On October 20, 2023, the U.S Food and Drug Administration (FDA) granted accelerated approval to entrectinib (Rozlytrek®) for pediatric patients older than 1 month with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance variant, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. In August 2019, FDA granted entrectinib accelerated approval for pediatric patients aged 12 years or older for the indication.
FDA also approved a new oral pellet formulation for entrectinib, and the prescribing information now includes instructions for making an oral suspension from the capsules.
Efficacy in NTRK-positive tumors was investigated in 33 pediatric patients who received entrectinib based on body surface area (20–600 mg orally or via enteral feeding tube once daily) in one of two multicenter, single-arm clinical trials: STARTRK-NG (NCT02650401) or TAPISTRY (NCT04589845). NTRK gene fusion status was identified with nucleic acid–based tests at local laboratories or a central laboratory prior to enrollment.
The major efficacy outcome measure was overall response rate (ORR), as assessed by blinded independent central review according to RECIST v1.1 for extracranial tumors and response assessment in neuro-oncology for primary central nervous system tumors. An additional efficacy outcome measure was duration of response (DOR). Among the 33 pediatric patients, the ORR was 70% (95% CI: 51, 84) and median DOR was 25.4 months (95% CI: 14.3, not evaluable). The most common cancers were primary central nervous system tumors and infantile fibrosarcoma. The indication received accelerated approval based on ORR and DOR. Continued approval for the indication may necessitate verification and description of clinical benefit in confirmatory trials.
Reported in at least 20% of the pooled safety population of pediatric patients receiving entrectinib (N = 76), the most common adverse reactions 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.
The recommended dose for pediatric patients aged 1–6 months is 250 mg/m2 orally once daily. The recommended dose for pediatric patients older than 6 months is based on body surface area, up to a maximum of 600 mg once daily. See the prescribing information for specific dosing details.
The review used Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
The application was granted priority review, breakthrough designation, and orphan drug designation. FDA-expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.
For assistance with single-patient applications for investigational new oncology products, healthcare professionals may contact the Oncology Center of Excellence’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.