Larotrectinib — Drug Monograph

Brand names: Vitrakvi

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Highly selective pan-TRK (NTRK1, NTRK2, NTRK3) inhibitor that blocks kinase activity of all three tropomyosin receptor kinase isoforms. First tissue-agnostic FDA-approved TKI, active against any NTRK gene fusion regardless of tumor histology. CNS-penetrant. Resistance develops via NTRK kinase domain mutations (e.g., NTRK1 G595R, NTRK3 G623R) → overcome by repotrectinib or selitrectinib.

FDA Indications

• Adult and pediatric patients with solid tumors harboring NTRK gene fusions without a known acquired resistance mutation, that are metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment (FDA approved November 2018 — first tumor-agnostic TKI; pooled NAVIGATE/LOXO-TRK analysis: 79% ORR across 17 tumor types)

Common Side Effects

• Fatigue (37%)
• Nausea (24%)
• Dizziness (28%)
• ALT/AST elevation (23%)
• Vomiting (19%)
• Constipation (23%)
• Weight gain (14%)
• Anemia
• Peripheral neuropathy

Clinical Pearl

Larotrectinib was the first tissue-agnostic oncology drug approval, demonstrating 79% ORR across 17 tumor types solely on the basis of NTRK fusion status. Weight gain is a distinctive side effect. Resistance emerges via solvent-front kinase domain mutations (G595R, G623R), which are specifically addressed by next-generation TRK inhibitors repotrectinib and selitrectinib.

Related Therapies & Mechanisms

• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC
• Pralsetinib (Gavreto) — Tyrosine Kinase Inhibitor · NSCLC
• Selpercatinib (Retevmo) — Tyrosine Kinase Inhibitor · NSCLC
• Trametinib (Mekinist) — Tyrosine Kinase Inhibitor · NSCLC