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\begin{document}

\title{Sustained Response with Dose Reduced Selpercatinib in a Pediatric
Patient with Metastatic NCOA4-RET Fusion Papillary Thyroid Carcinoma}



\author[1]{Anna C. Suydam}%
\author[2]{Alicia Bach}%
\author[3]{Stephanie Markovina}%
\author[3]{Perry Grigsby}%
\author[1]{Jennifer Sprague}%
\author[1]{Amy Armstrong}%
\affil[1]{Washington University in St Louis Department of Pediatrics}%
\affil[2]{University of Missouri School of Medicine}%
\affil[3]{Washington University in St Louis Washington University Physicians}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Understanding the molecular landscape of papillary thyroid carcinoma
(PTC), the most common thyroid cancer in children, creates additional
therapeutic approaches. \emph{RET} gene rearrangements are observed in
pediatric PTC and selective inhibition of RET is now possible with
specific tyrosine kinase inhibitors designed to target diverse
\emph{RET}-activating mutations. We present a 13-year-old female with
radioactive iodine-refractory metastatic PTC, found to harbor a
\emph{NCOA4-RET} fusion, who responded to treatment with selpercatinib
with elimination of supplemental oxygen need, marked reduction in
pulmonary nodules and mediastinal lymphadenopathy, and substantial
improvement in thyroglobulin levels. Response was maintained despite 2
dose reductions for possibly-related weight gain.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Papillary thyroid carcinoma (PTC) is the most common type of
differentiated thyroid cancer (DTC) in children and adolescents,
accounting for approximately 90\% of thyroid cancers in pediatric
patients.\textsuperscript{1} Unlike adults, pediatric patients with PTC
often present with advanced, metastatic disease but tend to favorably
respond to total thyroidectomy with lymph node dissection followed by
radioactive iodine (RAI) therapy.\textsuperscript{2} For the subset of
patients who become refractory to RAI treatment or have RAI non-avid
disease, molecularly targeted kinase inhibitors may provide a medical
therapeutic option.\textsuperscript{1} Furthermore, children with
metastatic or relapsed/refractory PTC frequently harbor clinically
relevant genomic alterations, with \emph{RET} fusions most commonly
observed.\textsuperscript{1,3,4} A review of approximately 2000
pediatric patients with PTC revealed \emph{RET} fusions in 25-30\% of
sporadic cases (range 14-55\%).\textsuperscript{1}

Selpercatinib (LOXO-292) is a first-in-class, highly selective,
ATP-competitive, small-molecule RET kinase inhibitor. In LIBRETTO-001, a
phase 1/2 clinical trial evaluating selpercatinib in \emph{RET} -mutant
medullary thyroid cancer and \emph{RET} fusion-positive thyroid cancer,
79\% of 19 adult patients with \emph{RET} fusion-positive previously
treated thyroid cancer had an objective response with activity seen
across histologic subtypes, with durable antitumor
activity.\textsuperscript{5} In May 2020, the Food and Drug
Administration granted accelerated approval to selpercatinib for
patients [?]12 years of age with advanced or metastatic
\emph{RET}fusion-positive thyroid cancer who require systemic therapy
and are RAI-refractory when RAI is appropriate.\textsuperscript{6} Data
for selpercatinib use in pediatrics is less robust, but shows promising
activity in cases of medullary thyroid
cancer,\textsuperscript{7,8}\emph{CCDC6-RET} fusion positive
PTC\textsuperscript{4} and soft tissue sarcoma,\textsuperscript{7} with
preliminary safety and efficacy seen in pediatric patients with
\emph{RET} -altered solid tumors enrolled on
LIBERTTO-121.\textsuperscript{9} Here we report the sustained response
to selpercatinib, despite 2 dose reductions, in a 13-year-old patient
with metastatic PTC harboring a somatic \emph{NCOA4-RET} fusion.

\textbf{Methods and Case Description}

A 9-year-old former 33-week female triplet presented with
exercise-induced dyspnea and intermittent oral cyanosis when chest x-ray
revealed innumerable pulmonary nodules thought to be consistent with
miliary tuberculosis or granulomatous disease. At age 11 she was
evaluated for a right-sided neck mass; ultrasound showed a 2.7x1.7x2.9
cm hypervascular lesion at the carotid bifurcation. Magnetic resonance
imaging was attempted, but due to hypoxemia, study was aborted and she
was hospitalized for further evaluation and respiratory support. Chest
computed tomography demonstrated diffuse sub-centimeter nodules with
mediastinal and cervical lymphadenopathy. Rheumatologic and infectious
work-ups were unrevealing. She underwent thoracoscopic lung biopsy where
pathology confirmed metastatic PTC. Total thyroidectomy and lymph node
dissection was performed showing classic subtype, with final
tumor-node-metastasis staging of T1bN1bM1. Post-surgical thyroglobulin
(Tg) level was 2850 ng/mL; antithyrogloblulin antibody was elevated at
46 IUnits/mL (normal \textless{}1.8 IUnits/mL).

The patient then started RAI treatment, receiving an initial dose of 20
mCi, which was initially complicated by radiation pneumonitis requiring
hospitalization and steroid therapy. The next dose was reduced to 10mCi
without recurrent symptoms of radiation pneumonitis. Subsequent doses
were slowly increased and well-tolerated. She received a cumulative 280
millicuries from 7 treatments over 29 months. Post-treatment total body
iodine scans performed 3-5 days after RAI administration continued to
show stable, diffuse increased uptake throughout her lungs and thyroid
stimulating hormone (TSH)-suppressed Tg level remained persistently
elevated at 810 ng/mL, anti-Tg antibody was 8.1 IUnits/mL. She continued
to require 3 liters of oxygen via nasal cannula and endorsed dyspnea
with exertion. Somatic genetic testing was pursued using TEMPUS
(Chicago, IL) and revealed a \emph{NCOA4-RET} fusion.

The patient began oral selpercatinib 120 mg twice daily (BID) at the age
of 13 years, following weight-based dosing guidelines (120 mg BID for
weight \textless{}50 kg and 160 mg BID for weight \(\geq\)50
kg). Within 1 week, we noted an increase in oxygen saturation levels to
[?]98\% off supplementation while active in clinic. After two 28-day
cycles imaging showed improving partially calcified mediastinal
lymphadenopathy with marked improvement in innumerable pulmonary
metastases (Fig.1). Tg level decreased to 143 ng/mL with
anti-thyroglobulin antibody of 16 IUnits/mL (Fig. 2). Dosing was
subsequently increased to 160 mg BID due to weight gain. The patient
slowly trialed off of oxygen support, and after 4 cycles of therapy, she
was off of supplemental oxygen and cleared by pulmonology for exercise.

Overall selpercatinib has been well tolerated; however, the patient
continued to gain weight above her expected baseline and underwent a
dose reduction to 120 mg BID after 9 cycles of therapy for
possibly-related grade 3 weight gain. The patient noted a decrease in
her appetite after the reduction but continued to endorse poor food
choices and limited activity. Dose reduction again occurred after 18
cycles of therapy to 80 mg BID. She otherwise continued on levothyroxine
for appropriate TSH suppression to \textless{}0.1 mcIUnit/mL.

The patient remains on selpercatinib at dose level -2 and was last
evaluated after initiation of her twenty-eighth cycle. Imaging,
thyroglobulin response, and resolution of anti-Tg antibodies (Figs.
1-2), as well as elimination of supplemental oxygen need, has continued
despite dose adjustments. We plan to continue therapy indefinitely
barring disease progression or intolerable toxicities.

\textbf{Discussion}

While disease-specific mortality for pediatric patients with DTC is very
low, and surgery with adjuvant RAI is curative for most patients,
approaches are not without associated toxicity. The American Thyroid
Association has recommended selective use of RAI in children with DTC,
including those with distant metastases which occurs in upwards of 30\%
of patients.\textsuperscript{10-12} Early toxicities of RAI
administration in children can include radiation thyroiditis, xerostomia
and transient bone marrow suppression, with late complications of
permanent salivary gland dysfunction, bone marrow suppression, pulmonary
fibrosis, and secondary cancers.\textsuperscript{13} Furthermore, no
standard limit for cumulative RAI therapy in pediatrics
exists.\textsuperscript{14} Consideration of usage and appropriate
timing of alternative therapeutic approaches may not be needed to
decrease mortality, but may reduce morbidity and improve quality of life
in patients with DTC.

\emph{RET} fusions retaining the kinase domain are drivers of PTC
with\emph{CCDC6-RET} and \emph{NCOA4-RET} reported as the most common
rearrangements.\textsuperscript{15} Inhibition of RET was previously
achieved by multi-tyrosine kinase inhibitors such as lenvatinib and
cabozantinib, but the emergence of selective RET-inhibitors has provided
a targeted approach with a potentially reduced side effect
profile.\textsuperscript{16,17} In our patient with metastatic PTC who
was not achieving desired response to repeated doses of RAI, discovery
of a \emph{NCOA4-RET} fusion allowed for initiation of systemic therapy
with selpercatinib, which quickly provided clinical, radiographic, and
biochemical response. She has not experienced the more common
selpercatinib-related adverse events, such as hypertension,
transaminitis, diarrhea or constipation,\textsuperscript{5-9} but was
noted to have weight gain which while likely multifactorial, has been
reported with selpercatinib\textsuperscript{18} and was deemed to be
possibly related to medication use.

Our patient's treatment response has continued despite two dose
reductions of selpercatinib, allowing us to minimize possible associated
toxicity without compromising efficacy. Given the chronic need for
targeted therapy without knowledge of long-term side effects,
understanding the minimal dose required for desired effect is of utmost
importance. More precise administration of tyrosine kinase inhibitors is
being studied, and it is proposed that the wider therapeutic index of
targeted agents may allow for pediatric dosing to be less than the
maximum tolerated dose documented in adults.\textsuperscript{19} In
summation, a better understanding of the molecular landscape of
pediatric PTC offered an effective systemic treatment modality, and we
will continue to closely observe the dose response in our patient.

\textbf{References}

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\tightlist
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\end{enumerate}\selectlanguage{english}
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