Darovasertib and Crizotinib First-Line Treatment for Metastatic Uveal Melanoma: Overall Survival, Efficacy, and Safety From the OptimUM-01 Study
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, Alexander Wei, Jordi Ahnert, Marlana Orloff, Sreenivasa Chandana, Lucy Kennedy, Gerald Falchook, Ryan Weight, Mohammed Milhem, Asad Javed, Justin Moser, Vijay Patel, Fadi Kayali, James Reeves, Rony Abou-Jawde, Ebenezer Kio, Filip Janku, Victoria AtkinsonPurpose
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
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.