brigatinib — Drug Monograph
Brand names: Alunbrig
Drug class: ALK Inhibitor
Mechanism of Action
Brigatinib is a next-generation, orally bioavailable ALK and ROS1 inhibitor with a dimethylphosphine oxide (DMPO) pharmacophore that confers potent activity against a broad spectrum of ALK resistance mutations, including the solvent-front G1202R mutation and compound mutations that confer resistance to second-generation inhibitors. It binds the ATP-binding cleft of ALK, blocking autophosphorylation and downstream activation of MAPK, PI3K/AKT, and JAK/STAT signaling. Brigatinib also inhibits EGFR deletion mutants (exon 19 del, L858R), though not EGFR wild-type, and has activity against…
FDA Indications
- Metastatic ALK-positive NSCLC — 1st-line treatment (2020, ALTA-1L trial)
- Metastatic ALK-positive NSCLC previously treated with crizotinib (2017 accelerated approval; ALTA trial)
Common Side Effects
- Hypertension
- Nausea
- Diarrhea
- Fatigue
- Cough
- Headache
- Rash
- Elevated CPK (creatine phosphokinase)
- Peripheral neuropathy
- Myalgia/muscle pain
- Elevated lipase
- Visual disturbances
Clinical Pearl
Brigatinib's unique early-onset pulmonary toxicity pattern — occurring within the first 7 days and distinct from the late-onset ILD seen with other ALK inhibitors — necessitates a mandatory 7-day lead-in period at 90 mg before dose escalation; the day-8 dose escalation is explicitly contraindicated if any pulmonary event occurred during the lead-in. In the ALTA-1L trial, brigatinib demonstrated a median PFS of 24 months versus 11 months for crizotinib, establishing its first-line efficacy. Its…
Related Therapies & Mechanisms
- Ceritinib (Zykadia) — ALK Inhibitor · NSCLC
- Crizotinib (Xalkori) — ALK Inhibitor · NSCLC
- Lorlatinib (Lorbrena) — ALK Inhibitor · NSCLC
- Adagrasib (Krazati) — NSCLC