Discussion
EML4::ALK is an oncogenic kinase fusion found in ~4% of
non-small cell lung cancer (NSCLC).13-15 It has also
been described in other cancers, including anaplastic large cell
lymphoma16 and inflammatory myofibroblastic tumor
(IMT)17, 18. The fusion results in a chimeric protein
with constitutive kinase activation that drives cancer
growth.19 Extensive drug discovery efforts have
focused on inhibiting EML4::ALK, with the first ALK inhibitor,
crizotinib, approved in 2011 for ALK-fusion positive NSCLC. Crizotinib
is multi-targeted, inhibiting MET, ROS1, and MST1R, in addition to ALK.
Though early studies showed remarkable response rates in ALK-positive
NSCLC,20 on-target resistance emerged
early21, 22, and second generation inhibitors, more
potent and specific against ALK, were developed. There are now 5
additional ALK inhibitors FDA-approved for ALK-fusion positive NSCLC:
ceritinib, alectinib, brigatinib, ensartinib, and
lorlatinib.23 In NSCLC, crizotinib is no longer first
line; instead, alectinib is often given for non-CNS disease because it
is potent and well tolerated. In patients with CNS metastasis,
lorlatinib, specifically designed for CNS penetration, is usually
recommended. Though lorlatinib is potent and ALK-specific, its use as
first-line therapy is limited by side effects. Hypercholesterolemia,
hypertriglyceridemia, and neurocognitive effects occur in
Repurposing of targeted therapies from malignant tumors has emerged as
an important therapeutic strategy in vascular anomalies. The first FDA
approval for a vascular anomaly was in 2022 with the
molecularly-targeted PI3Kα inhibitor, alpelisib, approved for PROS. That
approval was based on two studies that demonstrated over 90% efficacy
and included patients who previously failed
sirolimus,7, 8 suggesting that, for some patients,
targeted therapies directly blocking the mutant protein may be more
effective than inhibiting downstream targets, such as mTOR.
Here, we report the first cases of ALK inhibitors being used for
EML4::ALK mutant LMs. Despite being treated with different ALK
inhibitors, both patients responded well to therapy with significant
improvement in quality of life and objective shrinkage of lesions,
suggesting EML4::ALK is driving growth of these LMs. Much remains to be
learned about properly administering these therapies in the setting of a
chronic non-malignant childhood condition. For the patients presented
here, drug access and side effect profile were key factors in selecting
from the 6 available ALK inhibitors. Notably, crizotinib was approved in
2022 for patients over 1 year old with ALK-fusion positive IMT, so
partnering with our malignant oncology colleagues to understand the
short- and long-term toxicities of ALK inhibitors in children will be
important. Although EML::ALK fusions are a rare in LMs, the discovery of
novel targetable mutations in vascular anomalies that can drive
treatment management with profoundly successful outcomes underscores the
critical need for widespread availability of somatic molecular testing
and ongoing collaboration across sites to pool experience about drug
choice, dosing, and length of therapy.