Translational Strategies for Repotrectinib in Neuroblastoma.

Limited clinical data are available regarding the utility of multi-kinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multi-kinase 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 anti-tumor 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 anti-tumor activity and prolonged event-free survival compared to 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 anti-tumor activity in genotypically diverse neuroblastoma models, and that combination of a multi-kinase inhibitor with chemotherapy may be a promising treatment paradigm for translation to the clinic.