ALK fusions in the pan-cancer setting: another tumor-agnostic target?

Abstract

AbstractAnaplastic lymphoma kinase (ALK) alterations (activating mutations, amplifications, and fusions/rearrangements) occur in ~3.3% of cancers.ALKfusions/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 forALK-aberrant NSCLCs, and crizotinib is also approved forALK-aberrant IMTs and ALCL, including in children. Herein, we review the pharmacologic tractability ofALKalterations, focusing beyond NSCLC. Importantly, the hallmark of approved indications is the presence ofALKfusions/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) bearingALKfusions/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 bearALKmutations (rather than fusions/rearrangements), but response rates are lower (~10–20%). Current data suggests that ALK inhibitors have tissue-agnostic activity in neoplasms bearingALKfusions/rearrangements.