Reference Detail

Ref Type

Journal Article

PMID

(37012551)

Authors

Goldsmith KC, Park JR, Kayser K, Malvar J, Chi YY, Groshen SG, Villablanca JG, Krytska K, Lai LM, Acharya PT, Goodarzian F, Pawel B, Shimada H, Ghazarian S, States L, Marshall L, Chesler L, Granger M, Desai AV, Mody R, Morgenstern DA, Shusterman S, Macy ME, Pinto N, Schleiermacher G, Vo K, Thurm HC, Chen J, Liyanage M, Peltz G, Matthay KK, Berko ER, Maris JM, Marachelian A, Mossé YP

Title

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature medicine			2023 Apr 03	1092-1102	Nat Med

URL

Abstract Text

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .

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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	F1245Y	missense	unknown	ALK F1245Y lies within the protein kinase domain of the Alk protein (UniProt.org). F1245Y has been identified in the scientific literature (PMID: 37012551, PMID: 30523111), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK act mut	neuroblastoma	sensitive	Cyclophosphamide + Lorlatinib + Topotecan	Phase I	Actionable	In a Phase I trial, the combination of Lorbrena (lorlatinib), Topotecan, and Cytoxan (cyclophosphamide) treatment was well tolerated and resulted in a modified response rate of 63% (5/8) in pediatric patients with neuroblastoma harboring an ALK activating mutation, including ALK F1174C, F1174L, R1275Q, or R1275L (PMID: 37012551; NCT03107988).	37012551
ALK act mut	neuroblastoma	sensitive	Lorlatinib	Phase I	Actionable	In a Phase I trial, Lorbrena (lorlatinib) treatment was well tolerated and resulted in a modified response rate of 30% (7/23) in children and 67% (10/15) in adults with neuroblastoma harboring an ALK activating mutation, including ALK F1174C, F1174L, R1275Q, or R1275L, F1245Y, F1245L, D1276_R1279delinsE, or amplification (PMID: 37012551; NCT03107988).	37012551