Briefly, this was a study of vepdegestrant versus fulvestrant in patients with ER positive advanced breast cancer that had already received endocrine therapy and a CDK4/6 inhibitor. Briefly, vepdegestrant is an oral PROTAC inhibitor, this really has the advantage of being an ER degrader with a different mechanism of action. It harnesses the ubiquitin-proteasome system, so essentially on one side of the molecule binds the estrogen receptor, on the other side of the molecule it binds E3 ligase which brings this into close proximity and ultimately ubiquitinates the estrogen receptor. This flags this for intracellular degradation and the proteasome comes in and degrades the estrogen receptor.
This was a phase III global study in 25 countries. It enrolled over 600 patients that had already seen endocrine therapy and a CDK4/6 and was a pretty straightforward 1:1 randomisation to vepdegestrant 200mg orally once daily or fulvestrant given day 1 and day 15 of the first cycle and then on day 1 of each subsequent cycle. Fulvestrant, again, is administered intramuscularly. The desire for this study was really in the post-CDK4/6 setting, there’s no consensus really with an individual therapy. We have several choices of therapies driven based on mutational status, CDK, after CDK etc., but our standard drug like fulvestrant really does not perform well in the post-CDK4/6 space. It has a challenge of intramuscular administration and a progression free survival, unfortunately, of less than 2 months which is simply not good enough for our patients.
In this study our statistical design was to look at those patients that had ESR1 mutations first, if that was positive then we would look at progression free survival in all patients. Then if that was positive we would move on to look at overall survival.
I’m happy to report that vepdegestrant did significantly improve progression free survival in those patients that had ESR1 mutations when compared with fulvestrant. So this was 5.0 months versus 2.1 months, it was a hazard ratio of 0.57 and a p-value less than 0.001. We then looked at progression free survival in all patients and this was not significantly different, a hazard ratio of 0.83, again that was not statistically significant.
When we looked at some of our key secondary endpoints such as clinical benefit rate, among patients that had ESR1 mutations clinical benefit rate was more than double with vepdegestrant. This was 42.1% versus 20.2% and a very similar story in terms of objective response rate – a more than quadrupling of this value with vepdegestrant: 18.6% versus 4% among those patients that had ESR1 mutations. In terms of overall survival this was very immature, there were only 20% of the events had occurred so too early to comment on this.
I also want to comment on the tolerability of vepdegestrant because this really did stand out to me. When we talk about something being well tolerated sometimes this word does get overused a little bit but I like to look at dose reductions and discontinuations as a way to tell me how did people really tolerate this drug. Vepdegestrant was only discontinued in 3% of patients and was only dose reduced in 2% of patients, really suggesting that the majority of patients did tolerate this well. The most common side effects were fatigue – 27% any grade, meaning only a quarter of patients on the drug reported any fatigue at all. Then the two subsequent most common side effects were liver function test elevations and nausea, in the teens, again any grade. In terms of gastrointestinal events, this can be a common side effect of the SERDS and what we did not see was vomiting and diarrhoea. This does not appear on our adverse events table during the presentation because this was only 6% any grade for patients so it was less than that 10% threshold to appear.
In summary, vepdegestrant was well tolerated, as evidenced by low rates of discontinuation or reduction and did significantly from a statistical standpoint and also clinically significantly improve progression free survival in those patients with ER positive advanced breast cancer that had already progressed on endocrine therapy and a CDK4/6 inhibitor and had ESR1 mutations. This does support the potential for vepdegestrant as a single agent in this population moving forward. Thank you.
