Dr Orloff on OS Outcomes With Darovasertib Plus Crizotinib in Metastatic Uveal Melanoma

“The median OS [was 22.1 months], and [pushing beyond 2 years] is our goal right now. Hopefully we can go beyond that [2-year mark], and it may be [darovasertib] that takes us out that far. Then we could [potentially] sequence it with another treatment that might get a patient another 12 or 24 months [of OS].”

Marlana Orloff, MD, an associate professor and the Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma at the Sidney Kimmel Medical College of Thomas Jefferson University, discussed efficacy data from the phase 1/2 OptimUM-01 trial (NCT03947385) investigating darovasertib plus crizotinib (Xalkori) for the first-line treatment of patients with metastatic uveal melanoma.

A significant challenge in the management of metastatic uveal melanoma, particularly in patients presenting with hepatic involvement, has historically been the profoundly limited overall survival (OS) outcomes, Orloff began. Historical data frequently cite a median OS of less than 6 months following the diagnosis of metastatic disease, she said. This prognosis was generally observed prior to the adoption of advanced interventional strategies, such as liver-directed therapies, and the implementation of vigilant surveillance protocols using MRI for the timely detection of smaller tumor burdens, she reported.

Due to these modern clinical practice shifts, median OS metrics are demonstrably improving, according to Orloff. Current therapeutic development focuses on exceeding a median OS of 2 years, she explained. A key strategy involves identifying novel systemic agents, such as darovasertib, that may confer significant survival extensions, thereby enabling subsequent sequential therapeutic interventions that could provide an additional 12 to 24 months of accrued OS, she noted. For instance, in OptimUM-01, the median OS was 21.1 months (95% CI, 12.5-27.1), although future data may report longer outcomes, she added.

Furthermore, Orloff emphasized that overall response rates (ORRs) historically observed with systemic agents in uveal melanoma were typically confined to the single-digit percentage range. However, preliminary data with darovasertib plus crizotinib suggest a profound advancement in response metrics. This combination has yielded an ORR of 34.1% (95% CI, 20.1%-50.6%) in OptimUM-01, which is approximately threefold higher than the rates achieved with alternative systemic strategies, she concluded.