Entrectinib Receives Expanded Accelerated Approval for Pediatric NTRK-Positive Tumors

NTRK diagram.

The FDA has granted an expanded accelerated approval for entrectinib (Rozlytrek®, Genentech Inc.) for pediatric patients, one month or older, with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, that are metastatic or where surgical resection is likely to result in severe morbidity, and that have progressed following treatment or have no satisfactory standard therapy. Previously, entrectinib was granted accelerated approval for this indication in August 2019 for pediatric patients 12 years or older. In addition, the FDA approved a new oral pellet formulation for entrectinib, and instructions are provided in the prescribing information for making an oral suspension from the capsules.  

Why it matters: “Specific evaluation of entrectinib in pediatric patients is necessary to determine the appropriate dose and whether similar safety and efficacy can be achieved in this population,” wrote Ami V. Desai, MD, MSCE, Associate Professor of Pediatrics at The University of Chicago Medicine, and colleagues, in their published results of the STARTRK-NG trial (NCT02650401), one of the two trials on which approval was based. “The STARTRK-NG study demonstrates that entrectinib is an important therapeutic option for pediatric patients with NTRK or ROS1 fusion-positive intracranial and extracranial solid tumors.”

What they studied: Efficacy was measured in two phase 1/2, multicenter, single-arm trials, STARTRK-NG or TAPISTRY (NCT04589845). A combined population of 33 pediatric patients with NTRK-positive tumors received 20 mg to 600 mg of entrectinib based on their body surface area, orally or via enteral feeding tube, once daily. Prior to enrollment, NTRK-positive fusion status was determined in a local or central laboratory using nucleic acid-based tests.

The main efficacy end point studied was overall response rate, assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1 for extracranial tumors, and Response Assessment in Neuro-Oncology (RANO) for primary central nervous system tumors. An additional end point of duration of response was also studied.

What they found: The most common cancers represented in the trials were primary central nervous system tumors and infantile fibrosarcoma. For the 33 pediatric patients studied, the overall response rate with entrectinib was 70% and the median duration of response was 25.4 months.

Adverse events: The most common adverse events seen in ≥20% of the pooled safety pediatric patient population (n=76) were pyrexia, constipation, increased weight, vomiting, diarrhea, nausea, cough, fatigue, pain in extremity, skeletal fracture, decreased appetite, headache, abdominal pain, urinary tract infection, upper respiratory tract infection, and nasal congestion.

What to know: Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

What’s next: Ongoing studies are assessing the age-appropriate formulation, determining the optimal treatment duration, and monitoring for resistance and long-term side effects in pediatric patients.

Conclusion: “In conclusion, entrectinib demonstrated rapid and durable activity against pediatric intracranial and extracranial solid tumors with target gene fusions in NTRK1/2/3 or ROS1,” concluded Dr. Desai and colleagues. “Although tumors that harbor these fusions remain rare, the profound effect of this single agent on these pediatric patients with life-threatening diseases makes it invaluable to this population.”

Instructions: The recommended dosage of entrectinib for pediatric patients one month to six months of age is 250 mg/m2 orally, once daily. For patients older than six months, the recommended dose is based on body surface area, with a maximum of 600 mg once daily. See the prescribing information for specific dosing information.

For More Information

Desai AV, Robinson GW, Gauvain K, et al (2022). Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol;24(10):1776-1789. DOI:10.1093/neuonc/noac087

Drilon AE, Liu H, Wu F, et al (2021). Tumor-agnostic precision immuno-oncology and somatic targeting rationale for you (TAPISTRY): A novel platform umbrella trial. J Clin Oncol, 39 (suppl_15). Abstract TPS3154. DOI:10.1200/JCO.2021.39.15_suppl.TPS3154

Clinicaltrials.gov (2023). Study of entrectinib (Rxdx-101) in children and adolescents with locally advanced or metastatic solid or primary CNS tumors and/or who have no satisfactory treatment options (STARTRK-NG). NLM identifier: NCT02650401.

Clinicaltrials.gov (2023). Tumor-agnostic precision immuno-oncology and somatic targeting rational for you (TAPISTRY) platform study. NLM identifier: NCT04589845.

Rozlytrek® (entrectinib) prescribing information (2023). Genentech Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212725Orig1s009lbl.pdf

US Food and Drug Administration (2023). FDA expands pediatric indication for entrectinib and approves new pellet formulation. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pediatric-indication-entrectinib-and-approves-new-pellet-formulation

Image credit: University of Basil. Licensed under CC BY-SA 4.0 DEED

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