Entrectinib

ROZLYTREK is a kinase inhibitor indicated for the treatment of: Adult patients with ROS1- positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. Adult and pediatric patients older than 1 month of age with solid tumors that: have a neurotrophic tyrosine receptor kinase ( NTRK) gene fusion, as detected by an FDA-approved test 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. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [ NTRK ] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK) with IC 50 values of 0.1 to 2 nM. Entrectinib also inhibits JAK2 and TNK2 with IC 50 values > 5 nM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes.

Select patients for treatment based on the presence of ROS1 rearrangement(s) or NTRK gene fusion. Evaluate left ventricular ejection fraction, serum uric acid levels, QRS, and QTc interval and electrolytes prior to ROZLYTREK initiation. Select appropriate dosage form: oral capsules, capsules prepared as an oral suspension or oral pellets. Use capsules prepared as suspension for enteral tube administration. Do not use pellets for enteral tube administration. Administer ROZLYTREK capsules, capsules prepared as a suspension, or pellets once daily, with or without food. Adult Dosage for ROS1- Positive Non-Small Cell Lung Cancer: 600 mg orally once daily. Adult and Pediatric Dosage for NTRK Gene Fusion-Positive Solid Tumors: Adults: 600 mg orally once daily. Pediatric Patients: Recommended dosage is based on age and body surface area (BSA) as shown below.

None. None.

Congestive Heart Failure (CHF): Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK. Monitor patients for clinical signs and symptoms of CHF. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For new onset or worsening CHF, withhold ROZLYTREK, reassess LVEF and institute appropriate medical management. Reduce dose or permanently discontinue ROZLYTREK based on severity of CHF or worsening LVEF. Ventricular Arrhythmias: Monitor patients who have or who are at risk for QRS or QTc interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment. Withhold and then resume at same or reduced dose, or permanently discontinue ROZLYTREK based on severity.

The following clinically significant adverse reactions are described elsewhere in the labeling: Congestive Heart Failure Ventricular Arrhythmias Central Nervous System Effects Skeletal Fractures Hepatotoxicity Hyperuricemia Vision Disorders 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.

Moderate and Strong CYP3A Inhibitors: For adult and pediatric patients 2 years and older, reduce the dose of ROZLYTREK if coadministration of moderate or strong CYP3A inhibitors cannot be avoided. For pediatric patients less than 2 years, avoid coadministration with ROZLYTREK. Moderate and Strong CYP3A Inducers: Avoid coadministration with ROZLYTREK. Drugs That Prolong QRS or QTc Interval: Avoid concomitant use with ROZLYTREK.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F). Storage time should not exceed 2 hours (below 30°C (86°F)) if capsules are prepared as an oral suspension using drinking water or milk. Storage: Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F). Store ROZLYTREK capsules in the original container and keep the bottle tightly closed in order to protect from moisture. Store ROZLYTREK oral pellets in the original container in order to protect from moisture.