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Alicia Morgans: Hi, I'm thrilled to have here with here today Dr. Matt Galsky, who is a Professor of Urology and Medicine at Mount Sinai. Thank you so much for being here.

Matt Galsky: Thank you for having me.

Alicia Morgans: Of course. So you've done a lot of work with some really interesting protocols in muscle-invasive metastatic bladder cancer, thinking about combinations of chemotherapy with immunotherapy and maintenance strategies. It would be really interesting to hear you thought on those combination and maintenance-type strategies.

Matt Galsky: Absolutely, so now immunotherapy has changed the landscape of treatment for urothelial cancer. We have approvals in the post-chemotherapy setting, and of course, a common paradigm in drug development and oncology is to first test the safety and activity of drugs in later disease states and move them earlier. So it's logical to move these drugs earlier in the course of treatment.

Our first line standard treatments are chemotherapy and so that would be a logical path to combine these therapies with chemotherapy. But there are several reasons why we might want to do that, and several reasons why it might not be such a good idea. And early on, there was a lot of skepticism before the immune checkpoint blockade era, in the era of vaccines, a lot of skepticism initially about whether or not we should combine these drugs with chemotherapy. 

Certainly, we know that chemotherapy suppresses the immune system, causes myelosuppression, causes some lymphopenia. Are we shooting ourselves in the foot by combining these drugs with immunotherapies or other strategies that modulate the immune system? So there was some concern about it and some early studies with vaccines that suggested maybe it wasn't a great idea.

There's a number of reasons why this might be a good idea, though, and really I think about three major reasons for combining chemotherapy with immune checkpoint blockade. One is this concept of immunogenic cell death, so this is this concept, this specific way of cells dying that leads to release of danger signals that first stimulate an innate immune response ideally followed by an adaptive immune response. 

And we talk about immunogenic cell death a lot. In the laboratory, it's been well described. We actually have very little data that this occurs in patients. We don't have great assays to test for this. We don't know the right assays to test for it. So that's very commonly proposed as a reason for combining treatments, but very little data that this happens in patients.

In addition to that, and I'll come back to this a little bit, it might matter what drugs we use when it comes to immunogenic cell death. A second reason that's often proposed is depletion of suppressive immune cell subsets like myeloid-derived suppressor cells. Similarly, we don't have a ton of evidence that that happens in patients.

We tested this in the peripheral blood in a study where we gave chemotherapy with ipilimumab with CTLA-4 blockade. In that study, using flow cytometry in the peripheral blood, you don't see a lot of depletion of MVSEs, but of course what's happening in the tumor might be different. 

And then the third reason, and I think, you know, despite all of our thoughtfulness about trying to be scientific about how we approach these combinations, I think the third reason why combining drugs might be beneficial is just independent drug action. These drug classes are non-cross-resistant, and when you combine non-cross-resistant drugs and give them to patient populations, you increase the likelihood that any one patient is going to respond to treatment. There's a beautiful study in Cell a couple years ago that modeled combination treatments in oncology and showed that probably most of our combinations simply work because of independent drug action and not additivity or synergy.

Alicia Morgans: Interesting, great. So how have you thought about these concepts in the studies that you've designed, because like I said you've got some interesting concepts in the metastatic setting, in the maintenance sort of setting. And you've done a lot of work in this area that I'd like people to learn about.

Matt Galsky: So, the first step was really to test whether or not this could be done, and I mentioned we did this with ipilimumab with CTLA-4 blockade. That was in an era before PD-1 and PD-L1 blockade was really on the map in urothelial cancer. And that study showed that you can safely combine these drugs. There was some concern about potentially not only suppressing the impact of immunotherapy but not being able to interpret that. We do see immune-related side effects when you combine chemotherapy and immune checkpoint blockade. 

So in general, there's probably not the suppression of the immune system in terms of the immune modulation that occurs with immune checkpoint blockade with chemotherapy that we thought might be problematic. 

So, the next generation of studies after that has really been testing a few concepts, and we try and test these concepts in different studies, not try and test everything in the same study.

Alicia Morgans: Correct.

Matt Galsky: So, one of these is whether or not immunogenic cell death really matters. In the laboratory, oxaliplatin induces immunogenic cell death, but interestingly carboplatin and cisplatin don't. And so carboplatin, cisplatin, is our backbone of treatment for metastatic urothelial cancer. And there is some data for the combination of gemcitabine and oxaliplatin from all their Phase 2 studies, and interestingly the response rates are pretty similar to gemcitabine and carboplatin. 

And so it would be logical if you have two doublets that have similar activity without immune checkpoint blockade, and the only difference is in the platinum drug that might induce immunogenic cell death, that if you combined those regimens with PD-1 or PD-L1 blockade, perhaps you'll see synergy with the regimen employing the drug that induces immunogenic cell death. 

So in a randomized Phase 2 study that's randomizing patients between gemcitabine and oxaliplatin, nivolumab, and gemcitabine, carboplatin, nivolumab, this is for first-line treatment of cisplatin-ineligible patients. 

Interestingly today, there was a presentation of a randomized study of gem-carbo versus gem-oxaliplatin without an immune checkpoint blockade that showed that the regimens indeed in a head-to-head study were pretty similar. Gem-oxaliplatin is associated with a bit less toxicity and the response rate numerically was a little bit higher, but overall pretty similar providing some further support for that concept.

The other approach is whether or not we should give these drugs concomitantly or sequentially, and one way to give these drugs sequentially is to not wait until patients have relapse or recurrence of disease after initial chemotherapy but to move the immune checkpoint blockade right after the end of chemotherapy in a switch maintenance-type fashion. So that's a concept that's being tested in a trial that recently completed accrual where patients received four to six cycles of first-line chemotherapy for metastatic disease and then were randomized to receive maintenance treatment with immune checkpoint blockade with pembrolizumab versus placebo. That study's closed. We're waiting for the results.

Alicia Morgans: So great studies, but those are probably focused, I think, predominantly on urothelial.

Matt Galsky: That's right.

Alicia Morgans: You know, we also end up facing these variant histologies which I think can be especially challenging, particularly as studies don't necessarily focus on them, and they're not necessarily always get into the trials. What are your thoughts on the treatment of variant histologies, whether they're small cell, squamous, adeno, a mix? What are your thoughts there, and how do we move that part of the field forward?

Matt Galsky: So, this is very challenging clinical practice as you laid out, and it's difficult to generate prospective evidence in these less common patient populations, and so we're really left with managing these patients based on retrospective series, often single-center series, often anecdote. It's really a setting where we need to generate prospective evidence. And with some of the rare cancer initiatives that are international collaborations going on now, I think we'll learn a little bit at least about some of these variant histologies.

Neuroendocrine cancers of the bladders, small cell cancers of the bladder are particularly problematic based on the aggressive nature of that disease. I think we've learned a lot genomically about those cancers, probably outpacing what we're able to do clinically, but one of the interesting genomic findings is that those cancers look very similar to urothelial cancer of the bladder in terms of the genomic landscape, really supporting a common clonal progenitor for those cancers rather than this older concept that there's a progenitor neuroendocrine cell.

In addition to that, small cell cancers of the bladder have a relatively high tumor mutational burden, very similar to urothelial cancer, very similar to small cell cancer of the lung. And so this does raise the possibility of whether immune checkpoint blockade can have a role in the treatment of this disease as well. We know from the small cell lung cancer data that not only are immune checkpoint blockade single drugs and doublets potentially active but also there seems to be some correlation with activity in tumor mutational burden. In an analysis of small cell lung cancer, in the highest tumor mutational burden tertile, ipilimumab plus nivolumab had a response rate of about 48%, which is really quite impressive.

So, I think in the absence of prospective data, the use of immune checkpoint inhibitors could certainly be considered in this patient population, until we have prospective evidence suggesting that there is a better strategy.

Alicia Morgans: Great. Well, I expect you to get us some prospective data as soon as you can, Matt, and get the study going. We're happy to participate if you're opening that study. It sounds like it's at least in your thoughts.

Matt Galsky: Absolutely.

Alicia Morgans: If not on paper in a protocol. I truly appreciate you sharing your expertise and your thoughts on bladder cancer with me today. Thank you. 

Matt Galsky: Thank you. My pleasure.