Reference Detail

Ref Type

Journal Article

PMID

(34210658)

Authors

Liu T, Merguerian MD, Rowe SP, Pratilas CA, Chen AR, Ladle BH

Title

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed ALK F1174L-mutated neuroblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cold Spring Harbor molecular case studies			2021 Jul 01		Cold Spring Harb Mol Case Stud

URL

Abstract Text

Treatment of high-risk neuroblastoma typically incorporates multi-agent chemotherapy, surgery, radiation therapy, autologous stem cell transplantation, immunotherapy, and differentiation therapy. The discovery of activating mutations in ALK receptor tyrosine kinase (ALK) in approximately 8% of neuroblastomas opens the possibility of further improving outcomes for this subset of patients with the addition of ALK inhibitors. ALK inhibitors have shown efficacy in tumors such as non-small cell lung cancer and anaplastic large cell lymphoma where wild-type ALK overexpression is driven by translocation events. In contrast, ALK mutations driving neuroblastomas are missense mutations in the tyrosine kinase domain yielding constitutive activation and differing sensitivity to available ALK inhibitors. We describe a case of a patient with relapsed, refractory, metastatic ALK F1174L-mutated neuroblastoma who showed no response to the first generation ALK inhibitor crizotinib but had a subsequent complete response to the ALK/ROS1 inhibitor lorlatinib. The patient's disease relapsed after 13 months of treatment. Sequencing of cell-free DNA at the time of relapse pointed toward a potential mechanism of acquired lorlatinib resistance: amplification of CDK4 and FGFR1, and a NRAS Q61K mutation. We review the literature regarding differing sensitivity of ALK mutations found in neuroblastoma to current FDA-approved ALK inhibitors and known pathways of acquired resistance. Our report adds to the literature of important correlations between neuroblastoma ALK mutation status and clinical responsiveness to ALK inhibitors. It also highlights the importance of understanding acquired mechanisms of resistance.

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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
PIK3CA	C692Ffs*8	frameshift	unknown	PIK3CA C692Ffs8 indicates a shift in the reading frame starting at amino acid 692 and terminating 8 residues downstream causing a premature truncation of the 1068 amino acid Pik3ca protein (UniProt.org). C692Ffs8 has been identified in the scientific literature (PMID: 34210658), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2024).

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 lasting 13 mo in a pediatric patient with metastatic, relapsed neuroblastoma harboring ALK F1174L and PIK3CA C692Ffs*8, who had previously progressed on combination therapy with Xalkori (crizotinib), Cytoxan (cyclophosphamide), and Topotecan (PMID: 34210658).	34210658
ALK F1174L	neuroblastoma	conflicting	Crizotinib + Cyclophosphamide + Topotecan	Case Reports/Case Series	Actionable	In a clinical case study, combination treatment with Xalkori (crizotinib), Cytoxan (cyclophosphamide), and Topotecan resulted in progressive disease within 1 cycle of therapy in a pediatric patient with metastatic, relapsed neuroblastoma harboring ALK F1174L and PIK3CA C692Ffs*8 (PMID: 34210658).	34210658