Combination Therapies in Bladder Cancer: Insights and Challenges

In part four of this roundtable, Roger Li, MD, Vitaly Margulis, MD, Kyle Rose, MD, and Paul Crispen, MD, debate the potential of combining intravesical immunotherapy with immune checkpoint inhibitors and the evolving role of chemotherapy in BCG-unresponsive disease. The panelists provide insights on emerging data, treatment durability, and practical considerations like patient accessibility and cost, highlighting the complex decision-making landscape for high-risk non-muscle-invasive bladder cancer therapies.

Watch the fifth part of this series: Frontline vs Sequenced Therapies in BCG-Unresponsive Bladder Cancer: What’s the Best Approach?

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Dr. Li:
Going back to this combination idea, I guess we’ve seen some combinations with immunotherapeutic agents delivered intravesically plus an immune checkpoint blockade that have augmented the efficacy if you will. Is there something between the chemotherapy, comparing a chemotherapeutic agent versus versus an immune checkpoint versus an immunotherapeutic agent with immune checkpoint?

Dr. Rose:
Who wants to take that one?

Dr. Crispen:
So I think that definitely falls outside of my area of experience. I have not done that. I’ve not used an intravesical checkpoint inhibitor.

Dr. Li:
Well not necessarily intravesical checkpoint, but just intravesical immunotherapeutics. So with CG or with adstiladrin, an agent that kind of primes the bladder, if you will, and then you add on the immune checkpoint to augment the efficacy of that. Versus chemotherapy, we still think of as more of a chemo-ablative agent.

Dr. Crispen:
Sure.

Dr. Li:
And so it’s not as immunogenic as some of the other agents.

Dr. Crispen:
Sure. I have very limited to no experience with that. I think you’re probably the most experienced here in the room to discuss that topic. You’re kind of the pioneer in that space.

Dr. Li:
To me, again, certainly there are some rationale to adding gemcitabine to immune checkpoint inhibitors. Gemcitabine also has some immunogenic effects. It can decrease the myeloid-derived suppressive cells also in the tumor microenvironment. But again, I think the results are what they are, and the monotherapy seems to be working really, really well here. So it’s very encouraging.

Dr. Margulis:
I would say the idea of combination of a cytotoxic drug with immunotherapeutic drug is not novel. In kidney cancer, if you think about it, you combine TKI’s with immunotherapy and the idea is you destroy the tumor a little bit, increase the antigenic load, get the immune system primed. I think at least there’s a rationale for that, but I’m just surprised that unfortunately that didn’t fully come out in this clinical trial.

Dr. Li:
Yeah, it’d be very interesting to see what the tumor microenvironment actually looks like before and after treatment for this trial. So, good primary response, good durability, seems like very well-tolerated as well. We’re obviously very eagerly awaiting the final results from this trial, but I think it’s very promising. So where does this fit in with all of the other available agents, I guess, currently that are approved by the FDA and also available in the clinic?

Dr. Rose:
I think it’ll come down to a patient discussion. Looking at the data from the finalized published trials, looking at the efficacy and the tolerability, and just having a frank conversation with these patients. We had discussed for BCG unresponsive disease that every step along the way, we talk about the cystectomy with standard of care. I think these three agents, two to four agents, this is going to become part of our high-risk non-muscle-invasive cancer talk. I think it’s something that we’re going to… These are data points that we’re going to need to know as surgeons, and patients come in informed and they want to know, to your point, not what three months looks like from now, but two to three years from now.

Dr. Li:
So when patients come in, are you counseling them on the efficacy? Is that their primary goal or are you also taking into account the toxicity and the logistics?

Dr. Crispen:
All of it. Like Kyle pointed out, they’re primarily motivated by the efficacy, and so then they want to know, “Okay, all things equal then, what about access? How many trips am I going to have to take for one versus the other? Side effect profile, which is going to be more toxic?”

But I do think efficacy is going to win out. Aside from that, maybe it’s going to be, is one going to be better in terms of sequencing before another, or is their last treatment going to impact their next one? And those things we don’t know yet.

Dr. Margulis:
Not much to add to that. I mean, I think we’re… Obviously, I think the therapeutic index of any product is really what drives the decision, but I can tell you that these are elderly patients. They have already been pre-treated. So I think they are quality of discussions that happen. And again, I’m dealing right now with this in terms of trying to get adstiladrin or nogapendekin alfa inbakicept to somebody. And if somebody has $2,000.00 out of pocket cost, regardless of what you may think, the patient’s just not going to be able to afford it. These are real issues. So I think that the coverage with these, these are expensive agents. And just being able to pay for this, I think, may be the primary deciding factor whether you like it or not.