Syndax Misses Primary PFS Endpoint for Entinostat

Syndax announced on Thursday that they missed PFS in their P3 E2112 study comparing entinostat + exemestane (Aromasin) to placebo + exemestane in advanced HR+ breast cancer, which resulted in a top-notch corporate quote:

“While the PFS analysis did not show a statistically significant benefit, E2112 was primarily designed to determine whether the combination of entinostat and exemestane could improve OS based on the compelling OS results obtained in the Phase 2b ENCORE 301 trial …”

They didn’t even WANT to hit PFS, okay?

Never mind that there are two primary endpoints in E2112, meaning it’s an and/or situation and the study was not, in fact, primarily designed to assess OS. 

ENCORE 301, the basis on which Syndax received their Breakthrough Therapy designation, is reported here. That study (N=130, randomized 1:1 to entinostat + exemestane or placebo + exemestane) met its primary endpoint, with PFS of 4.3 months in the entinostat arm and 2.3 months in the control arm. OS was an exploratory endpoint, with entinostat associated with median OS of 28.1 months, compared to 19.8 months in the control arm. The enrollment criteria are similar between ENCORE 301 and E2112, except premenopausal patients and prior fulvestrant are both allowed in E2112, and E2112 appears to have a cohort with non-measurable disease. 

It would be unusual for the benefit of an anti-cancer therapy to be better reflected in OS than PFS; this might happen with PD-1/PD-L1s, but that may not be universally agreed, and it’s not likely to be the case for entinostat. Syndax are trying to recast entinostat as an immunotherapy with their checkpoint inhibitor collaborations (oh look, it’s a 10% response rate with pembro), but when I tried the drug a couple years ago, it was just an HDAC inhibitor. And it sucked. 

I was on entinostat for three cycles and got dose reduced after the first and again after the second, which remain my only dose reductions in eight years of nonstop treatment. I was off study for progression at the end of the third cycle, once I’d used up my two protocol-permitted dose reductions without improvement in my labs. Weird how that happened, right?  

Whatever: I was happy to be kicked off, because I have never felt more like dying in my life as on that drug. It was miserable. I felt sick and tired all the time, it wiped out my white cells, red cells and platelets, and my bones felt hollow. It sounds ridiculous, and this was never attributed to the study drug, but they were not like that before. They were totally normal bones before.

The feeling resolved after I went off study, but not before I broke my hand in a freak incident involving a leash that … brushed across my hand very fast. You would think this sort of thing would not cause a spectacular extremity fracture (the surgeon who wired it together later presented it at a conference!), and it could have been a coincidence, but I blame the entinostat.  

The lack of efficacy is the focus here (with a pointed reminder that not all drugs anointed Breakthroughs pan out), and a P3-grade PFS fail rightly overshadows toxicity and my unconfirmed Bird Bones anecdote. I just like the story, lest there be any suspicion that entinostat has “well-tolerated” going for it. In a true stretch of corporate credibility, we’re being forced to wait for E2112 to fail definitively, because Syndax were clear they would keep performing scheduled OS analyses until everyone was dead. Or, you know, they see an OS benefit. Whichever comes first. 

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