Adding IL-2 to Tebentafusp to Eradicate Cancer Progression

A recent clinical trial found that after 36 months, patients taking tebentafusp had a median survival of 21.6 months, compared to 16.9 months for those in the control group. Since recruitment for tebentafusp in metastatic uveal melanoma (mUM) has ended, a new trial is starting to test whether adding IL-2 can help overcome resistance to tebentafusp and improve its effectiveness. This study aims to answer: 1. Can combining tebentafusp with IL-2 improve tumor response and overall survival? 2. What are the benefits and side effects of this combination therapy? All participants will receive both IL-2 and tebentafusp in a 28-day treatment cycle. The dosing schedule is as follows: Cycle1: Day1-3 IL-2 Day4 Tebentafusp Day 10 IL-2 Day 11 Tebentafusp Day 17 IL-2 Day 18 Tebentafusp Day 24 IL-2 Day 25 Tebentafusp Cycle 2 \& thereafter Day 1 IL-2 Day 2 Tebentafusp Day 8 IL-2 Day 9 Tebentafusp Day 15 IL-2 Day 16 Tebentafusp Day 22 IL-2 Day 23 Tebentafusp

Uveal melanoma (UM) is a rare and highly malignant neoplasm affecting the vascular layers of the eye (iris, ciliary body, or choroid). UM primarily metastasizes to the liver and less commonly to the lungs and bones. Once patients develop mUM, the prognosis is very poor with a median survival of \< 12 months. There are limited treatments for mUM that extend survival, and there is no proven standard of care. Enrolment in investigational clinical trials is the treatment option recommended by national and regional guidelines. A clear unmet medical need exists for patients with this serious and life- threatening disease. Tebentafusp is a bispecific protein therapeutic comprising a soluble, affinity-enhanced T cell receptor (TCR; targeting domain) fused to an antibody single-chain variable fragment (scFv) targeting cluster of differentiation (CD)3 (effector domain). Tebentafusp recognizes a peptide derived from gp100, a melanocyte lineage antigen expressed strongly in tumors derived from melanocytes that is presented on the cell surface by HLA-A\*02:01. Once the soluble TCR of tebentafusp is engaged, the scFv effector domain can bind to CD3 on any T cell, redirecting the T cell to produce effector cytokines and kill the cell presenting the target peptide. In addition, tebentafusp-mediated lysis may prime an endogenous antitumor immune response via epitope spreading. This mechanism is distinct from all other therapies that have been studied for melanoma. The most recent evidence for the utility of Tebentafusp was just published demonstrating that at a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). Now that all registrational metastatic trials in UM with Tebentafusp are closed to recruitment, this trial is being initiated to explore the addition of IL2 to offer a mechanism to overcome tebentafusp resistance and explore its efficacy and toxicities. This Phase Ib study aims to administer tebentafusp in combination with IL-2 to improve primary endpoint of radiographic response rate as well the secondary endpoint of Overall Survival (OS).