Repotrectinib — Drug Monograph

Brand names: Augtyro

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Next-generation macrocyclic ROS1 and pan-TRK (NTRK1/2/3) inhibitor. Its compact macrocyclic structure eliminates steric clashes with solvent-front mutations (ROS1 G2032R, NTRK xDFG mutations) and xDFG resistance mutations that confer resistance to first-generation ROS1/TRK inhibitors (crizotinib, entrectinib, larotrectinib). CNS-penetrant.

FDA Indications

• ROS1-positive locally advanced or metastatic NSCLC, TKI-naive (FDA approved November 2023; TRIDENT-1: 82% ORR)
• ROS1-positive locally advanced or metastatic NSCLC, previously treated with one ROS1 TKI with or without platinum-based chemotherapy (TRIDENT-1: 37.5% ORR, including ROS1 G2032R)
• NTRK fusion-positive solid tumors, adults and pediatric patients, TKI-naive or previously treated (tumor-agnostic)

Common Side Effects

• Dizziness (62%)
• Dysgeusia (55%)
• Peripheral neuropathy (26%)
• Constipation (46%)
• Dyspnea (25%)
• Fatigue (28%)
• Cognitive impairment (memory impairment)
• Weight gain
• Edema

Clinical Pearl

Repotrectinib's macrocyclic structure is specifically engineered to overcome the ROS1 G2032R solvent-front mutation, the most common acquired resistance mechanism to first-generation ROS1 inhibitors. It is a preferred option for both TKI-naive patients (82% ORR) and those who progressed on a prior ROS1 TKI (37.5% ORR including G2032R).

Related Therapies & Mechanisms

• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor · NSCLC
• Alectinib (Alecensa) — Tyrosine Kinase Inhibitor · NSCLC
• Capmatinib (Tabrecta) — Tyrosine Kinase Inhibitor · NSCLC
• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC