FDA Approves Entrectinib for the Treatment of NTRK Fusion-Positive Solid Tumours in Adult and Adolescent Patients

It also approves entrectinib for the treatment of ROS1-positive metastatic NSCLC in adults

On 15 August 2019, the US Food and Drug Administration (FDA) granted accelerated approval to entrectinib (Rozlytrek) for the treatment of adults and paediatric patients 12 years of age and older with solid tumours that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy.

This is the third time the FDA has approved a cancer treatment based on a common biomarker across different types of tumours rather than the location in the body where the tumour originated. The approval marks a new paradigm in the development of cancer drugs that are tissue agnostic. It follows the policies that the FDA developed in a guidance document on ‘Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease’ released in 2018.

The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumours with microsatellite instability-high or mismatch repair deficient tumours in 2017 and larotrectinib for NTRK gene fusion-positive tumours in 2018.

Efficacy in NTRK-positive tumours was investigated in 54 adult patients who received entrectinib at various doses and schedules in one of three multicentre, single-arm, clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267); 94% received entrectinib 600 mg orally once daily. Identification of positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrolment.

Among 54 adult patients, the overall response rate (ORR) as determined by independent review was 57% (95% CI: 43, 71). Response duration was 6 months or longer for 68% of patients and 12 months or longer for 45% of patients. The most common tumour types were sarcoma, non-small cell lung cancer (NSCLC), mammary analogue secretory carcinoma, breast, thyroid, and colorectal cancers.

This approval considers an indication for paediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumours by relying on efficacy information obtained primarily in adults. “The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Dr. Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

Rozlytrek was also approved on 15 August 2019 for the treatment of adult patients with metastatic NSCLC whose tumours are ROS1-positive. Efficacy in ROS1-positive metastatic NSCLC was investigated in 51 adult patients who received entrectinib at various doses and schedules in the same three trials; 90% received entrectinib 600 mg orally once daily. The ORR was 78% (95% CI: 65, 89) and response duration was 12 months or longer for 55% of patients. 

The most serious adverse reactions to entrectinib are congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT interval prolongation, and vision disorders.

The most common adverse reactions in at least 20% of patients were fatigue, constipation, dysgeusia, oedema, dizziness, diarrhoea, nausea, dysesthesia, dyspnoea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders.

Healthcare professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing foetus or newborn baby.

The recommended entrectinib dose for adults with NTRK gene fusion-positive solid tumours or with ROS1-positive metastatic NSCLC is 600 mg orally once daily. For paediatric patients ≥12 years with NTRK gene fusion-positive solid tumours, the prescribing information provides dosage recommendations based on body surface area.

Full prescribing information for Rozlytrek is available here.

Rozlytrek was granted accelerated approval. Continued approval for the NTRK-positive tumours may be contingent upon verification and description of clinical benefit in the confirmatory trials. Entrectinib received priority review, Breakthrough Therapy, and Orphan Drug Designation.

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.

The approval of Rozlytrek was granted to Genentech, Inc.