Entrectinib — Drug Monograph

Brand names: Rozlytrek

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Potent, ATP-competitive inhibitor of ROS1 (c-ros oncogene 1), NTRK1/2/3 (TrkA/B/C), and ALK (anaplastic lymphoma kinase) receptor tyrosine kinases. Oncogenic fusions involving these kinases — such as CD74-ROS1, ETV6-NTRK3, and EML4-ALK — confer constitutive kinase activity that drives tumor proliferation and survival. Unlike crizotinib, entrectinib was engineered with CNS penetrance in mind, achieving measurable intracranial concentrations, enabling responses in brain metastases. Active against most acquired resistance mutations to first-generation TKIs at ROS1 and NTRK, but resistance via…

FDA Indications

• ROS1-positive, locally advanced or metastatic NSCLC in adults (FDA approved August 2019 — STARTRK-2, STARTRK-1, ALKA-372-001 integrated analysis; ORR 77%, intracranial ORR 55%)
• NTRK fusion-positive solid tumors — locally advanced or metastatic, adults and pediatric patients ≥12 years, with disease requiring systemic therapy or where surgery likely to result in severe morbidity (FDA approved August 2019 — tissue-agnostic approval; STARTRK-2/1 ORR 57%)

Common Side Effects

• Fatigue (48%)
• Constipation (38%)
• Dizziness / dysgeusia (cognitive effects — CNS penetration)
• Peripheral edema (38%)
• Nausea (35%)
• Diarrhea (22%)
• Weight gain
• Arthralgia / myalgia
• Vision disorders (blurred vision, diplopia)
• Elevated creatinine (tubular secretion inhibition, not true GFR decline)

Clinical Pearl

Entrectinib achieves intracranial responses in ROS1+ NSCLC (intracranial ORR ~55%) owing to its CNS penetration — a critical advantage over crizotinib, which has poor BBB penetrance. CNS side effects (dizziness, cognitive slowing, mood changes) are a direct extension of this CNS activity and are among the most impactful quality-of-life toxicities. Acquired resistance most commonly occurs via secondary kinase domain mutations (ROS1 G2032R, L2026M); repotrectinib (next-gen ROS1/NTRK inhibitor)…

Related Therapies & Mechanisms

• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor
• Alectinib (Alecensa) — Tyrosine Kinase Inhibitor
• Alpelisib (Piqray) — Tyrosine Kinase Inhibitor
• Asciminib (Scemblix) — Tyrosine Kinase Inhibitor