Darovasertib and Crizotinib First-Line Treatment for Metastatic Uveal Melanoma: Overall Survival, Efficacy, and Safety From the OptimUM-01 Study
Mené sur 44 patients atteints d'un mélanome de l'uvée de stade métastatique, cet essai de phase I/II évalue l'efficacité, du point de vue du taux de réponse objective, de la durée de la réponse, du taux de contrôle de la maladie, de la survie sans progression et de la survie globale, et la toxicité d'un traitement de première ligne combinant darovasertib et crizotinib
Purpose: Metastatic uveal melanoma (mUM) has poor prognosis with limited therapies. GNAQ/11 mutations that activate protein kinase C (PKC) are detected in 95% of UM tumors. Darovasertib is a first-in-class, oral, targeted PKC inhibitor that, in combination with the MET inhibitor crizotinib, has shown responses and encouraging survival outcomes in early mUM clinical trials. Here, we present phase 2 results in first-line patients with mUM treated with darovasertib 300 mg twice a day and crizotinib 200 mg twice a day.
Methods: The OptimUM-01 study was a phase I/II, multicenter, open-label, dose escalation and expansion study of darovasertib in patients with solid tumors harboring GNAQ/11 mutations irrespective of human leukocyte antigen status; this analysis focuses on the phase II expansion in previously untreated patients with mUM. Eligibility criteria included Response Evaluation Criteria in Solid Tumors v1.1 measurable disease, Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function. Study end points included safety, objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
Results: Overall, 44 treatment-naïve patients were enrolled. The most common adverse events (AEs) were diarrhea (95.2%), nausea (84.1%), peripheral edema (61.4%), and vomiting (52.3%). The most common grade 3 or greater AEs were pulmonary embolism (9.1%) and iron deficiency anemia (6.8%). AEs leading to discontinuation occurred in three patients (6.8%). ORR was 34.1%, DOR was 9.0 months, and DCR was 90.2% at 8 weeks. The median PFS and OS were 7.0 months (95% CI, 5.0 to 8.3) and 21.1 months (95% CI, 11.9 to 20.7), respectively.
Conclusion: Results from OptimUM-01 suggest that the combination of darovasertib and crizotinib has encouraging efficacy with a manageable safety profile and may represent a first-in-class targeted treatment option for patients with previously untreated mUM.
Journal of Clinical Oncology , résumé, 2026