Entrectinib, known by its brand name Rozlytrek, is a targeted cancer therapy. It addresses specific genetic alterations found within cancer cells, rather than focusing on the tumor’s origin. This approach offers a precise treatment option for cancers driven by particular molecular changes.
Mechanism of Action
Entrectinib functions as a kinase inhibitor, specifically targeting tyrosine kinases. These proteins regulate cell processes like growth and division. In some cancers, genetic changes cause these kinases to become overactive, promoting uncontrolled cancer cell proliferation.
Entrectinib precisely inhibits neurotrophic tyrosine receptor kinase (TRK) proteins (TRKA, TRKB, TRKC) and ROS1 proteins. These proteins become abnormally activated through gene fusions, such as NTRK and ROS1 fusions, which create new, oncogenic proteins. Entrectinib binds to these fusion proteins, blocking their signaling pathways and stopping cancer cells from growing and spreading.
Approved Uses and Patient Eligibility
Entrectinib is approved for solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. This “tumor-agnostic” approval means it can treat various cancers, including sarcoma, lung, breast, thyroid, and colorectal cancers, if they carry this specific genetic marker. The medication is also approved for adults with metastatic non-small cell lung cancer (NSCLC) that is ROS1-positive. To determine eligibility, a patient’s tumor must undergo biomarker testing, which identifies the presence of NTRK or ROS1 gene fusions.
Administration and Dosing
Entrectinib is administered orally in capsule form, usually once daily, with or without food. Capsules must be swallowed whole and not opened, crushed, chewed, or dissolved. The prescribing physician determines the specific dosage. For adults, the recommended dose is generally 600 milligrams orally once daily, though it may be adjusted based on patient tolerance and response.
Potential Side Effects
Patients taking entrectinib may experience various side effects. Common side effects include fatigue, constipation, changes in taste perception, dizziness, diarrhea, nausea, swelling (edema), weight gain, muscle or joint pain, cough, vomiting, or fever.
More serious side effects require careful monitoring. These include heart problems like congestive heart failure (e.g., swelling, rapid weight gain, shortness of breath). Central nervous system (CNS) effects can also occur, such as cognitive impairment, mood changes, confusion, or hallucinations. Liver toxicity (hepatotoxicity) is another risk, with symptoms like nausea, vomiting, or yellowing of the skin or eyes. There is also an increased risk of skeletal fractures and elevated uric acid levels.
Efficacy and Clinical Trial Results
Entrectinib’s efficacy has been demonstrated in several clinical trials, including an integrated analysis of the STARTRK-2, STARTRK-1, and ALKA-372-001 studies. These trials evaluated the drug’s effectiveness in patients with NTRK gene fusion-positive solid tumors and ROS1-positive non-small cell lung cancer. Key metrics assessed were the Overall Response Rate (ORR) and the Duration of Response (DoR).
For NTRK fusion-positive solid tumors, the ORR was approximately 57% to 59.3%. The median DoR for these patients was around 12.9 months. In ROS1-positive non-small cell lung cancer, the ORR ranged from approximately 67.1% to 78%. The median DoR for this group was about 15.7 months. These results underscore the drug’s ability to provide meaningful clinical benefits for patients with these specific genetic alterations.