Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

Friday brought some very unwelcome news in oncology. I’ve written about IDO inhibitors before, partly in the context of an odd situation between Incyte and Flexus, and partly in response to a recent failed trial of a compound from NewLink. That last one shook people up a bit, but (as I mentioned in the post) there was still hope for combination of the Incyte drug with Merck’s Keytruda (pembrolizumab). The idea is that IDO inhibition would increase T-cell activity and add to Keytruda’s effects.

Unfortunately, that is not the case. The companies have announced that the Phase III trial of this combination in melanoma has utterly missed its endpoints, and that appears to be a massive setback for the whole idea. Add that to the earlier difficulties with other IDO compounds, and the picture is Not Good. Bristol-Myers Squibb has a big trial going with their own Opdivo (nivolumab) and their own IDO1 inhibitor (BMS-986205) in melanoma, and this bodes very ill for those results indeed. It has to be noted that they’ve announced what appear to be positive results for that combination in other trials, but hey: Merck and Incyte had what appeared to be decent-looking results early on, too. The feeling when this trial was announced was that since the company was not waiting for the Merck readout that they must have been pretty confident. But that could also reflect the company’s feeling – not unjustified at all – that they’re locked in a brutal struggle with Merck in this area and had no time to sit around.

This is not only bad news for melanoma patients, for Merck, and (especially) for Incyte. And it’s not only potentially bad news for BMS. It’s potentially bad news for everyone who thought that their understanding of these pathways was good enough to predict success for this trial. One of the biggest things going in immuno-oncology is the combination of the existing agents (PD pathway drugs) with other mechanisms to potentiate their effects and move them into new areas. This trial shows that we don’t know as much about how to do that as we thought we did. So although the IDO-based trials are now very uncertain, this news throws uncertainty around the entire field, whether it goes through that mechanism or not.

Now all eyes are on Bristol-Myers Squibb: will their current trial run to completion? I don’t know when they have any interim data reads coming up, but that’s going to be fraught with interest. The expectation at this point is that the trial will fail, for the same reasons – whatever those are – that the Merck/Incyte one just did. But there’s an outside chance that our ignorance of the field is even more profound and that it’ll actually work. (Update: I should emphasize that the binding mode of the BMS compounds is in fact different from the earlier ones – will this make a difference?) Wouldn’t that be a twist? But you’d have to be brave to bet that way. . .we shall see.

Update 2 (April 30): it appears that the company has halted their IDO trials. . .