Clinical trial in progress: Phase II trial of neoadjuvant tebentafusp in patients with locally advanced primary uveal melanoma.

TPS9607 Background: Uveal melanoma (UM) is the most common intraocular malignant tumor in adults. Primary UM are effectively treated by plaque radiotherapy or enucleation; however, up to 50% of UM patients ultimately succumb to advanced disease. Tebentafusp-tebn is a bispecific gp100 peptide human leukocyte antigen (HLA)-directed cluster of differentiation 3 (CD3) T-cell engager that became the first FDA approved treatment for unresectable or metastatic UM. Among the metastatic UM patients who received tebentafusp on clinical trial (IMCgp100-01 (n=19), IMCgp100-102 (n=146), and IMCgp100-202 (n=245)), 12 patients had recurrent orbital tumors. All orbital lesions were stable or had achieved shrinkage with tebentafusp. The best percentage changes from baseline were reported as -3 to -40% reduction in intra-ocular target lesions. All intra-ocular non-target lesions were stable or achieved a complete response after tebentafusp treatments. These preliminary data indicate that tebentafusp may have potential for treating surgically unresectable primary UM. Methods: This is an investigator-initiated, prospective, single arm phase II trial evaluating neoadjuvant tebentafusp in patients with locally advanced primary UM NCT06414590. Patients must be 18 years or older, HLA-A*02:01 with a primary UM with T3 or T4 category tumor size. Patients cannot have a symptomatic UM that requires immediate ophthalmological intervention such as enucleation. Patients will be treated with up to 8 weeks of neoadjuvant tebentafusp, followed by radioactive plaque or enucleation. Tebentafusp will be administered as follows: 20mcg on Day 1, 30mcg on Day 8, 68 mcg on Day 15, and weekly doses of 68 mcg thereafter. The first three treatments will require inpatient hospitalization for overnight observation. The primary endpoint of the study is regression (defined as ≥ 20% reduction in tumor volume) of primary UM after tebentafusp treatment in 20% of treated patients. Secondary endpoints include toxicity assessment and ctDNA analysis in both blood and aqueous humor. Exploratory endpoints include changes to visual acuity, radiation dose to the fovea, and treatment (enucleation to plaque brachytherapy). The efficacy of this combination treatment will be assessed using the Simon’s two stage design. In stage I, a total number of 8 patients are accrued and if there are 0 responses among these 8 patients, further enrollment of patients may be stopped. Otherwise, an additional 11 patients will be accrued in stage II, resulting in a total sample size of 19 patients. Enrollment began in September 2025 at Thomas Jefferson University Hospital, in conjunction with Wills Eye Hospital. Clinical trial information: NCT06414590 .