Back in late 2015, I wrote about cancer stem cells, the idea that some tumors are driven by populations of slow-dividing stem cells. The theory has been that these are always going to be in there fighting against your efforts to kill off the downstream tumor cells, so unless you find a way to target them, you’re not going to be successful. As that blog post shows, though, this area was imperfectly understood at the time, and it has not gotten a great deal more clear since then.
The company that I wrote about, though, Stemcentrx, was bought a few months later by AbbVie for 5.8 billion dollars in cash (and promises of about four billion more if things worked out). At the time, I wrote (uncontroversially, I think) that “this deal is going to end up looking either very smart or very stupid”. The lead program out of this deal, Rova-T, is an antibody-drug conjugate (rovalpituzumab tesirine) which was aimed at small-cell lung cancer (SCLC), specifically the DLL3 protein found on the surface of some cell types. The antibody targets DLL, and the conjugate has a cleavable linker that delivers a pyrrolobenzodiazepine dimer as a DNA-damaging payload. SCLC is bad news, so any advances in this field would be welcome.
Later on in 2016, AbbVie presented data from a small trial (I believe this one) that showed that response rates did seem to correlate with DLL3 expression. But the rates themselves were not all that impressive, in the larger scheme of things, and overall, people didn’t seem very impressed. AbbVie pushed on, though, seeking accelerated approval from the FDA, and today we have the latest results. Unfortunately. The company reported the response rate from the DLL3-high patient group, and it’s only 16% (which is the same or worse than standard of care response rates), and the survival data are not impressive, either. (Update: it’s quite likely that this is even worse than it seems!) The stock market is not taking this well. ABBV is down $12 a share as I write, which takes out nearly $20 billion dollars of market cap from the stock. The fear is that if this is the DLL3-high group, which is supposed to be the best of the bunch, what are the full Phase 3 results going to look like? Forget about accelerated approval – AbbVie sure has to – what are the chances that this program works well enough to be approved at all?
This also puts a bit of a hole in the cancer-stem-cell idea in general. It’s a complicated enough field that you’re not going to disprove it with a single agent or in a single type of cancer, but this does show that it’s not even as straightforward as it looks (and it didn’t look that straightforward!) As for this specific approach, and this specific deal, well. . .I suppose things could change eventually, but for now, it’s a disaster. We’ll see what AbbVie does after the full data come out. . .
Update: Matthew Herper’s take on this is well worth reading. I didn’t do the sack dance on Peter Thiel in this post, but it’s not completely inappropriate. . .