Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.
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SUBMITTER: Laetsch TW
PROVIDER: S-EPMC5949072 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
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Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.
Laetsch Theodore W TW DuBois Steven G SG Mascarenhas Leo L Turpin Brian B Federman Noah N Albert Catherine M CM Nagasubramanian Ramamoorthy R Davis Jessica L JL Rudzinski Erin E Feraco Angela M AM Tuch Brian B BB Ebata Kevin T KT Reynolds Mark M Smith Steven S Cruickshank Scott S Cox Michael C MC Pappo Alberto S AS Hawkins Douglas S DS
The Lancet. Oncology 20180329 5
<h4>Background</h4>Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients.<h4>Methods</h4>This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enroll ...[more]
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Project description:BackgroundNTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions.Patients and methodsThis multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity.ResultsSeventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose.ConclusionsLarotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients.Clincaltrials.gov numberNCT02122913.
| S-EPMC6386027 | biostudies-literature
Project description:The development of deep-sequencing methods is now unveiling a new landscape of previously undetected gene fusion across different tumor types. Chromosomal translocation involving the NTRK gene family occur across a wide range of cancers in both children and adults. Preclinical studies have demonstrated that chimeric proteins encoded by NTRK rearrangements have oncogenic properties and drive constitutive expression and ligand-independent activation. Larotrectinib (ARRY470, LOXO101, Vitrakvi) is a highly and potent inhibitor of TRKA, TRKB, and TRKC, and has demonstrated rema rkable antitumor activity against TRK-fusion-positive cancers with a favorable side-effect profile in phase I/II clinical trials. In November 2018, the US Food and Drug Administration granted accelerated approval to larotrectinib for adult and pediatric patients with solid tumors harboring NTRK gene fusions without known acquired resistance mutation. In this review, we discuss the clinical activity and safety profile of larotrectinib, focusing on the clinical trials that led to its first global approval.
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Project description:IntroductionNeurotrophic tyrosine receptor kinase (NTRK) gene fusions occur in ~ 0.3% of all solid tumours but are enriched in some rare tumour types. Tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib are approved as tumour-agnostic therapies for solid tumours harbouring NTRK fusions.MethodsThis study investigated the prevalence of NTRK fusions in Canadian patients and also aimed to help guide NTRK testing paradigms through analysis of data reported from a national clinical diagnostic testing program between September 2019 and July 2021.ResultsOf 1,687 patients included in the final analysis, NTRK fusions were detected in 0.71% (n = 12) of patients representing salivary gland carcinoma (n = 3), soft tissue sarcoma (n = 3), CNS (n = 3), and one in each of melanoma, lung, and colorectal cancer. All three salivary gland carcinomas contained ETV6-NTRK3 fusions. Thirteen (0.77%) clinically actionable incidental findings were also detected. Two of the 13 samples containing incidental findings were NTRK fusion-positive (GFOD1-NTRK2, FGFR3-TACC3 in a glioblastoma and AFAP1-NTRK2, BRAF c.1799T>A in a glioma). The testing algorithm screened most patient samples via pan-TRK immunohistochemistry (IHC), whereas samples from the central nervous system (CNS), pathognomonic cancers, and confirmed/ putative NTRK fusion-positive samples identified under research protocols were reflexed straight to next-generation sequencing (NGS).ConclusionThese findings highlight the benefit and practicality of a diagnostic testing program to identify patients suitable for tumour-agnostic TRK inhibitor therapies, as well as other targeted therapies, due to clinically actionable incidental findings identified. Collectively, these findings may inform future guidance on selecting the appropriate testing approach per tumour type and on optimal NTRK testing algorithms.
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Project description:NTRK (neurotrophic tyrosine receptor kinase) gene fusions that encode chimeric proteins exhibiting constitutive activity of tropomyosin receptor kinases (TRK), are oncogenic drivers in multiple cancer types. However, the underlying mechanisms in oncogenesis that involve various N-terminal fusion partners of NTRK fusions remain elusive. Here, we show that NTRK fusion proteins form liquid-like condensates driven by their N-terminal fusion partners. The kinase reactions are accelerated in these condensates where the complexes for downstream signaling activation are also concentrated. Our work demonstrates that the phase separation driven by NTRK fusions is not only critical for TRK activation, but the condensates formed through phase separation serve as organizational hubs for oncogenic signaling.
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Project description:Entrectinib (Rozlytrek®) is an orally active, CNS-penetrant, small-molecule, selective inhibitor of the tropomyosin receptor tyrosine kinases TRKA/B/C [encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1/2/3, respectively], the proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and the anaplastic lymphoma kinase gene (ALK). It is approved for the treatment of adults and paediatric patients aged ≥ 12 years with NTRK fusion-positive (NTRK+) solid tumours and adults with ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC). In trials in adults, entrectinib induced clinically meaningful and durable systemic responses in tyrosine kinase inhibitor (TKI)-naïve patients with locally-advanced or metastatic NTRK+ solid tumours or ROS1+ NSCLC, irrespective of the presence or absence of CNS metastases at baseline. Moreover, entrectinib demonstrated substantial intracranial efficacy in patients with baseline CNS metastases. Entrectinb efficacy in paediatric patients was established on the basis of extrapolation of clinical trial data from adults with NTRK+ solid tumours and children and adolescents aged < 21 years with recurrent or refractory NTRK+ CNS/solid tumours. Entrectinib was generally well tolerated, with a manageable safety profile. Thus, entrectinib expands the range of treatment options for advanced NTRK+ solid tumours and ROS1+ NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases.
| S-EPMC8149347 | biostudies-literature
Project description:BackgroundThe selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.MethodsPatients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).FindingsBetween May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.InterpretationThese data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.FundingBayer and Loxo Oncology.
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Project description: Not available
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Project description:BackgroundWe report dose-escalation results from an open-label, phase 1/2 trial evaluating avelumab (anti-PD-L1) in paediatric patients with refractory/relapsed solid tumours.MethodsIn phase 1, patients aged < 18 years with solid (including central nervous system [CNS]) tumours for which standard therapy did not exist or had failed were enrolled in sequential cohorts of 3-6 patients. Patients received avelumab 10 or 20 mg/kg intravenously every 2 weeks. Primary endpoints were dose-limiting toxicities (DLTs) and grade ≥ 3 treatment-emergent adverse events (AEs).ResultsAt data cut-off (27 July 2021), 21 patients aged 3-17 years had received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15). One patient had three events that were classified as a DLT (fatigue with hemiparesis and muscular weakness associated with pseudoprogression; 20 mg/kg cohort). Grade ≥ 3 AEs occurred in five (83%) and 11 (73%) patients in the 10 and 20 mg/kg cohorts, respectively, and were treatment-related in one patient (7%; grade 3 [DLT]) in the 20 mg/kg cohort. Avelumab exposure in paediatric patients receiving 20 mg/kg dosing, but not 10 mg/kg, was comparable or higher compared with approved adult dosing (10 mg/kg or 800 mg flat dose). No objective responses were observed. Four patients with CNS tumours (20 mg/kg cohort) achieved stable disease, which was ongoing in two patients with astrocytoma at cut-off (for 24.7 and 30.3 months).ConclusionIn paediatric patients with refractory/relapsed solid tumours, avelumab monotherapy showed a safety profile consistent with previous adult studies, but clinical benefits were limited.
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Project description:Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.
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