FDA Approves ROZLYTREK (Entrectinib) for ROS1-Positive Non-Small Cell Lung Cancer in Adults or Certain NTRK Gene Fusion-Positive Solid Tumors in Adults and Pediatric Patients 12 Years and Older

On August 15, 2019, the U.S. Food and Drug Administration (FDA) approved ROZLYTREK (entrectinib)
for the treatment of:
  • Adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive, or
  • Adult and pediatric patients 12 years of age and older with solid tumors 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 alternative therapy.

In adults, the approved recommended dosage of ROZLYTREK is 600 mg orally once daily. In pediatric patients 12 years and older, the approved recommended dosage of ROZLYTREK is either 400 mg, 500 mg, or 600 mg orally once daily based on body surface area (BSA). Administer ROZLYTREK with or without food and continue therapy until disease progression or unacceptable toxicity. Select patients for treatment based on the presence of ROS1 rearrangement(s) or NTRK gene fusion. 

Additional information regarding dosage and administration, recommended dosage modifications, as well as important warnings and precautions about congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT interval prolongation, vision disorders, and embryo-fetal toxicity can be found in the full prescribing information linked below. 

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: Entrectinib is an inhibitor of certain tropomyosin receptor tyrosine kinases (TRK).
  • General PK: Pharmacokinetics of entrectinib and its active metabolite, M5, are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and within two weeks for M5.
  • Absorption: The maximum entrectinib plasma concentration was reached 4-6 hours.
  • Distribution: Protein binding of entrectinib and M5 are both > 99% in vitro. The estimated apparent volume of distribution was 551 L and 81 L for entrectinib and M5, respectively.
  • Elimination: The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively. The estimated apparent clearance was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively.
  • Metabolism: Entrectinib is metabolized primarily by CYP3A4 (~76%) to the only major active circulating metabolite, M5. M5 has similar pharmacological potency to entrectinib in vitro and circulating M5 exposures at steady-state were 40% of the corresponding entrectinib exposure.
  • Excretion: Following a single oral dose of radiolabeled entrectinib, 83% of radioactivity was excreted in feces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).
  • Cardiac Electrophysiology: Across clinical trials, 3.1% of 355 patients, who received ROZLYTREK at doses ranging from 100 mg to 2600 mg daily (75% received 600 mg orally once daily) and had at least one post-baseline ECG assessment, experienced QTcF interval prolongation of > 60 ms after starting ROZLYTREK and 0.6% had a QTc interval > 500 ms. 

Drug Interactions

  • Moderate and Strong CYP3A Inhibitors: For adults and pediatric patients 12 years and older with BSA > 1.50 m2, avoid coadministration of strong or moderate CYP3A inhibitors with ROZLYTREK. If coadministration is unavoidable, reduce the once daily ROZLYTREK dose to 100 mg with strong CYP3A inhibitors or 200 mg with moderate CYP3A inhibitors. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the ROZLYTREK dose that was taken prior to initiating the CYP3A inhibitor. Avoid grapefruit products during treatment with ROZLYTREK, as they contain inhibitors of CYP3A. For pediatric patients 12 years and older with BSA ≤ 1.50 m2, avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors.
  • Moderate and Strong CYP3A Inducers: Avoid coadministration of strong and moderate CYP3A inducers with ROZLYTREK.
  • Drugs That Prolong QT Interval: Avoid coadministration of ROZLYTREK with other drugs known to prolong the QT/QTc interval.

Use in Specific Populations

  • Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr 30 to < 90 mL/min calculated by Cockcroft-Gault equation). ROZLYTREK has not been studied in patients with severe renal impairment (CLcr < 30 mL/min).
  • Hepatic Impairment: No dose adjustment is recommended for patients with mild (total bilirubin ≤ 1.5 times ULN) hepatic impairment. ROZLYTREK has not been studied in patients with moderate (total bilirubin > 1.5 to 3 times ULN) and severe (total bilirubin > 3 times ULN) hepatic impairment.

Efficacy and Safety

Efficacy of ROZLYTREK was evaluated in a pooled subgroup of adult patients with ROS1-positive metastatic NSCLC or unresectable or metastatic solid tumors with a NTRK gene from three multicenter, single-arm, open-label clinical trials. Additional information regarding the efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders.  

Full prescribing information is available at https://go.usa.gov/xVCD4.                                                                                        

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

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 by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.