Darovasertib and Crizotinib First-Line Treatment for Metastatic Uveal Melanoma: Overall Survival, Efficacy, and Safety From the OptimUM-01 Study.

Authors

Meredith McKean, Bartosz Chmielowski, Marcus O Butler, Richard D Carvajal, Jordi Rodon, Matteo S Carlino, Kevin B Kim, Trisha M Wise-Draper, Shaheer Khan, April K S Salama, Justin Moser, Agnes Ang, Kelly Barrios, Jasgit C Sachdev, Keith D Wilner, George W Cole, Long Kwei, Darrin M Beaupre, Marlana Orloff

Published in

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Pages JCO2600802. Oct 28, 2026. Epub Oct 28, 2026.

Abstract

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.
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).
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.
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.

PMID:
42950186
Bibliographic data and abstract were imported from PubMed on 29 Oct 2026.

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