FDA Expands Entrectinib Approval in Pediatric Patients With NTRK+ Solid Tumors

• The FDA’s accelerated approval program allows drugs that treat serious conditions or fill an unmet medical need to be approved faster.
• Entrectinib’s application was granted priority review, breakthrough drug designation, and orphan drug designation.
• Entrectinib was granted accelerated approval in August 2019 for pediatric patients ages 12 and up with certain solid tumors.

The FDA granted accelerated approval to entrectinib (Rozlytrek) for the treatment of pediatric patients 1 month and older with solid tumors that have an NTRK gene fusion without an acquired resistance mutation, are metastatic, are not favorable candidates for surgical resection, and have disease progression following treatment.¹

The FDA accelerated approval program facilitates an advanced approval timeline for drugs that treat serious conditions or fill an unmet medical need. The approval is based on findings from the phase 1/2 STARTRK-NG (NCT02650401) trial and the phase 2 TAPISTRY (NCT04589845) trial. Entrectinib’s efficacy was evaluated in 33 pediatric patients. The most common tumors among the patients treated were primary central nervous system tumors and infantile fibrosarcoma.

The primary end point was overall response rate (ORR) 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.

The ORR among the 33 patients was 70% (95% CI, 51%-84%). The secondary end point was duration of response, which was 25.4 months (95% CI, 14.3-not evaluable).

Safety was investigated in 76 patients. The most common (≥20%) adverse events (AEs) were pyrexia, constipation, weight gain, vomiting, diarrhea, nausea, cough, fatigue, pain in extremities, bone fractures, loss of appetite, headache, abdominal pain, urinary tract infection, upper respiratory tract infection, and nasal congestion.¹

Both the STARTRK-NG and TAPISTRY trials are ongoing. STARTRK-NG has an enrollment of 69 patients and an estimated completion date of June 2025.² TAPISTRY is still recruiting with an estimated enrollment of 920 patients and an estimated completion date of 2032.³

Entrectinib is available in 100 mg and 200 mg capsules, as well as a newer 50 mg pellet form for both adult and pediatric patients. The dosage for pediatric patients under 6 months is 250 mg/m2 daily. Dosage for pediatric patients older than 6 months is based on body surface area and ranges from 300 mg/m2 to 600 mg/m2 daily. The dosage for adult patients is 600 mg daily.⁴

The FDA granted entrectinib accelerated approval in August 2019 for pediatric patients ages 12 and older with an NTRK gene fusion and the same disease parameters as this most recent approval. At the same time, entrectinib was approved for ROS1-positive metastatic non­–small cell lung cancer.

REFERENCES

1. FDA expands pediatric indication entrectinib and approves new pellet formulation. News release. U.S. Food & Drug Administration. October 20, 2023. Accessed October 23, 2023. https://tinyurl.com/25a436v4

2. 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). ClinicalTrials.gov. Updated October 6, 2023. Accessed October 23, 2023. https://www.clinicaltrials.gov/study/NCT02650401

3. Tumor-agonistic precision immuno-oncology and somatic targeting rational for you (TAPISTRY) platform study. ClinicalTrials.gov. Updated October 19, 2023. Accessed October 23, 2023. https://www.clinicaltrials.gov/study/NCT04589845

4. Entrectinib (Rx). Medscape. Accessed October 23, 2023. https://tinyurl.com/2c8989d7