In the multicenter phase I/II OptimUM-01 trial, first-line treatment with the protein kinase C inhibitor darovasertib plus the MET inhibitor crizotinib demonstrated antitumor activity and a manageable safety profile in patients with previously untreated metastatic uveal melanoma, suggesting a potential targeted treatment option for this malignancy driven by near-universal GNAQ/GNA11 mutations, according to findings published by McKean et al in the Journal of Clinical Oncology.
Study Details
This dose-escalation and -expansion study evaluated darovasertib as monotherapy and in combination regimens, including with crizotinib, among patients with solid tumors harboring GNAQ/GNA11 mutations regardless of human leukocyte antigen (HLA) status. The current analysis focused on the phase II expansion cohort of previously untreated patients with metastatic uveal melanoma who had measurable disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and adequate organ function.
A total of 44 treatment-naive patients were enrolled; they received 300 mg of darovasertib plus 200 mg of crizotinib twice daily.
The study assessed safety alongside several efficacy endpoints, including objective response rate, duration of response, disease control rate, progression-free survival, and overall survival.
Key Findings
Diarrhea (95.2%), nausea (84.1%), peripheral edema (61.4%), and vomiting (52.3%) were the most frequently reported adverse events. Among grade 3 or higher adverse events, pulmonary embolism (9.1%) and iron deficiency anemia (6.8%) were the most common. Three patients (6.8%) discontinued treatment because of adverse events.
The objective response rate was 34.1%, with a median duration of response of 9.0 months and an 8-week disease control rate of 90.2%. Median progression-free and overall survival were 7.0 and 21.1 months, respectively.
Looking ahead, the investigators wrote, “The promising efficacy seen in patients with first-line [metastatic uveal melanoma] supports the OptimUM-02 trial, the ongoing registrational study in patients with first-line HLA-A*02:01–negative [metastatic uveal melanoma]. In addition, darovasertib is being evaluated as a monotherapy in the neoadjuvant setting for patients with primary [uveal melanoma] (OptimUM-10), and an adjuvant trial is being planned with darovasertib/crizotinib in patients at high risk of metastasis after local treatment for primary [uveal melanoma].”
Meredith McKean, MD, of Sarah Cannon Research Institute, Nashville, is the corresponding author of the article in the Journal of Clinical Oncology.
Disclosure: The study was supported by IDEAYA Biosciences. For full disclosures of the study authors, visit ascopubs.org.
