Reference Detail

Ref Type

Journal Article

PMID

(37561984)

Authors

Stiefel J, Kushner BH, Roberts SS, Iglesias-Cardenas F, Kramer K, Modak S

Title

Anaplastic Lymphoma Kinase Inhibitors for Therapy of Neuroblastoma in Adults.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	7		2023 Aug	e2300138	JCO Precis Oncol

URL

Abstract Text

Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase (ALK), deemed to be an oncogenic driver in NB. ALK inhibitors (ALKis), therefore, have the potential to be of therapeutic benefit. The purpose of this study is to report on their use in AON.A single-center retrospective review of adults with NB receiving ALKi (2012-2022) was performed. Response was evaluated using International Neuroblastoma Response Criteria.Fifteen patients with ALK-mutated AON were treated with US Food and Drug Administration-approved ALKi starting at a median age of 34 (16-71) years. Initial ALKi was lorlatinib, crizotinib, and alectinib in seven, five, and three patients respectively; seven received multiple ALKis due to progressive disease/intolerability of one agent. All patients experienced ≥grade 2 adverse events (AEs): crizotinib and alectinib were associated primarily with gastrointestinal AEs, lorlatinib with neurologic AEs, weight gain, and hyperlipidemia resulting in dose reduction or discontinuation of ALKi in several patients. No responses were observed with crizotinib (n = 5 patients), ceritinib, alectinib, or brigatinib (n = 1 each). Of the 13 patients receiving lorlatinib, four, five, and four patients had a complete or partial response (major response rate 69%), and stable disease, respectively. Responses were noted in all disease compartments; complete metabolic response was seen in two L2 patients. Ten of 13 patients remain progression-free at a median of 19 (6-50) months on lorlatinib. Three (two receiving dose-reduced therapy) had progressive disease. Median survival from start of first ALKi was 43 ± 26 months.ALKis, particularly lorlatinib, are effective treatment options for AON. However, AEs necessitating dose reduction are common.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK F1174L	neuroblastoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a complete response in 3 of 5 patients and a partial response in 1 of 5 patients with neuroblastoma harboring ALK F1174L (PMID: 37561984).	37561984
ALK R1275Q	neuroblastoma	sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a partial response in 3 of 4 patients with neuroblastoma harboring ALK R1275Q (PMID: 37561984).	37561984
ALK F1174V	neuroblastoma	sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a complete response lasting greater than 20 months in a patient with neuroblastoma harboring ALK F1174V (PMID: 37561984).	37561984