Thanks for having me. A pleasure to be with you today. So we’ve been excited to be working on the development of Veptigestrant, which is the first PROTAC. That’s a proteolysis targeting chimera. This is an interesting new type of anti-estrogen molecule that binds to the estrogen receptor and actually recruits the ubiquitin ligase machinery of the cancer cell to come and more fully degrade the ER...
Thanks for having me. A pleasure to be with you today. So we’ve been excited to be working on the development of Veptigestrant, which is the first PROTAC. That’s a proteolysis targeting chimera. This is an interesting new type of anti-estrogen molecule that binds to the estrogen receptor and actually recruits the ubiquitin ligase machinery of the cancer cell to come and more fully degrade the ER. Here, we were presenting some updated biomarker analysis from some of the preliminary work predating the Phase III Veritac II study. We explore the spectrum of different ESR1 alterations that are present in this cohort, and we demonstrate dynamic changes on ESR1 as a function of total allelic fraction within the cells, showing that patients who have deeper drops in ESR1, better sort of target engagement with the molecule, also potentially demonstrate better response, even in this more heavily pre-treated early phase population. As I mentioned, this was a multi-center open-label study with a dose escalation component in patients with ER positive HER2 negative metastatic breast cancer. We had 154 patients treated with Veptigestrant, the vast majority of whom had available ctDNA samples for analysis, nearly 140 of these patients. We explored the landscape of ESR1 alterations. The most common type of ESR1 alteration, not surprisingly here, was the D538G variant with other common alterations in Y537 and E380. We looked at a number of different factors in an effort to determine if there was any predictive component for how well patients were going to do based on their ESR1 alteration. What we noticed was that the ESR1 variant allele fraction or overall tumor fraction at baseline were not directly associated with clinical benefit rate. However, when we created a ratio normalizing the ESR1 variant allele fraction to the overall tumor fraction, patients who had higher ESR1 variant to total ratio did end up having a better clinical benefit. And that makes sense. It means across the mutational spectrum of the cancer, those patients who had higher proportion of ESR1 alteration relative to the total tumor fraction detected got more benefit from the oral SERD. And that was of interest to us in thinking about different ways to help predict which patients may be optimal candidates for this type of approach, either with Veptigestrant or with other emerging next-generation anti-estrogen monotherapy or potentially doublet therapy regimens.
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