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 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.

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 Primary central nervous system tumors in Sergipe, Brazil: descriptive epidemiology between 2010 and 2018

2021 ◽  
Author(s):  
Bárbara Loiola SANTOS ◽  
Arthur Maynart Pereira OLIVEIRA ◽  
Hélio Araújo OLIVEIRA ◽  
Robson Luis Oliveira de AMORIM
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cns Tumors ◽  
World Health ◽  
High Morbidity ◽  
Age Group ◽  
Descriptive Epidemiology ◽  
The Subject ◽  
Health Organization ◽  
Age Range

ABSTRACT Background: Central nervous system (CNS) tumors are a heterogeneous group with high morbidity and mortality. Objectives: To describe the epidemiology of primary CNS tumors diagnosed in the state of Sergipe from 2010 to 2018. Methods: We evaluated histopathological and immunohistochemical reports on primary CNS tumors diagnosed in Sergipe, Brazil, between 2010 and 2018 and collected data regarding age, sex, location, World Health Organization (WHO) classification and histology. Results: Altogether, 861 primary CNS tumors were found. Tumors in brain locations occurred most frequently (50.8%; n=437). The neoplasms observed were most prevalent in the age range 45‒54 years (20.4%; n=176). Grade I tumors occurred most frequently, corresponding to 38.8% of the cases (n=38) in the age group of 0‒14 years, and 44.6% (n=340) in the population ≥15 years old. Between 0 and 14 years of age, other astrocytic tumors were the most prevalent (29.6%; n=29). In the age group between 15 and 34, gliomas were the most frequent (32.7%; n=54). Meningiomas predominated in the age group of 35 years and above, comprising 47.5% of cases (n=206) in the 35‒74 age group; and 61.2% (n=30) among patients over 75 years old. Conclusion: The epidemiology of primary CNS tumors in Sergipe between 2010 and 2018 is consistent with data in other current studies on the subject. Studies on the epidemiological evolution of these entities in Sergipe are needed.

scholarly journals EMBRYONAL TUMORS OF THE CENTRAL NERVOUS SYSTEM IN ADULTS: A REPORT OF THREE CASES. REVIEW OF THE LITERATURE

2021 ◽  
Vol 20 (1) ◽  
pp. 105-114
Author(s):  
M. V. Matsko ◽  
D. E. Matsko ◽  
E. N. Imyanitov ◽  
S. S. Sklyar ◽  
A. Yu. Ulitin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Objective Response ◽  
Immunohistochemical Analysis ◽  
Response To Therapy ◽  
Malignant Neoplasms ◽  
Embryonal Tumors ◽  
First Case ◽  
The Central Nervous System ◽  
Chemotherapy Patients

Background. Еmbryonal tumors of the central nervous system are malignant neoplasms that mainly occur in pediatric patients with a peak incidence at the age of 4 years. These tumors usually have small round blue cell histology and low differentiation.Method and case description. A report of three cases with embryonal CNS tumors of supratentorial localization has been presented. Immunohistochemical analysis classified these tumors as neuroblastoma (2 cases: Syn (+), NSE (+), CD (+) and Ki67 10/40 %; ages were 33 and 52 years) or ganglioneuroblastoma (1 case: Syn (+), NSE (+), CD 99 (+) and Ki67 40 %; age was 37 year). All patients underwent RT in a total dose of 60 Gy delivered to the area of the removed tumor and 6 cycles of adjuvant chemotherapy: patients with neuroblastoma received chemotherapy using EP regimen (cisplatin + etoposide), and patient with ganglioneuroblastoma received temozolomide.Results. An objective response to therapy was achieved in all 3 patients. The relapse-free survival (RFS) in the first case of neuroblastoma was 51 months, the overall survival (OS ) was more than 105 months (8 years 9 months); in the second case of neuroblastoma, RFS was 25 months 2 weeks and OS was more than 26 months. Both neuroblastomas contained ID H1(R132H) mutation. In the patient with ganglioneuroblastoma, the RFS was 87 months, and the OS was over 93 months (7 years, 9 months, 3 weeks).Conclusion. Supratentorial embryonal tumors of the central nervous system in adults are exceptionally rare and have a relatively favorable response to the standard treatment.

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.

scholarly journals PATH-27. MUTATION DETECTION USING PLASMA CELL-FREE DNA IN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii430-iii430
Author(s):  
Ross Mangum ◽  
Jacquelyn Reuther ◽  
Koel Sen Baksi ◽  
Ryan C Zabriskie ◽  
Ilavarasi Gandhi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasma Cell ◽  
Pediatric Patients ◽  
Cns Tumors ◽  
Cell Free Dna ◽  
Pilot Studies ◽  
Dna And Rna ◽  
Free Dna ◽  
Initial Cohort

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.

scholarly journals Co-Deregulated miRNA Signatures in Childhood Central Nervous System Tumors: In Search for Common Tumor miRNA-Related Mechanics

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3028
Author(s):  
George I. Lambrou ◽  
Apostolos Zaravinos ◽  
Maria Braoudaki
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cns Tumors ◽  
Normal Brain ◽  
Cns Tumor ◽  
Different Types ◽  
Receiver Operator Curve Analysis ◽  
The Central Nervous System ◽  
Tumor Types ◽  
Operator Curve

Despite extensive experimentation on pediatric tumors of the central nervous system (CNS), related to both prognosis, diagnosis and treatment, the understanding of pathogenesis and etiology of the disease remains scarce. MicroRNAs are known to be involved in CNS tumor oncogenesis. We hypothesized that CNS tumors possess commonly deregulated miRNAs across different CNS tumor types. Aim: The current study aims to reveal the co-deregulated miRNAs across different types of pediatric CNS tumors. Materials: A total of 439 CNS tumor samples were collected from both in-house microarray experiments as well as data available in public databases. Diagnoses included medulloblastoma, astrocytoma, ependydoma, cortical dysplasia, glioblastoma, ATRT, germinoma, teratoma, yoc sac tumors, ocular tumors and retinoblastoma. Results: We found miRNAs that were globally up- or down-regulated in the majority of the CNS tumor samples. MiR-376B and miR-372 were co-upregulated, whereas miR-149, miR-214, miR-574, miR-595 and miR-765 among others, were co-downregulated across all CNS tumors. Receiver-operator curve analysis showed that miR-149, miR-214, miR-574, miR-595 and miR765 could distinguish between CNS tumors and normal brain tissue. Conclusions: Our approach could prove significant in the search for global miRNA targets for tumor diagnosis and therapy. To the best of our knowledge, there are no previous reports concerning the present approach.

Defining and Timing of Palliative Opportunities in Children with Central Nervous System Tumors

2021 ◽  
Author(s):  
A McCauley Massie ◽  
Jonathan Ebelhar ◽  
Kristen E Allen ◽  
Nicholas P DeGroote ◽  
Karen Wasilewski-Masker ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
End Of Life ◽  
Phase 1 ◽  
Marrow Transplant ◽  
Cns Tumors ◽  
Do Not Resuscitate ◽  
Intensive Care Admission ◽  
Repeated Events

Abstract Background Children with brain and central nervous system (CNS) tumors experience substantial challenges to their quality of life during their disease course. These challenges are opportunities for increased subspecialty palliative care (PC) involvement. Palliative opportunities have been defined in the pediatric oncology population, but the frequency, timing, and factors associated with palliative opportunities in pediatric patients with CNS tumors are unknown. Methods A single-institution retrospective review was performed on children ages 0-18 diagnosed with a CNS tumor who died between 01/01/2012-11/30/2017. Nine palliative opportunities were defined prior to data collection (progression; relapse; admission for severe symptoms; intensive care admission; bone marrow transplant; phase 1 trial; hospice; do-not-resuscitate (DNR) order). Demographic, disease, treatment, palliative opportunity, and end-of-life data were collected. Opportunities were evaluated over quartiles from diagnosis to death. Results Amongst 101 patients with a median age at death of eight years (Interquartile range, IQR=8.0, range 0-22), there was a median of seven (IQR=6) palliative opportunities per patient, which increased closer to death. PC consultation occurred in 34 (33.7%) patients, at a median of 2.2 months before death, and was associated with having a DNR order (p=0.0028). Hospice was involved for 72 (71.3%) patients. Conclusion Children with CNS tumors suffered repeated events warranting PC yet received PC support only one-third of the time. Mapping palliative opportunities over the cancer course promotes earlier timing of PC consultation which can decrease suffering and resuscitation attempts at the end-of-life.

scholarly journals Clinical utility of comprehensive genomic profiling in central nervous system tumors of children and young adults

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Jianling Ji ◽  
Kristiyana Kaneva ◽  
Matthew C Hiemenz ◽  
Girish Dhall ◽  
Tom Belle Davidson ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Utility ◽  
Adolescent And Young Adult ◽  
Cns Tumors ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Clinically Significant

Abstract Background Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. Methods OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. Results NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. Conclusions Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

scholarly journals The influence of brain metastases on the central nervous system effects of methylnaltrexone: a post hoc analysis of 3 randomized, double-blind studies

2021 ◽  
Author(s):  
Darren M. Brenner ◽  
Neal E. Slatkin ◽  
Nancy Stambler ◽  
Robert J. Israel ◽  
Paul H. Coluzzi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Metastases ◽  
Cancer Patients ◽  
Opioid Withdrawal ◽  
Double Blind ◽  
Post Hoc Analysis ◽  
Pain Scores ◽  
Opioid Receptor Antagonists ◽  
Post Hoc

Abstract Purpose Peripherally acting μ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor®) are indicated for the treatment of opioid-induced constipation (OIC). The structural properties unique to MNTX restrict it from traversing the blood-brain barrier (BBB); however, the BBB may become more permeable in patients with brain metastases. We investigated whether the presence of brain metastases in cancer patients compromises the central effects of opioids among patients receiving MNTX for OIC. Methods This post hoc analysis of pooled data from 3 randomized, placebo-controlled trials included cancer patients with OIC who received MNTX or placebo. Endpoints included changes from baseline in pain scores, rescue-free laxation (RFL) within 4 or 24 h of the first dose, and treatment-emergent adverse events (TEAEs), including those potentially related to opioid withdrawal symptoms. Results Among 356 cancer patients in the pooled population, 47 (MNTX n = 27; placebo n = 20) had brain metastases and 309 (MNTX n = 172; placebo n = 137) did not have brain metastases. No significant differences in current pain, worst pain, or change in pain scores from baseline were observed between patients treated with MNTX or placebo. Among patients with brain metastases, a significantly greater proportion of patients who received MNTX versus placebo achieved an RFL within 4 h after the first dose (70.4% vs 15.0%, respectively, p = 0.0002). TEAEs were similar between treatment groups and were generally gastrointestinal in nature and not related to opioid withdrawal. Conclusion Focal disruptions of the BBB caused by brain metastases did not appear to alter central nervous system penetrance of MNTX.

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