Biomarkers and Immunotherapy for Bladder Cancer
Dr. Pal: Well, Matt, I’m going to cut right to the chase here. One of the big issues that we have in bladder cancer is now that we’ve got immunotherapy, can we use some of the biomarkers that we’ve got to sort out who should get IO and who should get chemo? Any thoughts on that?
Dr. Campbell: I think it remains one of the pivotal questions in our field. And we are building such incredible -omics platforms to try to address some of these questions, but I feel like we’re having shifting sands because whenever we have some very good profiling that is suggesting that some patients will benefit from certain approaches, it takes time for that data to all come back and we have to figure out ways that we can do real-time biomarker prediction for these patients so that we’re not having to wait several months to select therapy because that just doesn’t seem like that’s going to be clinically applicable.
We have clearly started to explore PD-L expression in these tumors and in their immune infiltrate, trying to decide how we can predict patients that will respond to immune therapy, but it’s been really challenging because it’s continually shifting data and every time I go through it, it seems like the goalposts keep moving.
Dr. Pal: That makes perfect sense, so I’ll pose to you a clinical scenario. Let’s say you’re sitting in front of the patient in clinic, modest creatinine clearance in the ballpark of 40 to 50, so cisplatin ineligible, they’ve got multiple metastases to the lungs, and you get their PD-L score back. And the PD-L score using let’s say the Foundation test is less than 1%. So in that scenario, the zero PD-L1 expression in this scenario, cisplatin ineligible, what are you going to be treating that patient with?
Dr. Campbell: Yeah, it’s interesting because I was a little bit upset, to be honest, with the FDA’s recommendation that patients have to be PD-L positive to receive treatment as front line for immune checkpoint if they’re carboplatin ineligible, and the reason why that upset me was because the initial trials were for cisplatin ineligible. Obviously, many more patients are carboplatin ineligible and the data that have been used so far has largely been archival-based tissue. And we learned that archival-based tissue with PD-L1 being a very dynamic marker with, often, heterogeneity between sites of metastases leads me to have tremendous doubt of deciding if the patient’s not going to be eligible.
With the exception, I guess, of some of the durvalumab data, even patients who are PD-L negative have a chance to respond to immune checkpoint therapy and if they don’t respond, I think if you have a rapid transition toward chemotherapy, I don’t think you’re going to harm patients with that approach and there’s a chance that you could hit a home run with immune checkpoint therapy.
Dr. Pal: That’s really interesting. Now I’m going to take a different scenario. It’s not too different from what I posed to you before, but let’s say for whatever reason, couldn’t get that PD-L1 test done but you got a high TMB in a patient. What do you think of that? Let’s say their mutational burden is estimated at 25 mutations per megabase. Again, using the Foundation platform.
Dr. Campbell: Yeah. Sorry to interrupt, but I think that is absolutely a fascinating question and I clearly think that there is some suggestion that high TMB is going to correlate well with response. I think that would motivate me to try to get them, again, immune checkpoint for the points I brought up earlier, but it’s really hard for us because our assumption is higher tumor mutation burden is going to lead to higher neoantigen load and that clearly hasn’t been the case because we see plenty of patients with higher tumor mutation burdens that do not respond. And so it’s this constant trying to discover better and better tests and better and better understanding of how we can best select patients.
Dr. Pal: Interesting. Now you’re kind of at this mecca for bladder cancer therapy with multiple, multiple individuals focused on different niches within bladder cancer. One thing that I’m always perplexed by is what to do with the rare histologies of bladder cancer. You know, you see patients occasionally in clinic with small cell, with, for instance, adenoid carcinomas of the bladder. One thing that always has puzzled me is what to do with pure squamous histology. Is that a scenario where you’re using immunotherapy or you’re jumping right to chemotherapy? What’s been your practice?
Dr. Campbell: Yeah, and so you know, we’ve been partnering with Dana-Farber and some other institutions on one of the rare GU tumor trials where we’re using immune checkpoint and with nivolumab and ipilimumab. And you know, I think that’s going to potentially down the road be a nice approach using immune checkpoint therapy for this histology. It’s hard in the United States because obviously it’s a very rare entity, but we do see a lot of patients that have squamous mixed in. And that is an entire other question because we never know for these mixtures, you know, what may be driving that tumor. And there are some of these mixtures where it seems like the variant itself is the one driving the ship, but you know, I’m perplexed.
I would say that you know, when we treat patients with small cell for instance that are a mixture and at the end of the day after chemotherapy and they get to the operating room for localized disease, they still have urothelial that remains without the small cell. So I think with the rare variants, we still have a tremendous amount to learn, but I do think that we’re going to have to begin to shift our treatment from one size fits all to a more nuanced approach as we move forward.
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