One way to look at the immuno-oncology landscape over the last few years has been to think of it as The Quest for Synergy. Once it became clear that pathways like PD-1/PD-L1 really were of use in treating some kinds of cancer (and remember, this was not obvious beforehand), then the question naturally arose: what else could be added to make this better? There are so many possibilities, cancer being what it is and immunology being what it is. And any time the immune system is involved, you have the possibility of very large effects from what seem like trivial changes. Of course, those effects can go either way, from anaphylactic shock over to suddenly clearing your bloodstream of a couple of pounds of excess cancerous leukocytes, but the promise of immunology (and therefore of immuno-oncology) has always been that such dramatic results are out there waiting to be uncovered.
As that above link shows, though, they have been elusive. One of the big targets in this area is TIGIT, with a lot of money and a lot of hopes riding on it. That acronym stands for “T Cell Receptor with Ig and ITIM Domains”. It’s been shown to be overexpressed (in much the same way the PD-1 is) in tumor-antigen-targeting T cells, making it a natural candidate for investigation. Literally dozens of programs have sprung up over the last few years targeting TIGIT; it’s really hard to even keep track of them all. The great majority of these seem to be anti-TIGIT antibodies, as you might imagine, and these scatter across a range of potencies, domain targets, and selectivities. So it’s been a wide-open race, and Roche/Genentech has been up near the front of it with an antibody called tiragolumab.
Now, that one read out in a trial a little bit earlier this year for small-cell lung cancer in combination with the anti-PD-1 antibody Tecentriq (atezolizumab), and unfortunately it failed. As that link goes into, this was a bit of a risky effort, because Roche didn’t really have direct evidence that SCLC was a good target – this was based on optimism from early results in non-small cell lung cancer, and the company decided to go for it. The results were unpleasant news, but at the same time, since this was a high-risk high-reward call, the lack of efficacy didn’t necessarily shake people up. Unfortunately, now those NSCLC results have read out completely, and it failed there as well. That’s a lot harder to brush off, and this has really sent nasty tremors through the oncology portfolios of a lot of other companies who were working on TIGIT.
Now there are some don’t-despair cases to be made (there are a lot of oncology indications out there, every antibody can be different, and so on), but while those arguments can’t be immediately dismissed, it doesn’t mean that they’re strong enough to win out, either. Maybe TIGIT really isn’t all that useful as an oncology target, and the absolute best case for it is that it crawls up to clinical significance if you manage to align everything perfectly. That’s not what folks were looking for. And (to get back to the first link in this post), there’s a larger concern: maybe there aren’t so many opportunities for synergy in the whole immuno-oncology space at all?
That’s a gloomy thought, to go from unlimited prospects a few years ago to “maybe there’s not much there” now, but the data are relentlessly dragging us in that direction. None of the big combo ideas so far have played out; it’s not just TIGIT. And while there are indeed plenty of indications and plenty of targets yet to be explored, with plenty of antibodies for each, etc., what we’ve been seeing are some of the best shots, the most-likely-to-succeeds, coming up short. If you hope for something big to get uncovered, then you are also tacitly conceding that we really don’t know what we’re doing while we search for that turnaround. “Hey, you never know” is a pretty rough business model.
Now, Roche is going ahead with their other TIGIT trials, as well they should, because you really never do know. And I would guess that many of the other players in this area will do likewise – Merck, for example, with vibostolimab. But they’ll do so with lowered expectations, for sure. Merck is now in Phase III in NSCLC with that antibody and Keytruda, and if that trial comes out strongly positive we’ll all be (happily) wondering why. As well as wondering how come Merck gets so lucky, although it’s worth remembering that Keytruda itself was an afterthought of an afterthought for them, detritus from their acquisition of Schering-Plough, for whom it was detritus from their acquisition of Organon, and that Merck was at one point trying to figure out a way to unload this mystery program onto someone else for whatever cash they could get. So it’s not like the whole immuno-oncology field used to sit around calling its shots perfectly until these latest setbacks; it’s always been a crap shoot and we should consider ourselves fortunate that we have what we have.
But going forward, you’d have to think that companies are going to be more willing to put money into targets (and drugs) that have shown some hints of efficacy on their own, rather than hoping for Big Synergy Wins. It’s a nasty paradox: everyone knows that these agents are going to have to be combined in clinical practice for best effect. But what if you have to run single-agent trials to sort them out in the first place?
