Phase III randomised trial comparing tebentafusp with investigator’s choice in first-line metastatic uveal melanoma

Dr Jessica Hassel - University Hospital Heidelberg, Heidelberg, Germany

This was a phase III trial for patients with metastasised uveal melanoma. Uveal melanoma is a rare melanoma with a very bad prognosis and about half of the patients will eventually develop metastasis to the liver and then we actually do not have any standard of care for the treatment because, in contrast to cutaneous melanoma, they do not respond very well to immune checkpoint blockade.

What was the methodology used in your study?

In this phase III trial we tested a new drug designed by the sponsor, Immunocore. The drug’s name is tebentafusp and it’s a bispecific consisting of a soluble TCR that detects the gp100 peptide presented on HLA-A0201 MHC class 1 molecules. This soluble TCR is fused to an anti-CD3 that binds and activates T-cells irrespective of their native specificity. By this tebentafusp redirects T-cells to gp100 expressing cells and uveal melanoma is a tumour that commonly expresses gp100 and therefore can be targeted by tebentafusp.

In this trial we randomised patients with metastasised uveal melanoma first line to receive either tebentafusp or investigator’s choice in a two to one randomisation setting. Investigator’s choice consisted of either pembrolizumab, ipilimumab or dacarbazine and actually in the trial most of the patients received pembrolizumab in the investigator’s choice arm.

What were your findings?

One of the co-primary endpoints in this trial was overall survival in the intent to treat population of patients receiving tebentafusp or investigator’s choice. This phase III trial showed that the relative risk to die is halved by tebentafusp, so the hazard ratio was 0.51 and the Kaplan-Meier curves separate early and continuously between the patients treated with tebentafusp and the patients treated with investigator’s choice.

So some more numbers, maybe. The median overall survival was 22 months under tebentafusp and 16 months under investigator’s choice. The follow-up of these patients was 14 months. When you look at the different subgroups you can see that all the subgroups benefit from tebentafusp but you have a tendency that patients with a lower tumour load have a better hazard ratio than patients with a higher tumour load.

What was surprising in this trial was that you only have a little effect on progression free survival and we had only a low response rate under tebentafusp with only 9% of patients responding to the treatment according to RECIST, compared to 5% in the investigator’s choice arm which, again, mainly consisted of pembrolizumab. But, nevertheless, in a landmark analysis that we did starting from day 100 we could see that patients under tebentafusp benefitted from the treatment in overall survival, even if the best response they had to the treatment was progressive disease. So we have an effect on overall survival but only a little effect really on response. We see some tumour shrinkage but the effect on overall survival is so impressive that these results are great for our patients with metastasised uveal melanoma nevertheless.

What are you concluding from these results?

Yes, tebentafusp is the first drug showing a benefit in overall survival which is clinically meaningful for patients with metastasised uveal melanoma. So I think this will be practice changing and there will be an early access programme for patients with metastasised uveal melanoma to be able to get the drug before it is approved.

What we have to say is that unfortunately we can help only about 50% of patients because only patients with the HLA-A0201 can be treated with the drug. So there is still a need of developing this drug for the other HLA types.

What is the next step for this trial?

There are actually many things you could analyse, of course. The next step is, of course, to get approval for the drug for patients with metastasised uveal melanoma. In the meantime there will be an early access programme. Then, of course, we question ourselves if patients would benefit from combination therapy with PD-1 antibodies so that would be something you could further investigate. But the most important thing is first to make it accessible for our patients with metastasised uveal melanoma.

Is there anything else important you would like to mention?

I’d just like to thank all the co-authors and all the people who worked within the trial and Immunocore, of course, to develop this drug and to create this trial for our patients with metastasised uveal melanoma.