Dataset Information

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

ABSTRACT:

Background

Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors.

Methods

STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D.

Results

At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4).

Conclusions

Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

SUBMITTER: Desai AV

PROVIDER: S-EPMC9527518 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Desai Ami V AV Robinson Giles W GW Gauvain Karen K Basu Ellen M EM Macy Margaret E ME Maese Luke L Whipple Nicholas S NS Sabnis Amit J AJ Foster Jennifer H JH Shusterman Suzanne S Yoon Janet J Weiss Brian D BD Abdelbaki Mohamed S MS Armstrong Amy E AE Cash Thomas T Pratilas Christine A CA Corradini Nadège N Marshall Lynley V LV Farid-Kapadia Mufiza M Chohan Saibah S Devlin Clare C Meneses-Lorente Georgina G Cardenas Alison A Hutchinson Katherine E KE Bergthold Guillaume G Caron Hubert H Chow Maneval Edna E Gajjar Amar A Fox Elizabeth E

Neuro-oncology 20221001 10

<h4>Background</h4>Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors.<h4>Methods</h4>STARTRK-NG (NCT02650 ...[more]

PMID: 35395680

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Project description:Abstract The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b study of entrectinib in pediatric patients with cancer, including primary brain tumors, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring NTRK, ROS1, or ALK gene fusions (NCT02650401). Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2?nM (biochemical kinase assay). Overall, gene fusions are rare in the cancer population (<3%); however, they have been seen in over 40 solid tumor histologies, including non-small cell lung cancer, salivary gland cancers, soft tissue sarcomas and glioneuronal tumors. A survey of two pediatric cancer databases, St. Jude pediatric cancer database (PeCan; total n=1,604) and the University of Michigan database (Peds-MiOncoSeq; total n=91), identified malignancies with gene fusions in all three NTRK genes, including infantile fibrosarcoma, juvenile breast cancer, mesoblastic nephroma, intrinsic pontine gliomas, acute leukemias and anaplastic lymphoma. Previously, we reported an objective response rate of 79% was seen in 24 tyrosine kinase inhibitor-naïve patients with solid tumors harboring NTRK, ROS1, or ALK gene fusions, who were treated at doses consistent with the RP2D (Drilon et al, AACR 2016). The most common (>10% incidence) treatment-related adverse events have been fatigue/asthenia, dysgeusia, paresthesia, nausea, myalgia, diarrhea, dizziness, arthralgia, vomiting, and constipation; importantly, there has been no evidence of cumulative toxicity. In addition, we have treated a 20-month-old boy presenting with infantile fibrosarcoma metastatic to the brain, which harbored an ETV6-NTRK3 fusion. Tumor restaging following 1 month of therapy showed a significant tumor regression of CNS metastases accompanied by significant clinical improvement. Together, these data provide compelling evidence to identify pediatric patients harboring NTRK, ROS1, or ALK fusions for enrollment in the STARTRK-NG trial.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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