Immuno-oncology! It’s such a big deal, let’s just do what everyone in the field is doing and call it “IO”. The recent successes in this area have rearranged every company’s oncology strategy, in some cases rearranging its entire oncology portfolio right out the door. There are several possibilities open to you now, if you’re working in the anti-cancer area, but these have closed off a lot of others. You can (1) be an IO player yourself, competing directly in the immuno-focused targets, or (2) not have any of those yourself, but align your efforts to complement those that are already on the market or are heading there, or (3) deliberately aim for those oncology indications that look like they’re going to be difficult to target via immunotherapy at all. What you can’t do, most likely, is carry on as if IO hasn’t reshaped everything, because it has.
And that reshaping is a pretty lively process. Witness the news that Roche has had a major unexpected clinical failure with their antibody therapy Tencentriq (atezolizumab) in bladder cancer. This is another antibody targeting the PD-1/PD-L1 system, like Keytrude, Opdivo, etc. (in this case, it’s going after PD-L1 itself), and it was the first one approved against any form of bladder cancer. It’s also been approved for metastatic non-small cell lung cancer, which is a more traditional indication in this area, if by “tradition” we mean the last couple of years. The bladder cancer approval, though, was an accelerated one after just Phase II data, with re-evaluation to come after the Phase III numbers came in.
Well, now they’re in, and the drug missed its primary endpoint. This not only puts Tencentriq’s continued approval for this indication in doubt, but it cannot be good news for the other companies in this space who are targeting it as well. Opdivo (nivolumab) from Bristol-Myers Squibb got approval in February, Pfizer and Merck KGaA’s Bavencio (avelumab) got a similar accelerated approval just a couple of days ago. Merck’s Keytruda (pembrolizumab), meanwhile, showed a good response Phase III (so much so that the trial was cut short), and is under review at the FDA, and there’s AstraZeneca’s entry in this area Imfinzi (durvalumab), too.
Roche is saying that one problem was an unexpectedly robust response in the chemotherapy standard-of-care group, but there are other things to worry about. PD-L1 status in bladder cancer seems to be correlated with disease progression, but perhaps not as tightly as in some other areas. In lung cancer, Merck was able to succeed by rigorously screening its clinical trial populations for PD-L1 expression (and BMS famously has fallen behind by trying to expand their own patient populations, although the situation is murky). The bright spot is that Keytruda now has some improved survival numbers to back up its durable-response data, but this Roche news makes you wonder if everyone else is going to see that or not, or if the FDA is going to back off some of these accelerated approval requests in light of it. No one knows yet if there’s a difference in this indication between targeting PD-1 (Opdivo and Keytruda) or PD-L1 (the others), or if there are differences between the drugs in each class.
I do have to note, though, that this is different from the Alzheimer’s issue that I was writing about the other day, and from most right-to-try ideas. In the case of these approvals for bladder cancer, the drugs have indeed shown efficacy, up to a point – the tumors are responding to the therapy. That’s a lot more than just saying “OK, this drug passed an initial safety screen, so why don’t you people all have at it”. The question here is the long-running one in oncology, that is, the relationship between a response (tumor shrinkage or the like) and overall survival and/or quality of life. It does a patient little good to die at exactly the same time they would have died without treatment, but just with a smaller tumor load. Survival data are, and always have been, the real currency.
It’s worth remembering that this whole area is still very new, and that there’s a lot that we don’t know about it. To that point, here’s a new paper in Science Translational Medicine from a Mass General/Harvard Medical School team that has some insights into just what happens to these antibodies in vivo. They’re using fluorescently tagged versions and tracking them intracellularly, and it turns out that although these mAbs have long circulating half-lives, their target engagement time may be a lot shorter than anyone realized. :
Here, by using time-lapse intravital microscopy, we uncovered in real time how the immune checkpoint blocker aPD-1 mAb distributes in tumors and physically interacts with tumor microenvironment components. This approach enabled us to detect aPD-1 mAb association with cytotoxic T cells infiltrating tumors in vivo. Furthermore, by following the drug’s pharmacokinetics over time, we found the drug to be rapidly removed from PD-1+ CD8+ T cells and transferred to neighboring PD-1−TAMs. The transfer of aPD-1 mAbs from T cells to macrophages was unexpected because macrophages do not directly take up aPD-1 mAbs in culture. We further identified that aPD-1 uptake by macrophages depends both on the Fc domain of the antibody and on FcgRs expressed by macrophages. Interactions between the drugs and macrophages are likely important because blocking Fc/FcgR binding inhibited aPD-1 transfer from CD8+ T cells to macrophages in vivo and enhanced aPD-1 therapeutic efficacy.
The paper demonstrates transfer of the antibodies to macrophages taking place within a half hour, which is rather alarming. That’s the bad news. But the good news is that these antibodies are still showing efficacy anyway, and that this response might be greatly enhanced by blocking this macrophage transfer pathway. FcgR binding has already been shown to be very important for the action of other monoclonal antibodies, and this paper suggests that the PD-1 and PD-L1 antibodies are going to be in the same category. These results also have implications for the antibodies used as diagnostic tools to select patients, both for clinical trials and in clinical practice itself. We’re going to have to better understand the role of Fc receptors in all this before we can get a handle on things.