Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG)

Desai, Ami; Robinson, Giles; Gauvain, Karen; Basu, Ellen M.; Macy, Margaret E.; Maese, Luke; Whipple, Nicholas; Sabnis, Amit J.; Foster, Jennifer; Shusterman, Suzanne; Yoon, Janet; Weiss, Brian; AbdelBaki, Mohamed S.; Armstrong, Amy E.; Cash, Thomas F.; Pratilas, Christine A.; Corradini, Nadège; Marshall, Lynley V.; Farid‐Kapadia, Mufiza; Chohan, Saibah; Devlin, Clare; Meneses-Lorente, Georgina; Cardenas, Alison K.; Hutchinson, Katherine E.; Bergthold, Guillaume; Caron, Hubert; Maneval, Edna Chow; Gajjar, Amar; Fox, Elizabeth

doi:10.1093/neuonc/noac087

Cited by 59 publications

(58 citation statements)

References 31 publications

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“…Its use in pediatric hematological cancers is still discussed, regardless of its tumor-agnostic action. The STARTRK-NG phase I/II study on pediatric patients (none with NHL) treated with entrectinib for locally advanced or metastatic solid tumors or primary CNS tumors and/or who had no satisfactory treatment options, revealed no increased risk of infection (grade ≥3 infections, neutropenia, and lymphopenia in 2.3%, 7%, and 2.3%, respectively; mainly lung and urinary tract infections; significantly more device-related infections than in adults) [ 13 , 147 ]. Logistic regression models indicated that the probability of a patient experiencing a grade ≥3 treatment-related or a serious adverse event increased with entrectinib exposure > 600 mg/day [ 148 ].…”

Section: Tyrosine Kinase Inhibitors (Tkis)mentioning

confidence: 99%

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

Kyriakidis

Mantadakis

Stiakaki

et al. 2022

Cancers

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The aim of this review is to highlight mechanisms of immunosuppression for each agent, along with pooled analyses of infectious complications from the available medical literature. Rituximab confers no increase in grade ≥3 infectious risks, except in the case of patients with advanced-stage non-Hodgkin lymphoma. Gemtuzumab ozogamicin links with high rates of grade ≥3 infections which, however, are comparable with historical cohorts. Pembrolizumab exhibits a favorable safety profile in terms of severe infections. Despite high rates of hypogammaglobulinemia (HGG) with blinatumomab, low-grade ≥3 infection rates were observed, especially in the post-reinduction therapy of relapsed B-acute lymphoblastic leukemia. Imatinib and nilotinib are generally devoid of severe infectious complications, but dasatinib may slightly increase the risk of opportunistic infections. Data on crizotinib and pan-Trk inhibitors entrectinib and larotrectinib are limited. CAR T-cell therapy with tisagenlecleucel is associated with grade ≥3 infections in children and is linked with HGG and the emergence of immune-related adverse events. Off-label therapies inotuzumab ozogamicin, brentuximab vedotin, and venetoclax demonstrate low rates of treatment-related grade ≥3 infections, while the addition of bortezomib to standard chemotherapy in T-cell malignancies seems to decrease the infection risk during induction. Prophylaxis, immune reconstitution, and vaccinations for each targeted agent are discussed, along with comparisons to adult studies.

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Section: Tyrosine Kinase Inhibitors (Tkis)mentioning

confidence: 99%

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

Kyriakidis

Mantadakis

Stiakaki

et al. 2022

Cancers

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“…Entrectinib is a potent multikinase inhibitor with systemic inhibition activity against multiple oncogenic kinases, such as neurotrophic tyrosine receptor kinase (NTRK), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine protein kinase ROS1 (ROS1; Desai et al, 2022 ). Compared with similar drugs like larotrectinib and crizotinib, the designment of entrectinib facilitates it easily to penetrate the blood–brain barrier for the chemotherapy of tumors in the central nervous system (CNS; Doebele et al, 2020 ; Drilon et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of planktonic growth and biofilm formation of Staphylococcus aureus by entrectinib through disrupting the cell membrane

Liu

Xiong²,

Xiao³

et al. 2023

Front. Microbiol.

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Over the last few decades, Staphylococcus aureus infection remain a major medical challenge and health concern worldwide. Biofilm formation and antibiotic resistance caused by S. aureus make it difficult to be eradicated from bacterial infections in clinics. In this study, our data demonstrated the antibacterial and excellent anti-biofilm activity of entrectinib against S. aureus. Entrectinib also exhibited the good safety, suggesting no toxicity with antibacterial concentration of entrectinib toward the erythrocytes and mammalian 239 T cells. Moreover, entrectinib significantly reduced the bacterial burden of septic tissue in a murine model of MRSA infection. Global proteomic analysis of S. aureus treated with entrectinib showed significant changes in the expression levels of ribosomal structure-related (rpmC, rpmD, rplX, and rpsT) and oxidative stress-related proteins (Thioredoxin system), suggesting the possible inhibition of bacterial protein biosynthesis with entrectinib exposure. The increased production of reactive oxygen species (ROS) was demonstrated in the entrectinib-treated S. aureus, supported the impact of entrectinib on the expression changes of ROS-correlated proteins involved in oxidative stress. Furthermore, entrectinib-induced resistant S. aureus clone was selected by in vitro induction under entrectinib exposure and 3 amino acid mutations in the entrectinib-induced resistant S. aureus strain, 2 of which were located in the gene encoding Type II NADH: quinoneoxidoreductase and one were found in GTP pyrophosphokinase family protein. Finally, the bactericidal action of entrectinib on S. aureus were confirmed by disrupting the bacterial cell membrane. Conclusively, entrectinib exhibit the antibacterial and anti-biofilm activity by destroying cell membrane against S. aureus.

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“…Ceritinib, a second-generation ALK inhibitor, also benefit patients with ROS1-positive NSCLC [108]. In 2019, entrectinib that targets ROS1 and ALK was approved for adults with metastatic ROS1-positive NSCLC [109]. Entrectinib can pass through the blood-brain barrier and is clinically proven effective against primary and metastatic brain diseases [110].…”

Section: Ros1 Fusions/rearrangementsmentioning

confidence: 99%

Advances in Targeted Therapy Against Driver Mutations and Epigenetic Alterations in Non-Small Cell Lung Cancer

Shi¹,

Chen²,

Peng³

et al. 2022

Oncologie

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The incidence and mortality of lung cancer rank top three of all cancers worldwide. Accounting for 85% of the total number of lung cancer, non-small cell lung cancer (NSCLC) is an important factor endangering human health. Recently, targeted therapies against driver mutations and epigenetic alterations have made encouraging advances that benefit NSCLC patients. Druggable driver mutations, which mainly occur in EGFR, KRAS, MET, HER2, ALK, ROS1, RET and BRAF, have been identified in more than a quarter of NSCLC patients. A series of highly selective mutant targeting inhibitors, such as EGFR tyrosine kinase inhibitors and KRAS inhibitors, have been well studied and applied in clinical treatments, which greatly promote the overall survival of NSCLC patients. However, drug resistance has become a major challenge for targeted treatment, and a variety of methods to overcome drug resistance are constantly being developed, including inhibitors against new mutants, combination therapy with other pathway inhibitors, etc. In addition, epigenetics-based therapy is emerging. Epigenetic regulators such as histone deacetylases and non-coding RNA play a crucial role in the development of cancer and drug resistance by affecting multiple signaling pathways. Epigenetics-based therapeutic strategies combined with targeted drugs show great clinical potential. Many agents targeting epigenetic changes are being investigated in preclinical studies, with some already under clinical trials. This article focuses on driver mutations and epigenetic alterations in association with relevant epidemiological data. We introduce the current status of targeted inhibitors and known drug resistance, review advances in major targeted therapies with recent data from preclinical and clinical trials, and discuss the possibility of combination therapy against driver mutations and epigenetic alterations in overcoming drug resistance.

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Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG)

Cited by 59 publications

References 31 publications

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

Inhibition of planktonic growth and biofilm formation of Staphylococcus aureus by entrectinib through disrupting the cell membrane

Advances in Targeted Therapy Against Driver Mutations and Epigenetic Alterations in Non-Small Cell Lung Cancer

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