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<h5 class="title" id="d788038e337">Background</h5>
<p id="P4">The 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.
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<h5 class="title" id="d788038e342">Methods</h5>
<p id="P5">Patients 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/m
<sup>2</sup> (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
<a data-untrusted="" href="http://ClinicalTrials.gov" id="d788038e349" target="xrefwindow">ClinicalTrials.gov</a>,
<a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT02122913" id="d788038e352"
target="xrefwindow">NCT02122913</a> (active not recruiting),
<a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT02637687" id="d788038e355"
target="xrefwindow">NCT02637687</a> (recruiting), and
<a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT02576431" id="d788038e358"
target="xrefwindow">NCT02576431</a> (recruiting).
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<h5 class="title" id="d788038e362">Findings</h5>
<p id="P6">Between 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.
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<h5 class="title" id="d788038e367">Interpretation</h5>
<p id="P7">These 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.
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<h5 class="title" id="d788038e372">Funding</h5>
<p id="P8">Bayer and Loxo Oncology.</p>
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