Transcript:David I. Quinn, MD: Sequencing in combinations is a very important topic now in urothelial cancer. For first-line metastatic or recurrent disease, we’ve traditionally used cisplatin in combination with other drugs. Or for patients who are cisplatin-ineligible, typically we’ve used carboplatin or gemcitabine, based on evidence from Maria DeSantis’ study a few years ago in that population done in Europe.
So, how is that likely to change? Well, we have fully accrued the DANUBE study that looked at our CTLA-4 inhibitor, tremelimumab, in combination with durvalumab, which is a PD-L1 inhibitor, compared to durvalumab alone and compared to standard chemotherapy with either cisplatin or carboplatin in the standard way. That study is fully accrued and we’re waiting for it to report out, and they’re following the patients. And if in that study there is superiority for the combination, or there’s superiority in a selected group—potentially on the biomarker PD-L1 for single-agent therapy—that will change practice and it will give us another option. I think the premise there in our first fully accrued study is that I think immunotherapy is coming to the first-line space.
How we’re going to use it depends on the result of the studies. And we have studies that now are also exploring the other checkpoint inhibitors in the first-line setting. We have studies that are incorporating pembrolizumab and atezolizumab with chemotherapy, and also looking at chemotherapy alone but with a third arm in the first-line of just the checkpoint inhibitor to see whether there’s a population of patients who might benefit from just having the single checkpoint inhibitor. So, there is a lot of activity in the first-line space evolving, and I’d encourage people to accrue to those studies because we need to try and get the questions answered for these patients who, quite frankly, are not always great candidates for chemotherapy.
If we look in the second-line space, we’ve already talked about comparative studies in KEYNOTE-045 and the IMvigor 211, we’re going to have to digest those. But what’s happening now is the majority of our patients still get first-line chemotherapy and they’re candidates for checkpoint inhibitor treatment of single agents, a choice of 5 different agents. So, we’re spoiled for choice. But from that perspective, what I recommend people try and do is to look at a rational combination in the clinical trial with one of these agents. And there are many combinations coming forward of agents that modify immunotherapy—they have an effect that we know on the immune system. An example of that might be a combination of ipilimumab, a CTLA-4 inhibitor, and a PD-1 inhibitor, nivolumab. That’s a study that’s proceeding for patients who have previously had first-line chemotherapy. Most of the others are combinations of immuno-oncology agents, but also interesting combinations of chemotherapy and targeted therapy.
Now you may all ask, “Well, why would we put them together in that space?” Interestingly, the toxicity does not seem to overlap too badly between the agents. And many of our chemotherapeutic agents and novel targeted agents have a fix on the microenvironment that may produce an additive or synergistic effect with the checkpoint inhibitor. So, we’re moving forward with those studies to try and look at that.
So, the question often comes up from patients about if they go on a clinical trial of a checkpoint inhibitor or in combination at any stage, how will chemotherapy potentially work afterwards? We don’t have good data on this yet, but our anecdotal experience is that patients respond very well to chemotherapy after immunotherapy, and this is also seen in a variety of other conditions—melanoma and renal cell cancer with targeted therapy after immunotherapy. It’s likely that the patient’s not giving up anything to go on the trials, and you need to go through each trial with the patient and do the consent process properly and make sure they’re informed. But I’d really encourage people to consider these trials, and the patients are now doing better overall, remaining well, and often are able to tolerate chemotherapy sometimes as a third-line, whereas before we wouldn’t have considered that. And so, I think all the options are on the table.
We do have some new things coming. We have a VEGF receptor 2 monoclonal antibody that was combined with docetaxel in the RANGE study, ramucirumab, which is approved in gastric cancer in combination with chemotherapy.
We have a VEGF receptor 2 antibody, ramucirumab, that has been tested, and that completed accrual in a study in combination with docetaxel that we’ll see, and it looked quite active in the randomized phase II. That also has potential with chemotherapy and has been looked at in early studies where we combine that agent with monoclonal antibodies that directed the PD-1 or PD-L1. So, there’s some interesting stuff happening there.
There’s also an antibody—drug conjugate that was reported at ESMO 2016. It is a linked compound directed at nectin, which is highly expressed on urothelial cancer. It’s about 90% or more, and it delivers a payload of chemotherapy through a mechanism that’s similar to TDM1 in breast cancer. In breast cancer, it’s HER2 with a payload of chemotherapy, and that’s an effective agent in HER2-positive patients.
There are studies that are going to be proceeding with that agent, which currently has a code name which is AGS-22CE, but I think is about to be named, along with some other antibody¬—drug conjugates. And we hope that that will be active. Interestingly, that appears to be active after checkpoint inhibitor therapy, and we’re working on filling out a phase II cohort. You will be seeing phase III studies to look at that agent as well. So, we have some exciting things coming.
Transcript Edited for Clarity