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Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma.

ABSTRACT: RTK plays important roles in many cellular signaling processes involved in cancer growth and development. ALK, TRKA, TRKB, TRKC, and ROS1 are RTKs involved in several canonical pathways related to oncogenesis. These proteins can be genetically altered in malignancies, leading to receptor activation and constitutive signaling through their respective downstream pathways. Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, and despite intensive therapy, there is a high mortality rate in cases with a high-risk disease. Alterations of ALK and differential expression of TRK proteins are reported in a proportion of NB. Several inhibitors of ALK or TRKA/B/C have been evaluated both preclinically and clinically in the treatment of NB. These agents have had variable success and are not routinely used in the treatment of NB. Entrectinib (RXDX-101) is a pan-ALK, TRKA, TRKB, TRKC, and ROS1 inhibitor with activity against tumors with ALK, NTRK1, NTRK2, NTRK3, and ROS1 alterations in Phase I clinical trials in adults. Entrectinib's activity against both ALK and TRK proteins suggests a possible role in NB treatment, and it is currently under investigation in both pediatric and adult oncology patients.

SUBMITTER: Pacenta HL

PROVIDER: S-EPMC6204873 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma.

Pacenta Holly L HL Macy Margaret E ME

Drug design, development and therapy 20181023

RTK plays important roles in many cellular signaling processes involved in cancer growth and development. ALK, TRKA, TRKB, TRKC, and ROS1 are RTKs involved in several canonical pathways related to oncogenesis. These proteins can be genetically altered in malignancies, leading to receptor activation and constitutive signaling through their respective downstream pathways. Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, and despite intensive therapy, there is a high mor ...[more]

PMID: 30425456

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Project description:Background: ALK inhibitors have shown positive advance in the treatment of ALK+ NSCLC. They have achieved better results in prolonging the progression free survival and improving quality of life in comparison to chemotherapy. We have assembled the evidence related to the efficacy and safety of these agents in the treatment of ALK positive NSCLC. Materials and Methods: A comprehensive search was conducted using electronic databases of PubMed, Medline and Cochrane Library to identify the studies involving comparison of ALK inhibitors to chemotherapy and Next generation ALK inhibitors to crizotinib. PFS was the primary outcome while other outcomes like ORR, adverse events, quality of life and OS were also analyzed and compared. Hazard ratios and odds ratios obtained were analyzed using fixed effect or random effects model in Review Manager Software. Results: A total of 12 studies (n = 3,297) met the criteria for inclusion in this review and meta-analysis. ALK inhibitors including crizotinib, ceritinib and alectinib revealed significantly better PFS (HR 0.42 [0.35, 0.50; p < 0.00001]), ORR (Overall OR 6.59 [4.86, 8.94; p < 0.00001] as compared to chemotherapy in the first line as well as second line treatment settings. Intracranial response rate was better with ALK inhibitors (ceritinib and alectinib) as compared to chemotherapy OR 6.51 [2.86, 14.83; p < 0.00001]. No significant increase in grade 3 or 4 adverse events was observed with crizotinib (OR 1.21 [0.82, 1.77; p = 0.34]) or ceritinib (OR 1.49 [0.86, 2.57; p = 0.17]) when compared to chemotherapy individually. Quality of life indicators assessed were significantly improved with ALK inhibitors. Next generation agents (ceritinib, alectinib and brigatinib) revealed significant improvement in PFS (HR 0.50 [0.43, 0.57; p < 0.00001]), ORR (OR 1.57 [1.21, 2.04; p = 0.0006]) in comparison to crizotinib. Next generation agents (Alectinib and brigatinib) yielded better response intra-cranially than crizotinib in terms of objective response rate (OR 5.87 [3.49, 9.87; p < 0.00001]) and time to CNS progression (HR 0.25 [0.13, 0.46; p < 0.0001]). Alectinib by far resulted in fewer adverse events than chemotherapy or crizotinib. Conclusions: Overall ALK inhibitors are safe and effective treatment option in ALK+ non-small cell lung cancer. Of the ALK inhibitors, Next generation agents in particular alectinib and brigatinib are safer and more effective intra-cranially and can be preferred as first option.

Dataset Information

Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma.

Publications

Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma.

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