 17 pediatric oncology centres in Canada. This registry included malignant and benign CNS tumors. We calculated the age-adjusted incidence rates (AAIRs) per 100 000 person-years for CNS tumors overall and by age group, major histology subgroups, and geographical distribution over the country. Results Overall, 3306 patients less than 15 years old had been diagnosed with a CNS tumor in Canada in 2001–2015 with a 1.23:1 male to female ratio. The overall AAIR is 3.80. The three most frequent groups of tumors were low-grade gliomas (36.4%), high-grade gliomas (22.3%), and embryonal tumors (18.7%) with incidence rates of 1.41, 0.86, and 0.72 per 100 000 person-years, respectively. The incidence rate of pediatric CNS tumors is stable during the period 2001–2015 in Canada and no significant differences were seen between malignant and benign tumors over the country. Conclusions These data represent all the pediatric patients 0–14 years old with a CNS tumor in the Canadian population. Incidence rates by age group, sex, and subgroups of tumors are similar to those seen in the literature.

scholarly journals RETROSPECTIVE ANALYSIS OF INTRACRANIAL AND INTRASPINAL SPACE OCCUPYING LESIONS AT A TERTIARY CARE CENTER- A FIVE YEAR STUDY

2018 ◽  
Vol 6 (10) ◽  
pp. 100-109
Author(s):  
Meena B. Patil ◽  
Manjiri N. Karandikar
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Who Classification ◽  
Frozen Section ◽  
Tertiary Care ◽  
Cns Tumors ◽  
Low Grade ◽  
Wide Range ◽  
The Central Nervous System

Background: Tumors of Central Nervous System constitute approximately 2% of all malignancies. Cancers of the central nervous system (CNS) are considered to be among the most notorious of all cancers. Low-grade cns tumors have been found over time to progress to high grade tumors. CNS is a common site for metastasis from other organs. Due to newer techniques used in radio diagnosis and stereotactic biopsies, more & more CNS tumors are being diagnosed & are being operated upon. Aims and objectives: The objective of this article is to provide an overview of intracranial and intraspinal space occupying lesions at a single tertiary care referral center. The aim was to study incidence of various lesions in light of the   WHO classification of tumours of the central nervous system, 2016 and to study relevant statistics. Material and methods: A total of 124 cases were received between January,2007 & December, 2011 at Bharati Vidyapeeth Deemed University Medical College and Hospital, Pune. Intraoperative diagnosis was desired in 70 cases. The final diagnoses in all the cases were made on Hematoxylin and Eosin stained slides of routinely processed tissue. Results: Neoplastic lesions comprised 83.88 %, including metastatic tumors while 16.12 % were nonneoplastic.  A wide range of histopathological spectrum of CNS tumors was observed and was classified according to WHO classification of CNS tumors, 2016. The primary CNS tumors were graded from Grade I to IV according to WHO grading system, 2016. Astrocytic tumors constituted the largest category with 33 cases and most of the astrocytomas were grade II at the time of diagnosis. Incidence was more in females than males and maximum number of lesions were seen in fifth and sixth decades of life. Conclusion: This study highlights the histological diversity of CNS tumors in both adults and children. The most common destructive but nonneoplastic lesions like, infections/abscesses, infarct and cysts can be diagnosed, by crush cytology and frozen section for the definitive management.

scholarly journals TB-08 PATIENT DERIVED XENOGRAFT’S BIOBANK FROM KANSAI MOLECULAR DIAGNOSIS NETWORK FOR CENTRAL NERVOUS SYSTEM TUMORS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii11-ii11
Author(s):  
Noriyuki Kijima ◽  
Daisuke Kanematsu ◽  
Tomoko Shofuda ◽  
Masahiro Nonaka ◽  
Ryoichi Iwata ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tumors ◽  
Molecular Diagnosis ◽  
Central Nervous System Lymphoma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade Glioma ◽  
Cns Tumors ◽  
Low Grade

Abstract Patient-derived xenografts (PDXs) are essential tools for translational research for brain tumors. However, it is sometimes difficult for each institution to establish PDXs because it needs experiences and techniques and it also takes a lot of works to establish them. Thus we aim to establish patient derived xenograft’s biobank among institutions of Kansai Molecular Diagnosis Network for Central Nervous System (CNS) Tumors, Osaka, Japan. We have already began sharing two anaplastic astrocytoma PDXs, twelve glioblastoma IDH wild type PDXs, two medulloblastoma Shh subgroup PDXs, one atypical teratoid/rhabdoid tumor (AT/RT) PDX, and three metastatic brain tumor PDXs. Furthermore these PDXs can also be cultured in vitro, except 2 medulloblastoma SHH subgroup PDXs, 1 AT/RT PDX. However, we have not yet established any PDXs from low grade glioma, ependymoma, primary central nervous system lymphoma (PCNSL), diffuse intrinsic pontine glioma (DIPG). We began sharing these PDXs among the institutions of Kansai Molecular Diagnosis Network for CNS Tumors, Osaka, Japan. However, further improvement is necessary to succeed in establishing PDX from low grade glioma, PCSNL, DIPG, etc. and get enough number of PDXs so we can share PDXs from almost all of the brain tumors.

CTNI-58. EFFICACY AND SAFETY OF LAROTRECTINIB IN ADULT AND PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi73-vi74
Author(s):  
François Doz ◽  
Cornelis M van Tilburg ◽  
Birgit Geoerger ◽  
Karsten Nysom ◽  
Ingrid Øra ◽  
...  
Keyword(s):  
Disease Control ◽  
Objective Response ◽  
Disease Control Rate ◽  
Cns Tumors ◽  
Low Grade ◽  
Grade 3 ◽  
Round Blue Cell Tumor ◽  
Glioneuronal Tumors ◽  
Favorable Safety ◽  
Systemic Therapies

Abstract BACKGROUND NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for patients with TRK fusion cancer, with a 75% objective response rate (ORR) in 206 evaluable patients with various non-CNS cancers (Hong et al, ASCO 2021). We report data on patients with TRK fusion-positive primary CNS tumors. METHODS Patients with TRK fusion-positive primary CNS tumors in 2 clinical trials (NCT02637687, NCT02576431) were identified. Objective responses were investigator-assessed. RESULTS As of July 2020, 33 patients with TRK fusion-positive primary CNS tumors were identified (19 high-grade gliomas [HGG], 8 low-grade gliomas [LGG], 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, 1 small round blue cell tumor). Median age was 8.9 years (range 1.3-79.0). Patients were heavily pre-treated, with 45% having ≥ 2 prior systemic therapies. ORR was 30% (95% CI 16-49): 3 complete responses (all pediatric), 7 partial responses, 20 stable disease, and 3 progressive disease. ORR in patients with HGG and LGG were 26% (95% CI 9-51) and 38% (95% CI 9-76), respectively. Median time to response was 1.9 months. Responses were seen regardless of the number of prior systemic therapies. The 24-week disease control rate was 73% (95% CI 54-87). Median PFS was 18.3 months (95% CI 6.7-not estimable [NE]) and median overall survival (OS) was not reached (95% CI 16.9-NE) at a median follow-up of 16.5 months; 12-month OS rate was 85% (95% CI 71-99). Treatment duration ranged from 1.2 to 31.3+ months. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 3 patients (9%). There were no treatment discontinuations due to TRAEs. CONCLUSIONS In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and favorable safety regardless of age or number of prior systemic therapies.

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