Dr Peter Black (2)

Dickon Hayne: Hello there, my name is Dickon Hayne. We’re at the ANZUP conference and I have the pleasure talking to Peter Black about bladder cancer and specifically the aspects related to changes in immunotherapy in bladder cancer. Thanks for talking to us Peter. Let’s start in the more advanced setting. There’s so much going on. It’s kind of bewildering for urologists and and med oncs as well, firstly, could you tell us what you think are the current trials that are going to be most elucidating in this space and then maybe and then move on to your top picks, so where things are going in the advanced setting?

Peter Black: Yes, so absolutely. Yes, there’s a dizzying number of different trials going on right now and we have five different drugs, five different checkpoint inhibitors that have been approved in the United States and their approvals trickling through in different countries including Australia. It’s all in patients with metastatic bladder and upper tract disease who failed platinum in general, so Carboplatin or Cisplatin. We’ve seen good results, about 20 percent will have a response but obviously there are a lot of patients who still are not responding. One thing that we are seeing as things move forward is that these drugs are moving into different disease states, so we have trials now also in the adjuvant setting after radical cystectomy. There are three different trials there and we also have some neoadjuvant trials going on and then it’s also moved into the non-muscle invasive disease setting and then the other thing that we can expect in the future are a combination therapy. There are a lot of trials ongoing with one of the established checkpoint inhibitors plus either another immunotherapy or in addition to chemotherapy in addition to radiotherapy, so here’s there’s an awful lot going on. and then there’s also a very rich research area around biomarkers in which biomarkers can we use to select out the 20% of patients who really are going to benefit so that they get the treatment and the other patients move on to something else.

Dickon: I’m interested to hear you mentioning trials in the adjuvant setting. Obviously, those of us who perform cystectomy and you’ve got high-risk patients, may be they’ve had neoadjuvant chemotherapy and they still got T3 disease or perhaps they’ve got anyone with positive lymph nodes, a cystectomy that maybe fit patients and other ones who really want to hit hard you really want to try and cure those patients. Can you tell us any more about any studies looking at that group and what worked?

Peter: Yes. If a patient is had neoadjuvant chemotherapy and still has any muscle invasive disease at the time of cystectomy, that already counts for all three of these trials and then, any patient regardless of neoadjuvant chemotherapy, if they have T3 or greater node positive. It’s very attractive because it’s relatively easy therapy to give. It’s very well tolerated, it’s much better tolerated than chemotherapy. We know that we have challenges giving adjuvant chemotherapy in some patients post cystectomy. This should be easier and so it’s very compelling. And then in the neoadjuvant setting of course, the problem is that if you only expect 20%, we’re gonna be reluctant to delay cystectomy for that kind of response rate.

Dickon: And what about combination immunotherapy, a PD1 or a PDL1 and CTLA-4’s? Is anyone using that in an adjuvant setting in the study that you’re aware of or is that a—

Peter: You know, I wouldn’t be surprised if someone’s doing it somewhere. I’m not aware of a bigger trial with it. I mean, the adjuvant trials with single agent PD1, PDL1, they’re all phase 3 trials, lots of patients, but there may be smaller trials. The trials we have seen again are in the second line metastatic that are combination trials and I think one of the most interesting trials has already completed accrual which is in the first line metastatic, so o no prior chemotherapy, where patients are either getting—or trial has finished accrual but they got Durvalumab alone which is a PDL1 inhibitor or they got Durvalumab plus Tremelimumab which is a CTLA-4 inhibitor or regular chemotherapy, so that’s very interesting in the first line [overlap]

Dickon: Three way randomization.

Peter: Three-way randomization.

Dickon: Okay, it will be fascinating to see the results of that one. What about the non-muscle invasive setting? So the urologists in Australia were obviously, that’s where we’re likely to be more directly involved in the immunotherapy space, is that are we going to be giving these patients some immunotherapies? How are we going to deliver it? What’s going to be happening?

Peter: Yes. I think right now second line metastatic you said as urologists, I’m not in that space. I don’t need to really know it but certainly adjuvant, yes, we certainly need to know it. Those are our patients that we’re sending on and then in the non-muscle invasive setting, the question is, should we be doing this ourselves? I think for the most part we’ll have to work in close collaboration with the medical oncologists and they will be giving the agents. But there are some compelling reasons why these drugs should be tested in clinical trials in patients who failed BCG. And so, again there are three different trials looking at this and one of those trials is open in Australia and New Zealand. It’s  a paradigm shift. We’re giving systemic therapy to patients with non-muscle invasive disease but we know this is a high-risk disease, high risk of progression, there is a mortality risk, and so I think it’s something patients certainly embrace.

Dickon: How would you feel about us at this stage with it because we have very little information about how these drugs may work in a non-muscle invasive setting? How do you feel about trials, which might utilize immunotherapies upfront against best practice, which would be BCG with maintenance?

Peter: Yes, I think that’s challenging. Again, if we look at this magic 20%, it’s not it’s not really a great response rate by itself, so more patients will respond to BCG than that. I don’t think we should be trying to necessarily replace BCG. I think we want to build on BCG. I think the trial design in the patients who have not yet failed BCG should be BCG alone versus BCG plus new drug and there are trials coming up in that space. The BCG failure population is attractive for the companies because there’s a clear pathway towards FDA registration, so that trial space is the BCG refractory or what we’re now seeing unresponsive, is a very busy trial space.

Dickon: And then there aren’t that many patients.

Peter: Yes, exactly. There’s actually a lot of competition, shall we say, for the patients to get them enrolled on these trials which, you know, it’s great if we can get these trials done and it’s great for the patients if they’re exposed to novel therapies but it is challenging to it.

Dickon: Okay, that’s been very interesting. Thank you very much.

Peter: Thank you.