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Rozlytrek Now Approved for Pediatric Patients Older Than 1 Month With Solid Tumors and NTRK Gene Fusion and in New Oral Pellet Form

Web Exclusives - FDA Approvals

On October 20, 2023, the FDA accelerated the approval of the tyrosine kinase inhibitor entrectinib (Rozlytrek; Genentech) for the treatment of pediatric patients aged >1 month who are diagnosed with metastatic solid tumors associated with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, as detected by an FDA-approved test, and no known acquired resistance mutation or whose disease is likely to lead to severe morbidity and has progressed after previous treatment, or patients who have no satisfactory standard therapy. In 2019, the FDA approved the same indication for patients aged ≥12 years.

The FDA granted this approval priority review and breakthrough and orphan drug designations.

On the same day, the FDA also approved a new oral pellet formulation for entrectinib, which was previously only available as an oral capsule (see the prescribing information for entrectinib for instructions on making an oral suspension from the capsules).

Entrectinib was previously approved by the FDA for the treatment of adults with metastatic, ROS1-positive non–small cell lung cancer, as detected by an FDA-approved test.

The FDA approved entrectinib for this indication for pediatric patients aged >1 month with NTRK-positive tumors based on the results in patients aged >1 month who received entrectinib 20 mg to 600 mg (based on the patient’s body surface area [BSA]), orally or via enteral feeding tube once daily, in 1 of 2 multicenter, single-arm clinical trials—the TAPISTRY study and the STARTRK-NG study.

Cohort B in the TAPISTRY study, a phase 2, international, multicenter, open-label, multicohort clinical trial, included adults and pediatric patients with metastatic or advanced solid tumors who received entrectinib once daily in repeated 28-day cycles, at a daily dose of 600 mg in patients with a BSA of ≥1.51 m2. The total daily dose of entrectinib administered to pediatric patients with a BSA of <1.51 m2 was lower.

The STARTRK-NG study is an open-label, phase 1/2 multicenter, dose-escalation trial of entrectinib in pediatric patients with relapsed or refractory extracranial solid tumors (phase 1), with additional expansion cohorts (phase 2) in patients with primary brain tumors harboring NTRK1, NTRK2, NTRK3, or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1, NTRK2, NTRK3, or ROS1 gene fusions. The most common tumor types included in these 2 studies were primary central nervous system (CNS) tumors and infantile fibrosarcoma.

The major efficacy measure in both studies 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 CNS tumors. Another efficacy measure was the duration of response (DOR). Overall, the ORR was 70% (95% confidence interval [CI], 51-84), and the median DOR was 25.4 months (95% CI, 14.3-not evaluable) in pediatric patients who received entrectinib.

In the pooled safety population (n=76) of pediatric patients who received entrectinib, the most common (≥20%) adverse events 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 dosage of entrectinib for pediatric patients aged between >1 month and 6 months is 250 mg/m2 orally once daily. The recommended dosage for patients aged >6 months is based on the patient’s BSA, up to a maximum of 600 mg once daily; see entrectinib’s prescribing information for specific details.

This indication for the new population was granted under the FDA’s accelerated approval process based on the ORR and DOR data. Continued approval for this indication for this population may be contingent on clinical benefit verification in ongoing and confirmatory studies.

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Last modified: December 6, 2023