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

Abstract

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.

Shifting from Immunohistochemistry to Screen for ALK Rearrangements: Real-World Experience in a Large Single-Center Cohort of Patients with Non-Small-Cell Lung Cancer

“…Among the patients with NSCLC, ALK gene alterations occur in approximately 3-7% of cases, consistent with findings from previous series [19,20]. Our study cohort demonstrated a similar prevalence of ALK alterations as reported in NSCLC patients [19,20].…”

Primary lung adenocarcinoma with breast metastasis harboring the EML4‑ALK fusion: A case report

“…In a study by Fukuyoshi et al ( 26 ), 90 patients with breast cancer were assessed, although the EML4-ALK fusion was not detected. Another study ( 27 ) reported that in comprehensive genomic analyses, ALK fusions/rearrangements were identified in ~0.5–0.8% of cancers ( 28 , 29 ). Specifically, among patients with NSCLC, the prevalence of ALK fusions/rearrangements exceeds 3%, while the frequency of ALK fusions/rearrangements in non-NSCLC tumors is ~0.2%.…”

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

“…They are also repeatedly found in anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, microsatellite-unstable colorectal carcinomas, KRAS mutation-negative pancreatic cancers, thyroid carcinomas, melanomas lacking common oncogene mutations, etc. While the NCI-MATCH trial failed to recruit a significant number of non-lung cancer patients with ALK rearrangements [80], there is a critical mass of case reports and small patient series strongly supporting the agnostic utilization of ALK inhibitors [81,82]. ROS1 is highly similar to ALK with regard to biochemical properties and the spectrum of tumor types carrying actionable rearrangements, although its alterations are detected at significantly lower frequencies [79].…”