Entrectinib

Entrectinib is an oral tyrosine kinase inhibitor that targets tropomyosin receptor kinase proteins encoded by NTRK1, NTRK2 and NTRK3, as well as ROS1 and ALK kinases. By inhibiting these signaling proteins, entrectinib can interfere with abnormal signaling that promotes cancer-cell growth and survival in tumors driven by specific gene fusions. It is taken orally once daily and is available as capsules and pediatric oral pellet formulations. Entrectinib is used primarily as a molecularly targeted treatment selected according to specific genetic alterations rather than tumor location alone. Its major approved uses include ROS1-positive metastatic non-small-cell lung cancer in adults and NTRK gene fusion-positive solid tumors meeting specific regulatory criteria. The NTRK indication can apply across different tumor types when an actionable NTRK gene fusion is identified. Entrectinib also penetrates the central nervous system, which is clinically relevant because ROS1-positive lung cancer and some NTRK fusion-positive tumors can involve the brain. Because treatment is selected according to a tumor's molecular characteristics, validated testing for ROS1 rearrangement or NTRK gene fusion is required before treatment. Entrectinib is generally administered as monotherapy rather than routinely combined with cytotoxic chemotherapy.

Entrectinib was developed as a selective inhibitor of TRK, ROS1 and ALK signaling, with early clinical development focused on cancers harboring these molecular alterations. The U.S. FDA granted the original approval on August 15, 2019 for adult patients with ROS1-positive metastatic non-small-cell lung cancer and for adult and pediatric patients aged 12 years and older with NTRK gene fusion-positive solid tumors meeting specified criteria. On October 20, 2023, FDA expanded the NTRK indication to patients older than 1 month and approved a new oral pellet formulation. The NTRK indication remains under accelerated approval based on overall response rate and duration of response, with confirmatory evidence required. The EMA granted conditional marketing authorisation for Rozlytrek on July 31, 2020 for NTRK gene fusion-positive solid tumors and ROS1-positive advanced non-small-cell lung cancer. Key clinical development programs included ALKA-372-001, STARTRK-1, STARTRK-2 and STARTRK-NG, with pediatric evidence also supported by the TAPISTRY study.

Entrectinib is used in adults with ROS1-positive metastatic non-small-cell lung cancer identified by an appropriate molecular test. It is also approved for adults and pediatric patients older than 1 month with NTRK gene fusion-positive solid tumors that are metastatic or where surgical removal would be expected to cause severe morbidity, when the disease has progressed following treatment or there is no satisfactory standard therapy. The NTRK indication requires absence of a known acquired resistance mutation in the relevant TRK protein under U.S. labeling. Treatment is generally given as monotherapy rather than combined routinely with cytotoxic chemotherapy. Because entrectinib is a biomarker-directed therapy, the presence of the relevant ROS1 rearrangement or NTRK fusion should be established before treatment.

Entrectinib is administered orally once daily, with or without food. The recommended adult dose for ROS1-positive metastatic non-small-cell lung cancer and for NTRK gene fusion-positive solid tumors is 600 mg once daily. Pediatric dosing for NTRK-positive solid tumors is based on age and body-surface area, with a maximum of 600 mg once daily; children older than 1 month through 6 months use a specific body-surface-area-based regimen. Capsules, capsules prepared as an oral suspension, or oral pellets may be used according to age and swallowing ability. The pellet formulation should not be administered through an enteral feeding tube. Treatment is generally continued until disease progression or unacceptable toxicity. Dose interruption or reduction may be required for adverse reactions or clinically significant drug interactions. Baseline and follow-up assessment may include cardiac function, QT interval, electrolytes, liver function and uric acid according to prescribing information.

Common side effects of entrectinib include fatigue, constipation, changes in taste, swelling or edema, dizziness, diarrhea, nausea, vomiting, weight gain, increased creatinine and anemia. Musculoskeletal pain, cognitive effects, cough, fever and laboratory abnormalities involving liver enzymes can also occur. In children, adverse effects may include fever, constipation, increased weight, vomiting, diarrhea, nausea, cough, fatigue, extremity pain, skeletal fractures, decreased appetite and headache. Many adverse reactions can be managed with monitoring, supportive treatment, dose interruption or dose modification when appropriate. Patients should report persistent or worsening symptoms so that treatment-related toxicity can be distinguished from complications of the underlying cancer.

Important risks associated with entrectinib include congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT-interval prolongation and vision disorders. Heart failure can occur during treatment, so patients with relevant cardiovascular risk factors require appropriate assessment and monitoring. Cognitive changes such as confusion, memory impairment, hallucinations or changes in attention can occur and may require treatment interruption or dose adjustment. Entrectinib can increase the risk of fractures, including fractures occurring with relatively minor trauma. Severe liver toxicity has also been reported. QT prolongation may increase the risk of cardiac arrhythmias, particularly in patients with other risk factors or interacting medicines. Treatment should be interrupted, reduced or discontinued according to the severity of the adverse event and applicable prescribing information. Entrectinib can also cause embryo-fetal harm when administered during pregnancy.

Before starting treatment, clinicians should confirm the relevant molecular alteration using an appropriate validated diagnostic test and assess baseline cardiac function, QT interval, electrolytes, liver function and uric acid as clinically appropriate. Entrectinib is metabolized predominantly through CYP3A pathways, so strong or moderate CYP3A inhibitors can increase exposure, while CYP3A inducers can reduce exposure and potentially decrease treatment effectiveness. Concomitant medicines that prolong the QT interval should be reviewed carefully because entrectinib can also prolong QT. Medicines that increase the risk of heart failure, central nervous system effects or other overlapping toxicities may require additional caution. Because entrectinib can cause fetal harm, pregnancy and reproductive considerations should be addressed before treatment. Breastfeeding is not recommended during treatment and for 7 days after the final dose under U.S. prescribing information. Pediatric patients require age- and body-surface-area-based dosing and appropriate growth, neurological and skeletal monitoring.

Confirm ROS1 or NTRK status with a validated molecular assay before initiating treatment and verify that the indication matches the applicable regulatory criteria. Review baseline cardiac history and assess cardiac function, QT interval, electrolytes, uric acid and liver function as appropriate. Review the complete medication list for CYP3A inhibitors or inducers and other QT-prolonging medicines before prescribing. Patients should be counselled to report shortness of breath, swelling, rapid weight gain, fainting, palpitations, confusion, hallucinations, severe dizziness, unusual bone pain or symptoms suggesting liver injury. Monitor for fractures and consider bone health in patients with relevant risk factors. For children, ensure accurate body-surface-area-based dosing and use the appropriate oral formulation. Pharmacists should verify preparation instructions when capsules are converted to an oral suspension and ensure that oral pellets are not administered through an enteral feeding tube. Treatment coordination should include appropriate oncology, pathology, pharmacy and supportive-care services.