Promising Results Are Provided by Tebentafusp in Metastatic Uveal Melanoma

Tebentafusp (IMCgp100), a novel bispecific molecule that redirects T-cells showed clinical benefit, including target lesion reduction, in patients with metastatic uveal melanoma, according to phase II study findings presented at the ESMO Immuno-Oncology Virtual Congress 2020, held from 9 to 12 December 2020.

Joseph J. Sacco of the Medical Oncology Department, Clatterbridge Cancer Centre and University of Liverpool, UK explained that tebentafusp is a bispecific fusion protein comprising an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100-positive (gp100+) cells. High expression of gp100 is seen in melanocytes, and melanoma cells.

Dr Sacco and colleagues conducted this phase II, multi-centre study evaluating safety and efficacy of tebentafusp in HLA-A*0201-positive patients with metastatic uveal melanoma. Phase I of this study determined the phase II dose as 68 mcg.¹

All patients received treatment at 24 centres with a regimen of weekly intravenous doses of 20 mcg C1D1, 30 mcg C1D8, and 68 mcg of C1D15+.

Of the 127 patients treated, 50% were male, 70% had ECOG performance status 0, and 58% had baseline LDH exceeding the upper limit of normal. All of the patients had received ≥1 prior therapy in the metastatic setting. Many (34%) patients had received ≥2 prior treatments, including liver directed therapy (LDT) in 45% of patients and 73% of patients had received immunotherapy; of these 65% received anti-PD1, and 31% of patients received anti-CTLA4 therapies.

Objective response rate (ORR) per RECIST v1.1 assessed by independent central review (ICR), served as the primary study endpoint and secondary endpoints included safety, overall survival (OS), and progression-free survival (PFS).

Following tebentafusp, the ORR was 5% (95% confidence interval [CI] 1.8%-10.0%), all of which were partial responses (PRs). Stable disease was achieved by 45% of patients.

The median duration of response was 8.7 months.

Of the 116 patients with evaluable tumours, 44% demonstrated a reduction in target lesions that included immune-related responses.

With median follow-up of 19.6 months, the median OS was 16.8 months (95% CI 12.9- 21.3). The 12- and 18-month OS rates were 62% and 45%, respectively.

Median PFS was 2.8 months.

In patients demonstrating any reduction in a target lesion, the 12-month OS rate improved to 86%.

Rash was an indicator of improved overall survival

The most commonly reported treatment-related adverse events (TRAEs) were generally cutaneous and likely linked to targeting gp100+ melanocytes, or cytokine mediated due to T-cell activation. TRAEs included pyrexia (80%), pruritus (67%), and chills (64%). Grade ≥3 TRAEs of maculo-papular rash occurred in 13% of patients, hypotension in 8%, and AST increased and hypophosphatemia were each reported in 5% of patients. In most patients, TRAEs decreased in frequency and severity after the first 3 doses of tebentafusp.

Cytokine release syndrome (CRS; Lee 2019 criteria) was reported in 86% of patients; CRS Grade 3 was reported in 3% of patients and 1% of patients experienced Grade 4 CRS.

There were no Grade 5 TRAEs.

Patients (64%) developing rash within 7 days of tebentafusp initiation demonstrated superior median OS of 22.5 months compared to 10.3 months in patients with no rash.

Conclusions

The investigators noted that although the primary endpoint showed only a 5% ORR, this was accompanied by a reduction in target lesion for 44% of patients. They further pointed out that the 12-month OS rate of 62% in patients overall was increased to 86% in patients achieving target lesion reduction, which they considered promising.

According to the authors, TRAEs were generally predictable and manageable; furthermore, they decreased in frequency and severity following the first few doses and were consistent with the proposed mechanism of action.

Tebentafusp is being studied further and is currently being evaluated in a randomised pivotal study with a primary endpoint of overall survival. This has reached its pre-defined boundaries for statistical significance of the primary endpoint of OS in its first pre-planned interim analysis with a hazard ratio of 0.51 in favour of tebentafusp over investigator choice, according to a recent press release.

Funding was reported from Immunocore Ltd.

Citation

1. Sato T, Nathan PD, Hernandez-Aya L, Sacco JJ, et al. Journal of Clinical Oncology 2018;36:15_suppl:9521-9521.   

Reference

64MO – Sacco JJ, Carvajal R, Butler MO, et al. A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM). ESMO Immuno-Oncology Virtual Congress 2020 (9-12 December).