A Phase 2 Study of the MEK1/2 Inhibitor Luvometinib in Patients with Extracranial Arteriovenous Malformations

PURPOSE: Extracranial arteriovenous malformation (AVM) is a rare and debilitating condition with significant morbidity. Clinical trial evidence for targeted therapies remains limited. We evaluated the efficacy and safety of luvometinib, a MEK1/2 inhibitor, in adults with complicated AVM that were inoperable, unsuitable for intervention, relapsed after surgery, or failed previous treatment. PATIENTS AND METHODS: This single-arm phase 2 study enrolled adults with inoperable or relapsed extracranial AVMs. Patients received luvometinib 8 mg once daily in 28-day cycles. Primary endpoint was objective response rate (ORR; patients with ≥20% reduction in lesion range) by digital subtraction angiography (DSA). Secondary endpoints included ORR (patients with ≥20% reduction in volume) by magnetic resonance imaging (MRI), lesion clearance, improvement in arterial flow and impedance, clinical symptoms, and safety. RESULTS: We enrolled 20 patients; 18 (90%) had stage III AVM (median follow-up duration 14.6 months). ORR by DSA was 64.3% [lesion reduction ≥20%; 95% confidence interval (CI), 35.1-87.2]; 35.7% achieved major partial response (lesion reduction >50%). ORR by MRI was 61.1% (95% CI, 35.7-82.7). Fourteen (77.8%) and 15 (83.3%) patients had improvements in arterial velocity and impedance, respectively; 12 (66.7%) had improvements in clinical symptoms. Response was achieved in RAS-MARK-mutated, EPHB4-mutated, or mutation-undetected patients, but not RASA1-mutated patients. Nineteen (95%) patients experienced treatment-emergent adverse events, mostly grade 1 to 2; 5 (25%) had grade ≥3. No deaths were reported. CONCLUSIONS: In the first clinical trial of targeted therapy in adults with inoperable or relapsed extracranial AVMs, luvometinib demonstrated promising efficacy and tolerability, supporting its further development for the treatment of AVMs.