Omid Hamid, MD, on Cutaneous Melanoma: Update on a Bispecific Protein Under Study

Today I am going to talk about IMC-F106C, which is an ImmTAC now called brenetafusp and this is made by Immunocore. We're all familiar with ImmTACs, immune-mobilizing T-cell receptors against cancer. It's a bispecific that targets CD3 on one side and a tumor produced protein on the other. This one targets PRAME, proteins of PRAME. This is an update of the data that I presented at ESMO 2022 about this ImmTAC that targets PRAME. In 2022 we talked about all solid tumors. This update is in cutaneous melanoma. 47 patients with single agent brenetafusp and then a nine patient combination with pembrolizumab looking at safety and efficacy. We know that ImmTACs work. This was proven with tebentafusp in uveal melanoma. We know that ImmTACs can be combined with anti-PD-1, PD-L1 and anti-CTLA-4. We did that in cutaneous melanoma and published it in JTSI. This shows a updated expansion in escalation cohorts in cutaneous melanoma. And what we saw was very interesting. We saw response, of course. There is a clinical benefit of about 50%. There is a response rate of 11% and then stable disease or better, a little shrinkage from stable diseases there. What we found is this drug, the clear benefit comes in stable disease or better. It's not just an overall response with this mechanism. We also found that the responses were durable. In those patients that had stable disease, minimal reduction or better, they had a long-term durable benefit. We saw this benefit in patients who were PRAME positive, which gives credence to the mechanism that this ImmTAC is targeting PRAME. We saw it in BRAF mutant patients. We saw it in heavy tumor burden patients and we saw it in patients with melanoma that have brain and liver metastases or both. And this is what we're looking for. This cohort of patients were heavily pretreated. They had had at least two PD-1 containing regimens. 80% had seen anti-CTLA-4 and four fifths of those had seen anti-CTLA-4 and PD-1 together. And about 38% had seen another immuno-oncology compound on top of that, which is why this is so interesting. Toxicity was tolerable, mainly grade one two cytokine release syndrome. And what we saw was it was tolerable when combined anti-PD-1 therapy. There were nine patients, six of them were primary resistant. And what we saw there is molecular response and a 1PR. And that was held throughout in the combination cohorts of brenetafusp and anti PD-1 with pembrolizumab in other solid tumors. Other solid tumors we saw that tolerability. Why is this important? Well, this is another tool in our toolkit against melanoma. Why else is it important? Melanoma sets the standard for other solid tumors. We've seen responses in other solid tumors as I presented endometrial, ovarian, uveal. And we're looking at it in lung cancer and that's interesting. What we also found is that there is a T-cell signature that indicates better response. Naive and STEM central memory T-cells, when those were higher, those patients were the ones that benefited the most. And that was found in earlier lines of therapy. We are now accruing to a major phase three trial of brenetafusp and nivolumab versus nivolumab alone or nivolumab and ipilimumab in the first line. And this will show the benefit of this drug in cutaneous melanoma. I look forward to accruing to that study. I look forward to understanding the mechanism of action of this class of drugs. I have no doubt that when we present more data on the T-cell fitness signature and in other cohorts upcoming meetings, that you'll be as excited about this platform and about this drug, brenetafusp, as I am.