In today’s episode, we spoke with Marlana M. Orloff, MD. Dr Orloff is the Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma, and associate professor at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.

In our exclusive interview, Dr Orloff discussed the distinct biology of uveal melanoma and why it has historically resisted systemic treatment. Unlike cutaneous melanoma, which carries a high tumor mutational burden and responds robustly to immune checkpoint inhibitors, uveal melanoma sits at the opposite end of the spectrum with low mutational burden, a predominantly liver-metastatic pattern, and an immune-tolerant microenvironment that renders traditional immunotherapy largely ineffective.

She provided context on the treatment landscape for patients with HLA-A*02:01–negative metastatic uveal melanoma prior to the phase 2/3 OptimUM-02 trial (NCT05987332), noting that this population had limited options: liver-directed therapies such as percutaneous hepatic perfusion, off-label immune checkpoint inhibitor combinations, or clinical trial enrollment.

Dr Orloff then walked through the design and efficacy findings of the trial, which evaluated the combination of darovasertib, an oral PKC inhibitor, plus crizotinib (Xalkori), a MET inhibitor, vs investigator’s choice in treatment-naive, HLA-A*02:01–negative patients. The combination demonstrated a median progression-free survival of 6.9 months vs 3.1 months with investigator’s choice, with an objective response rate of 37.1% compared with under 5.8% in the control arm. She highlighted the clinical significance of the complete responses observed while noting that overall survival data from the phase 3 portion of the trial remain pending.

The discussion also addressed the growing complexity of treatment sequencing as more options emerge, including tebentafusp-tebn (Kimmtrak) for HLA-A*02:01–positive patients, liver-directed and combination approaches, and the investigational TCR-engineered T-cell therapy anzutresgene autoleucel targeting PRAME. Dr Orloff emphasized that in the absence of head-to-head comparisons, sequencing decisions will increasingly be shaped by patient logistics, toxicity profiles, and access to specialized treatment centers.