SILVER (supplementing tebentafusp with subcutaneous IL-2 to verifiably eradicate radiological progression): A phase 1/2 trial of IL-2 with tebentafusp upon first radiological progression on first-line tebentafusp alone.

Abstract

TPS9606 Background: Metastatic uveal melanoma (mUM) remains a disease with a profound unmet clinical need. Tebentafusp, a bispecific T-cell receptor–anti-CD3 ImmTAC targeting gp100 is the first systemic therapy to demonstrate a reproducible overall survival benefit and is now the standard of care in eligible patients. Despite this advance, most patients ultimately develop radiological progression on tebentafusp, highlighting the need for rational combination strategies that can augment or restore antitumour immune activity. Interleukin-2 (IL-2) has long been recognised as a potent T-cell growth and activation factor. Pre-clinical data demonstrate that IL-2 enhances tebentafusp-mediated tumour cell killing by expanding and priming effector T-cell populations. These effects are mechanistically linked to increased cytotoxic function and improved immune synapse formation (Guc et al., 2025). Importantly, low-dose IL-2 administered subcutaneously has been shown in prior clinical studies to achieve biologically relevant serum concentrations with a substantially improved safety profile compared with historical high-dose intravenous regimens. Collectively, these data provide a strong biological and clinical rationale for combining tebentafusp with low-dose subcutaneous IL-2 in patients with mUM progressing on tebentafusp monotherapy. Methods: SILVER is an investigator-initiated, single-arm phase Ib study evaluating the safety, tolerability and preliminary efficacy of tebentafusp in combination with low-dose subcutaneous IL-2 in HLA-A*02:01–positive patients with metastatic or unresectable uveal melanoma who have RECIST-defined progression on tebentafusp alone. Patients receive IL-2 at 125,000 IU/kg subcutaneously, administered for three consecutive days prior to the initial tebentafusp dose, and then weekly 24 hours before each subsequent tebentafusp infusion. Tebentafusp is administered intravenously with step-up dosing in cycle 1, followed by standard weekly dosing thereafter. The primary endpoint is best overall response by iRECIST. Secondary endpoints include RECIST 1.1 response rate, clinical benefit rate, progression-free survival, overall survival, safety and tolerability (CTCAE v5.0), and quality of life. Extensive translational endpoints include serial diffusion-weighted MRI, ctDNA kinetics, and deep immune profiling from blood and tumour biopsies. Early treatment cycles incorporate inpatient monitoring to manage cytokine-mediated toxicities. Conclusion: By integrating robust pre-clinical rationale, an established and pragmatic IL-2 dosing strategy, and comprehensive translational analyses, this study aims to enhance tebentafusp activity and improving outcomes for patients with progressive mUM. Clinical trial information: NCT07063875 .