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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 Cold Spring Harbor molecular case studies
Vol
Issue
Date 2021 Jul 01
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 C692Ffs*8 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). C692Ffs*8 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, Jul 2021).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK F1174L neuroblastoma no benefit 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 F1147L and PIK3CA C692Ffs*8 (PMID: 34210658). 34210658
ALK F1174L neuroblastoma conflicting 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 F1147L and PIK3CA C692Ffs*8, who had previously progressed on combination therapy with Xalkori (crizotinib), Cytoxan (cyclophosphamide), and Topotecan (PMID: 34210658). 34210658