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 ◽  
...  

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.

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i42-i42
Author(s):  
Sébastien Perreault ◽  
François Doz ◽  
Birgit Geoerger ◽  
Karsten Nysom ◽  
Ingrid Øra ◽  
...  

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.


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 ◽  
...  

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.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii385-iii386
Author(s):  
Claudia Madrigal-Avila ◽  
Alfonso Perez-Bañuelos ◽  
Rafael Ruvalcaba-Sanchez ◽  
Lourdes Vega-Vega ◽  
Gabriela Escamilla-Asiain

Abstract BACKGROUND Central nervous system (CNS) tumors are the most common solid neoplasms in the pediatric age, they comprise about a quarter of all cancers at this age. Little is known about the specific epidemiology of this group in Mexico and there are no reports of results focused on the Performance Status of patients who are treated in a multidisciplinary setting. OBJECTIVE To describe the Performance Status of CNS pediatric patients after being treated with a multidisciplinary approach in a tertiary center. METHODS We report a retrospective chart review of all pediatric patients who presented to the Neuro-Oncology Clinic at Teleton Pediatric Oncology Hospital in Queretaro, Mexico, from December 2014 to January 2020. We analyzed age, gender, the extent of surgical resection and histopathology. Performance Status was assessed using ECOG and Karnofsky/Lansky scores during every patient’s last follow-up visit. RESULTS A total of 56 patients were treated, epidemiology and histopathology variants are similar to those described in the international literature. With a median follow-up of 33 months, 35 patients are alive (62.5%), 28 of them (74.2%) have an excellent Performance Status (ECOG score 0 or Lansky/Karnofsky ≥ 90), 5 (14.2%) scored ECOG 1–2 and only 4 (11.4%) scored ECOG 3–4. CONCLUSIONS A multidisciplinary approach with a focus on Performance Status and the potential for neurological recovery is essential in the management of pediatric patients with CNS tumors. Efforts should be aimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii127-ii127
Author(s):  
Nicholas Pytel ◽  
Erik Dedekam ◽  
Shahriar M Salamat ◽  
Diane Puccetti

Abstract Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii459-iii459
Author(s):  
Daniel J Indelicato ◽  
James Bates ◽  
Raymond Mailhot-Vega ◽  
Christopher Morris ◽  
Eric Sandler ◽  
...  

Abstract BACKGROUND Previous institutional data suggests the 10-year cumulative incidence of second tumors is 3% in children treated with photon radiation for central nervous system (CNS) malignancy, with 90% of these tumors occurring in areas receiving ≤36 Gy. Comparative figures for children treated with proton therapy (PT) does not exist. METHODS 1056 consecutive pediatric patients with a median follow-up of 5.0 years were treated between 2006–2019 with double-scattered PT to a site within the craniospinal axis. 230 patients were ≤3 years old and 14 had neurofibromatosis. A second tumor was defined as any solid neoplasm with histologic features different from the original tumor that had arisen within the irradiated volume. RESULTS Five patients developed second tumors resulting in a 5- and 10-year cumulative incidence of 0.2% (95% CI: 0–1.2%) and 1.6% (95% CI: 0.6%-3.9%), respectively. Of those who developed second tumors, median age at radiation was 4.3 years old (range, 2.1 to 5.1 years old) and diagnoses consisted of medulloblastoma (n=2), ependymoma (n=2), and craniopharyngioma (n=1). The second tumors included high grade gliomas (n=3) and high grade sarcoma (n=1) that occurred in regions receiving at least 54 Gy. One patient with neurofibromatosis developed both a low-grade glioma and choroidal melanoma in craniospinal irradiation regions receiving 36 Gy. Four of five patients with second tumors are alive. CONCLUSION The reduction in moderate-to-low dose radiation exposure from proton therapy may be associated with a decreased incidence of second tumors in children treated for CNS neoplasms. More follow-up is needed to confirm these findings.


2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Valérie Larouche ◽  
Annie-Kim Toupin ◽  
Benoît Lalonde ◽  
David Simonyan ◽  
Nada Jabado ◽  
...  

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.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi188-vi188
Author(s):  
Claudia Madrigal-Avila ◽  
Rafael Ruvalcaba-Sanchez ◽  
Alfonso Perez-Bañuelos ◽  
Gabriela Escamilla-Asiain ◽  
Andrea Ellis ◽  
...  

Abstract BACKGROUND Central nervous system (CNS) tumors are the most common solid neoplasms in the pediatric age. Despite this, there are no reports of results focused on the performance status of pediatric patients who are treated in a multidisciplinary setting. OBJECTIVE Describe the Performance Status of CNS pediatric patients after being treated with a multidisciplinary approach in a tertiary center. METHODS We review the chart of the pediatric patients at the Teleton Children Oncology Hospital from December 2014 to December 2019. The performance status was evaluated either using ECOG, Karnofsky, or Lansky scores. The multidisciplinary approach at our hospital includes: A Well-Equipped Diagnostic Center, integrated by a CAP-accredited laboratory, a Molecular Biology Unit, and the Imaging Unit, including a high-quality 2 tesla MRI. The surgical equipment comprises a surgical microscope, bipolar coagulation equipment, microsurgical instruments, and craniotomy equipment. For deep biopsies or functional surgery, we use Frame-Based Stereotactic Systems (FBSS) and neuronavigation systems. We provide first-line chemotherapy protocols and have a radiotherapy unit that can start treatment within a week. We have an Intensive Care Unit for oncologic patients with a 93% of overall survival. We provide ludic therapy and cognitive behavioral therapy, as well as emotional support. The Physical Rehabilitation Clinic uses the Bobath concept, proprioceptive and neuromuscular techniques as well as follow-up visits according to needs. RESULTS Of the 56 patients treated, 35 were evaluated with ECOG/Lansky performance status scale during the last follow up visit, resulting in 74.2% with a fully active performance, able to carry on all pre-disease activities without restriction. CONCLUSION A multidisciplinary approach is essential in the management of pediatric patients with CNS tumors. Efforts should be aimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term as we described many of them have an excellent performance status.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii451-iii451
Author(s):  
Nicholas Pytel ◽  
Erik Dedekam ◽  
M Shahriar Salamat ◽  
Diane Puccetti

Abstract Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii438-iii438
Author(s):  
Kathleen Dorris ◽  
Jessica Channell ◽  
Ashley Mettetal ◽  
Molly Hemenway ◽  
Natalie Briones ◽  
...  

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.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii430-iii430
Author(s):  
Ross Mangum ◽  
Jacquelyn Reuther ◽  
Koel Sen Baksi ◽  
Ryan C Zabriskie ◽  
Ilavarasi Gandhi ◽  
...  

Abstract BACKGROUND The role of plasma cell-free DNA (cfDNA) as a cancer biomarker for tracking treatment response and detecting early relapse has been well described for solid tumors outside the central nervous system (CNS). However, the presence of a blood-brain barrier complicates the application of plasma cfDNA analysis for patients with CNS malignancies. METHODS cfDNA was extracted from plasma of pediatric patients with CNS tumors utilizing a QIAmp® MinElute® kit and quantitated with Qubit 2.0 Fluorometer. Extensive genomic testing, including targeted DNA and RNA solid tumor panels, exome and transcriptome sequencing, as well as copy number array, was performed on matched tumor samples as part of the Texas KidsCanSeq study. An Archer® Reveal ctDNA28 NGS kit was then used for assaying the sensitivity of detecting tumor-specific mutations in the plasma of these patients. RESULTS A median of 10.7ng cfDNA/mL plasma (Interquartile range: 6.4 – 15.3) was extracted from 78 patients at time of study enrollment. Longitudinal samples from 24 patients exhibited a median yield of 7.7ng cfDNA/mL plasma (IQR: 5.9 – 9.1). An initial cohort of 6 patients was identified with 7 somatic variants covered by the Archer® Reveal kit. Four of seven mutations identified in matched tumor specimens were detected in patient plasma at variant allele frequencies ranging from 0.2–1%. CONCLUSIONS While challenging, detection of cfDNA in the plasma of pediatric patients with CNS tumors is possible and is being explored in a larger patient cohort along with pilot studies investigating cerebrospinal fluid as an additional source for tumor-specific cfDNA.


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