ESMO 2025 | IMcode001: autogene cevumeran & pembrolizumab in melanoma

The IMcode00 in melanoma trial was based on really decades worth of efforts trying to understand if we could vaccinate effectively in patients with cancer and more specifically in patients with melanoma. With the advent of mRNA technologies, what became known as autogene cevumeran was studied in a phase one trial as a single agent and in combination with atezolizumab. In that study, which was published in Nature Medicine a year or two ago, what was shown is that when developing a personalized neoantigen vaccine for patients with cancer that was given intravenously, it could vaccinate to up to 20 neoepitopes, that there was very good immunization rates and decent response rates, decent disease control rates, but there were no randomized studies to really understand the impact of whether it added efficacy in any specific patient population. So this trial was the first randomized study of a personalized cancer vaccine in patients with frontline melanoma. Patients were randomized two to one to receive autogene cevumeran plus pembrolizumab versus pembrolizumab alone, which was the standard of care for most patients with first-line melanoma or newly diagnosed melanoma in the frontline setting in 2018, 2019, when the trial was designed and then launched. Ultimately, we completed randomization in 2021 after a slight delay during the pandemic. And the results are as follows. The primary endpoint was progression-free survival. We did not see an improvement in progression-free survival for patients who received the combination versus single-agent anti-PD-1. We saw a numerical advantage for overall survival, which is one of the secondary endpoints, but that wasn’t statistically significant either. We also began to try and understand, did we do what we set out to do? Did we, in fact, immunize patients against the 20 neoepitopes that they were treated with. And so in looking at peripheral blood mononuclear cells, we could determine whether or not patients were immunized against zero to 20 of the new epitopes that were built into their therapy. And indeed, the majority of patients at least had one neoepitope that they were immunized against. And in fact, if we saw one, two, three, four, that if we compared greater than one to zero, one or two, sorry, greater than or equal to one to zero, greater than or equal to two to zero, greater than three to zero, greater than four to zero. So the more neoepitopes that patients actually generated immune response to, the better their outcomes were versus those who were in the other category. And so from that standpoint, it seems that when we achieved what we set out to do with the therapy, we had better outcomes. A further subgroup analysis that was performed was looking at tumor mutation burden. When a neoepitope vaccine is made, you have to make a call as to how many neoepitopes you’re willing to sort of use as your floor to be part of the vaccine. For this product, it’s five. And so you have to have a certain number of mutations in your tumor to try and be able to make this vaccine. And so for all patients, we have whole genome sequencing of tumor. We have germline DNA sequencing as well. And so we can very easily calculate tumor mutation burden. And when we looked at tumor mutation burden in patients who went on the study, the patients who had a very high tumor mutation burden, whether they received the combination or pembrolizumab alone, had very similar excellent outcomes. In the patients who had low tumor mutation burden, we actually saw a substantial improvement in progression-free survival, although it’s hard to know exactly what that means. I’m sorry, we had a significant improvement. They had a substantial improvement in overall survival, but it’s hard to know exactly what that means since we didn’t power the trial to that. That was an ad hoc analysis. But hypothesis-generating that perhaps it’s not the patients who have high tumor mutation burden that are going to benefit from a neoantigen therapy, but in fact the patients with a lower tumor mutation burden whose tumor doesn’t have enough anti-tumor immune cells that have been generated de novo and in fact need to be vaccinated to generate these that then can get into the tumor and provide anti-tumor immunity. The last thing I’ll say about this study, while we see toxicity from autogene severum, we don’t see any enhanced immune-related adverse effects from the pembrolizumab. So the vaccine has its own tox. The Pembro has its own tox. It’s additive. It’s not synergistic. And I think that’s another important point to make.

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