Reference Detail

Ref Type

Journal Article

PMID

(34482287)

Authors

O'Donohue TJ, Ibáñez G, Coutinho DF, Mauguen A, Siddiquee A, Rosales N, Calder P, Ndengu A, You D, Long M, Roberts SS, Kung AL, Dela Cruz FS

Title

Translational Strategies for Repotrectinib in Neuroblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	20	11	2021 11	2189-2197	Mol Cancer Ther

URL

Abstract Text

Limited clinical data are available regarding the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/FAK, which have all been implicated in the pathogenesis of neuroblastoma. We evaluated the preclinical activity of repotrectinib monotherapy and in combination with chemotherapy as a potential therapeutic approach for relapsed/refractory neuroblastoma. In vitro sensitivity to repotrectinib, ensartinib, and cytotoxic chemotherapy was evaluated in neuroblastoma cell lines. In vivo antitumor effect of repotrectinib monotherapy, and in combination with chemotherapy, was evaluated using a genotypically diverse cohort of patient-derived xenograft (PDX) models of neuroblastoma. Repotrectinib had comparable cytotoxic activity across cell lines irrespective of ALK mutational status. Combination with chemotherapy demonstrated increased antiproliferative activity across several cell lines. Repotrectinib monotherapy had notable antitumor activity and prolonged event-free survival compared with vehicle and ensartinib in PDX models (P < 0.05). Repotrectinib plus chemotherapy was superior to chemotherapy alone in ALK-mutant and ALK wild-type PDX models. These results demonstrate that repotrectinib has antitumor activity in genotypically diverse neuroblastoma models, and that combination of a multikinase inhibitor with chemotherapy may be a promising treatment paradigm for translation to the clinic.

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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 F1174V	neuroblastoma	predicted - sensitive	Irinotecan + Repotrectinib + Temozolomide	Preclinical - Pdx	Actionable	In a preclinical study, combination treatment with Augtyro (repotrectinib), Camptosar (irinotecan), and Temodar (temozolomide) resulted in inhibition of tumor growth in a patient-derived xenograft (PDX) model of neuroblastoma harboring ALK F1174V (PMID: 34482287).	34482287
ALK R1275Q	neuroblastoma	predicted - sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 34482287).	34482287
ALK F1174V	neuroblastoma	predicted - resistant	Repotrectinib	Preclinical - Pdx	Actionable	In a preclinical study, a neuroblastoma patient-derived xenograft (PDX) model harboring ALK F1174V was resistant to treatment with Augtyro (repotrectinib) (PMID: 34482287).	34482287
ALK amp	neuroblastoma	predicted - sensitive	Ensartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ensartinib (X-396) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK amplification in culture (PMID: 34482287).	34482287
ALK amp	neuroblastoma	predicted - sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Augtyro (repotrectinib) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK amplification in culture (PMID: 34482287).	34482287
ALK R1275Q	neuroblastoma	predicted - sensitive	Ensartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ensartinib (X-396) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 34482287).	34482287