Neoadjuvant darovasertib in uveal melanoma patients undergoing primary local therapy (OptimUM-10): Phase 3 trial.

Abstract

TPS9608 Background: Uveal melanoma (UM) is the most common intraocular malignancy and has high risk of metastatic progression and poor long-term survival. Standard treatment of the primary tumor includes enucleation (eye-removal), and radiation therapy including plaque brachytherapy (PB) and proton beam therapy, which can result in vision loss or removal of the eye. No approved neoadjuvant therapies exist that shrink the tumor or improve visual outcomes. Almost all UM tumors harbor GNAQ/GNA11 initiating mutations with downstream constitutive activation of protein kinase C (PKC). Darovasertib, a first-in-class oral PKC inhibitor tested in study OptimUM-09, has demonstrated the ability to reduce UM tumor size resulting in enucleation sparing in patients with large tumors, and radiation reduction in patients with medium sized tumors requiring PB. In addition, visual improvements have been observed not only during neoadjuvant therapy but also in the predicted risk of legal blindness post PB using a vision prognostication tool. Methods: OptimUM-10 is an ongoing phase 3, randomized, multicenter, open-label trial enrolling patients with primary non-metastatic UM. Eligible patients must have high metastatic risk (class 2 gene-expression profile, monosomy 3, or AJCC stage 3). Additionally, for the PB cohort, moderate to high risk of vision loss (> 30Gy predicted radiation dose to key visual structures) is required for eligibility. Major exclusion criteria include metastatic disease or extraocular tumor extension, prior UM primary treatment, attributes necessitating immediate enucleation, and relevant ocular comorbidities. The trial has two cohorts: Cohort 1 (n=330) includes patients with medium UM tumors where PB is the standard treatment. Cohort 2 (n=120) includes patients with large UM tumors where enucleation is the standard treatment. In each cohort, eligible patients are randomized 2:1 to receive neoadjuvant darovasertib (300 mg twice daily for up to six 28-day cycles) or standard-of-care treatment with PB (cohort 1) or enucleation (cohort 2). The primary endpoint for cohort 1 is the proportion of patients with loss of Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity of ≥15 letters (%VL15) from randomization, while in cohort 2 it is eye preservation rate. Across cohorts, the key secondary objective is to evaluate response rate with neoadjuvant darovasertib. Additional secondary endpoints include event-free survival and safety, as assessed by treatment-emergent adverse events and serious adverse events. Enrollment is ongoing, and results will determine whether OptimUM-10 may establish darovasertib prior to definitive PB as the first neoadjuvant treatment for primary UM to meaningfully reduce tumor burden and expand vision- and eye-preserving treatment options for patients. Clinical trial information: NCT07015190 .