Tebentafusp Shows Promising Clinical Activity with an Acceptable Safety Profile in Patients with Previously Treated Metastatic Uveal Melanoma

Data from a phase II study provide the longest follow-up of overall survival (OS) and safety of tebentafusp, a soluble T cell receptor (TCR) therapeutic to date. The observed 1 year OS rate of 62% and median OS of 16.8 months compare very favourably with an analysis using data on a similar population of previously treated patients with metastatic uveal melanoma from a recent meta-analysis that resulted in a 1 year OS rate of 37% and a median OS of 7.8 months. These data also support the recent approval of tebentafusp for HLA-A*02:01-positive adult patients with unresectable metastatic uveal melanoma regardless of prior treatment history in the US, EU and UK. The study findings are published by Dr. Takami Samo of the Sidney Kimmel Cancer Center, Jefferson University in Philadelphia, PA, US and colleagues on 13 October 2022 in the Nature Medicine.

Uveal melanoma is the most common primary eye tumour, but it is rare, affecting fewer than 10 individuals per million. Up to half of the patients with uveal melanoma will develop metastatic disease, with the liver as the predominant site of distant spread. Nearly all cases of uveal melanoma harbour one of four initiating oncogenic driver mutations in GNAQ, GNA11, PLCB4 or CYSLTR2 in a mutually independent fashion, as well as a secondary oncogenic event affecting EIFA1X, BAP1 or genes encoding for spliceosome components, most commonly SF3B1. Uveal melanoma has one of the lowest mutational burdens of all malignancies, with approximately 0.5 mutations per megabase and a median of 32 coding mutations per tumour, and is characterised by low expression of PD-L1.

Tebentafusp is a first-in-class immune-mobilising monoclonal TCR against cancer. It demonstrated in a phase III study to improve OS in patients with previously untreated metastatic uveal melanoma when compared with investigator’s choice and represents the first treatment to demonstrate such a benefit in this disease.

The objective of the phase II expansion of the IMCgp100-102 was to characterise the antitumour activity of tebentafusp in patients with previously treated metastatic uveal melanoma, a patient population distinct to that enroled in the randomised phase III study, and to explore the association of early circulating tumour DNA (ctDNA) dynamics with clinical outcomes in this setting.

This single arm, open-label, international, phase I/II study included a phase I dose escalation, as well as an expansion cohort and was subsequently expanded into a full phase II study. It was conducted in 127 patients with treatment-refractory metastatic uveal melanoma. The primary endpoint was the estimation of objective response rate based on RECIST v1.1. Secondary objectives included safety, OS, progression-free survival and disease control rate.

All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Side effects were mostly mild to moderate in severity but were greatly reduced in incidence and intensity after the initial 3 doses.

Despite a low overall response rate of 5% (95% confidence interval [CI] 2–10%), the 1 year OS rate was 62% (95% CI 53–70%) with a median OS of 16.8 months (95% CI 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria.

In an exploratory analysis, early on-treatment reduction in ctDNA was strongly associated with OS, even in patients with radiographic progression. The exploratory analysis of ctDNA levels was a retrospective hypothesis-generating analysis using samples collected from a single-arm phase II study, thus limiting interpretation. These results need to be confirmed in a prospective randomised study before ctDNA dynamics on tebentafusp can be introduced to routine clinical practice to manage patient treatment.

The authors concluded that tebentafusp demonstrates a promising survival benefit for patients with metastatic disease that has progressed on at least one line of prior treatment, with ctDNA as an early indicator of benefit. The addition of ctDNA analysis to assess the molecular response to treatment may provide a more sensitive means than standard imaging studies to identify those patients who will benefit most from tebentafusp.

The study was funded by Immunocore Ltd.

Reference

Carvajal RD, Butler MO, Shoushtari AN, et al. Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial. Nature Medicine; Published online 13 October 2022. DOI: https://doi.org/10.1038/s41591-022-02015-7

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