Tebentafusp for Uveal Melanoma

Tebentafusp is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of advanced uveal melanoma. Uveal melanoma is a rare cancer originating from melanocytes in the choroid, iris, or ciliary body of the eye. Around half of all people diagnosed with uveal melanoma will develop metastatic disease, primarily of the liver.

Tebentafusp belongs to a new medication class called immune-mobilising monoclonal T-cell receptors against cancer (ImmTACs). It is a bispecific fusion protein containing a T-cell receptor and antibody fragment. The T-cell receptor is specific for a peptide that is preferentially expressed in melanoma cells, and the antibody fragment is specific for the CD3 receptor. While the T-cell receptor recognises its target protein, the antibody fragment allows the recruitment and activation of CD3+ T-cells. In vitro studies demonstrate that when tebentafusp binds to these targets, it results in direct lysis of the tumour cells following the release of inflammatory cytokines and cytolytic proteins.

An open-label phase 3 trial compared the efficacy of tebentafusp with control (investigator’s choice of pembrolizumab, ipilimumab, or dacarbazine). At one year, the estimated overall survival was 73% in the tebentafusp group and 59% in the control group. The estimated median duration of overall survival was 21.7 months for tebentafusp and 16.0 months for control. A recently published three-year analysis demonstrates the long-term benefits of tebentafusp. At a minimum follow-up of 36 months, median overall survival was higher in the tebentafusp group than in the control (21.6 months vs 16.9 months).

Tebentafusp is administered as a weekly intravenous infusion. The most common treatment-related events observed in clinical trials were cytokine-mediated and skin-related events, such as rash, pyrexia, and pruritus. The product information contains a black box warning on cytokine release syndrome (CRS). Although this was reported in 89% of clinical trial patients, only 1% had grade 3 CRS, and no patients developed grade 4 or 5. This adverse event typically occurs within a few hours of the first three doses, and the manufacturer recommends additional monitoring for these initial infusions.