Reference Detail

Ref Type

Journal Article

PMID

(37147298)

Authors

Berko ER, Witek GM, Matkar S, Petrova ZO, Wu MA, Smith CM, Daniels A, Kalna J, Kennedy A, Gostuski I, Casey C, Krytska K, Gerelus M, Pavlick D, Ghazarian S, Park JR, Marachelian A, Maris JM, Goldsmith KC, Radhakrishnan R, Lemmon MA, Mossé YP

Title

Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature communications	14	1	2023 May 05	2601	Nat Commun

URL

Abstract Text

Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib 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
ALK	D1276_R1279delinsE	indel	gain of function	ALK D1276_R1279delinsE results in a deletion of four amino acids in the protein kinase domain of the Alk protein from amino acids 1276 to 1279, combined with the insertion of a glutamic acid (E) at the same site (UniProt.org). D1276_R1279delinsE results in constitutive activation of Alk and is transforming in cell culture (PMID: 37147298).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK G1202R ALK D1276_R1279delinsE	neuroblastoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in a complete metabolic response and a partial anatomic response in a neuroblastoma patient harboring ALK D1276_R1279delinsE and G1202R, who remained on the treatment for over 27 cycles (PMID: 37147298; NCT03107988).	37147298
ALK D1276_R1279delinsE	neuroblastoma	predicted - sensitive	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, Xalkori (crizotinib) treatment resulted in stable disease lasting for 3 years in a neuroblastoma patient harboring ALK D1276_R1279delinsE (PMID: 37147298).	37147298
ALK F1174L ALK L1196M	neuroblastoma	resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, two neuroblastoma patients harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and were found to have acquired ALK L1196M via circulating tumor DNA, and a neuroblastoma cell line harboring ALK F1174L and expressing L1196M was resistant to Lorbrena (lorlatinib) in culture (PMID: 37147298; NCT03107988).	37147298
ALK F1174L ALK G1202R ALK D1203N ALK amp	neuroblastoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, a neuroblastoma patient harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired ALK amplification, and ALK G1202R and D1203N each in cis with F1174L via circulating tumor DNA (PMID: 37147298; NCT03107988).	37147298
ALK G1202R ALK R1275Q	neuroblastoma	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, a neuroblastoma cell line harboring ALK R1275Q and expressing G1202R was resistant to Lorbrena (lorlatinib) in culture (PMID: 37147298).	37147298
ALK I1171T ALK R1192P ALK L1196M ALK F1245V	neuroblastoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, a neuroblastoma patient harboring ALK F1245V developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired additional ALK variants, I1171T, R1192P, and L1196M, via circulating tumor DNA (PMID: 37147298; NCT03107988).	37147298
ALK R1275Q	neuroblastoma	sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in a complete response in a neuroblastoma patient harboring a germline ALK R1275Q, who was on treatment for 18 months and remained in remission at 5 years (PMID: 37147298; NCT03107988).	37147298
ALK G1202R ALK D1276_R1279delinsE	neuroblastoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, a neuroblastoma patient harboring ALK D1276_R1279delinsE developed progressive disease on treatment with Xalkori (crizotinib) and was found to have acquired ALK G1202R via circulating tumor DNA (PMID: 37147298).	37147298
ALK F1245Y	neuroblastoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a complete response in a patient with neuroblastoma harboring ALK F1245Y (PMID: 37147298).	37147298
ALK F1245Y HRAS G13R	neuroblastoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, a neuroblastoma patient harboring ALK F1245Y developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired HRAS G13R via circulating tumor DNA (PMID: 37147298; NCT03107988).	37147298
ALK G1202R ALK R1275Q BRAF V600E	neuroblastoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, a neuroblastoma patient harboring ALK R1275Q developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired ALK G1202R and BRAF V600E via circulating tumor DNA (PMID: 37147298; NCT03107988).	37147298
ALK F1174L	neuroblastoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in a minor response with stable disease in a neuroblastoma patient harboring ALK F1174L (PMID: 37147298; NCT03107988).	37147298
ALK F1245V	neuroblastoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in a complete response of marrow disease in a neuroblastoma patient harboring ALK F1245V, along with NF1 P2472fs and BRCA2 F2410fs (PMID: 37147298; NCT03107988).	37147298
ALK F1174L PIK3CA H1047R	neuroblastoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, a neuroblastoma patient harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired PIK3CA H1047R via circulating tumor DNA (PMID: 37147298; NCT03107988).	37147298
ALK L1196M ALK R1275Q	neuroblastoma	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, a neuroblastoma cell line harboring ALK R1275Q and expressing L1196M was resistant to Lorbrena (lorlatinib) in culture (PMID: 37147298).	37147298
ALK F1174L ALK G1202R	neuroblastoma	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, a neuroblastoma cell line harboring ALK F1174L and expressing G1202R was resistant to Lorbrena (lorlatinib) in culture (PMID: 37147298).	37147298
ALK F1174C	neuroblastoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in a partial response in a neuroblastoma patient harboring ALK F1174C, along with CDKN2A A102V (PMID: 37147298; NCT03107988).	37147298
ALK F1174L FGFR1 N546K	neuroblastoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a Phase I trial, a neuroblastoma patient harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired FGFR1 N546K via circulating tumor DNA (PMID: 37147298; NCT03107988).	37147298