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ALK fusions in the pan-cancer setting: another tumor-agnostic target?
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Journal Article
ALK fusions in the pan-cancer setting: another tumor-agnostic target?
2023
Overview
Anaplastic lymphoma kinase (
ALK
) alterations (activating mutations, amplifications, and fusions/rearrangements) occur in ~3.3% of cancers.
ALK
fusions/rearrangements are discerned in >50% of inflammatory myofibroblastic tumors (IMTs) and anaplastic large cell lymphomas (ALCLs), but only in ~0.2% of other cancers outside of non-small cell lung cancer (NSCLC), a rate that may be below the viability threshold of even large-scale treatment trials. Five ALK inhibitors –alectinib, brigatinib, ceritinb, crizotinib, and lorlatinib—are FDA approved for
ALK
-aberrant NSCLCs, and crizotinib is also approved for
ALK
-aberrant IMTs and ALCL, including in children. Herein, we review the pharmacologic tractability of
ALK
alterations, focusing beyond NSCLC. Importantly, the hallmark of approved indications is the presence of
ALK
fusions/rearrangements, and response rates of ~50–85%. Moreover, there are numerous reports of ALK inhibitor activity in multiple solid and hematologic tumors (e.g., histiocytosis, leiomyosarcoma, lymphoma, myeloma, and colorectal, neuroendocrine, ovarian, pancreatic, renal, and thyroid cancer) bearing
ALK
fusions/rearrangements. Many reports used crizotinib or alectinib, but each of the approved ALK inhibitors have shown activity. ALK inhibitor activity is also seen in neuroblastoma, which bear
ALK
mutations (rather than fusions/rearrangements), but response rates are lower (~10–20%). Current data suggests that ALK inhibitors have tissue-agnostic activity in neoplasms bearing
ALK
fusions/rearrangements.
