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.