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Alicia Morgans: Hi. I'm thrilled to have here with me today Dr. Andrea Apolo, who is the Chief of the Bladder Section at the Genitourinary Malignancy's branch of the NCI, so thank you so much for being here today.

Andrea Apolo: Thank you for having me. 

Alicia Morgans: Oh, of course.

Andrea Apolo: It's great to be here.

Alicia Morgans: Excellent. So you have so much going on at all times. We were just actually trying to review it, and the list goes on and on. One of the most exciting things that you've been working on though is the AMBASSADOR Trial through the Alliance. I would love to hear where that stands, how things are going, and what patients should do if they're interested in becoming involved.

Andrea Apolo: Well, thank you for asking, so the AMBASSADOR Trial is an adjuvant trial, a Phase III trial that's run through the Alliance, and the goal of enrollment is 739 patients. It's a really big trial, and it's for patients with muscle-invasive bladder cancer that are high risk and have persistent disease after surgery. So, this is for patients that get chemotherapy, cisplatin-based chemotherapy, and have persistent disease, and really those patients after surgery, we observe them, so the patients are randomized to receive pembrolizumab or observation, which is what we would standardly do. We also enroll patients that are cisplatin ineligible that never got neoadjuvant platinum-based chemotherapy because they weren't cisplatin eligible, so those are the two populations that we're looking at, and you have to have persistent muscle-invasive disease. 

Then you get randomized to either observation or to receive pembrolizumab. Because really the question is, is there is a benefit of giving pembrolizumab early because once the patient develops metastatic disease, if they do develop metastatic disease, checkpoint inhibitors are approved in that setting, so you will be treated with a checkpoint inhibitor. So really the question is by giving the pembrolizumab early, do we change the disease-free survival, do we change the overall survival? That's the question that we have for the trial.

Alicia Morgans: Absolutely, and that's why you need so many patients, I would think, because for many diseases, prostate for example, as we're moving the therapies earlier and we're attacking it earlier, we might be able to presumably eradicate some of that remaining disease in these high risk patients and change the trajectory of their disease, so-

Andrea Apolo: Right, that's our hope.

Alicia Morgans: A really exciting trial. So what do patients do if they want to get involved with this because it's not just open in Alliance Centers, right?

Andrea Apolo: No, it's open all throughout the cooperative groups, so ask your medical oncologist if they have it open. If not, encourage them to open. We have many sites that are still opening up, and it's a national trial, so if your oncologist does not have it open, then say, "Hey, you should open it for me," and it's pretty easy to open a trial through the cooperative groups in the community.

Alicia Morgans: Wonderful, and it is like you said a standard of care treatment that's just being moved earlier, so expected toxicities are expected, but generally this is not some novel first in human type of a study, and something we expect patients can actually probably do really well with.

Andrea Apolo: Right.

Alicia Morgans: So wonderful. You know, we're actually here at GU ASCO, a very exciting meeting for you. You have multiple presentations, so tell us what you've been working on and what you're presenting.

Andrea Apolo: So another presentation that I have is follow-up on the avelumab second-line treatment of bladder cancer. We have the 250 cohort of metastatic bladder cancer patients, and the data for these patients is what led to FDA approval of avelumab, so we're doing the long-term follow-up. We have a 2.7 year follow-up, and we're looking at the efficacy and the durability of the efficacy. The overall response rate for second-line avelumab was 16.5%, and we found that in this long-term follow-up, the durability of response was 20.5 months, so that's very exciting, and about in a year, in 12 months, 65% of the patients were still responding, so what we see is that the responses are very durable, so that's very encouraging.

So that's one of the avelumab abstracts. I have another one where we're looking at prognostic factors. We're looking at liver metastases. We're looking at age, 75 years, older or younger. We're looking at albumin. We're looking at the kidney insufficiency, and we're also looking at whether it's upper tract urothelial carcinoma or whether it's a bladder primary, to see if these prognostic factors make a difference in terms of overall response rate. I did mention that the overall response rate of avelumab in this setting is 16.5%, and we saw for example in patients with liver metastases, the response rate is lower. It's 6% versus patients without liver metastasis is 22%. We saw a difference also in patients that were older, a response rate of 13% versus 25%. We saw a difference in response of patients with low albumin, 2% if you have low albumin less than 3.5 versus 19%. So, for the other factors, kidney function, creatinine clearance of 60 or less, or whether the tumor is upper tract or lower tract, we didn't see any difference.

We also looked at progression-free survival in terms of these high-risk factors, and we didn't really see a big difference among these, so that was encouraging, and we also looked at adverse events. If you have these high risk factors, are you more prone to having worse outcomes in terms of the toxicity, and we didn't see anything that was worse in the patients in the high risk group, so that was encouraging.

Alicia Morgans: Absolutely. So it's really interesting that there are some factors that seem associated, others that don't, really encouraging that upper tract tumors actually seem to respond similarly to regular bladder-type cancers. One thing that I think is interesting and potentially on which we could intervene might be the albumin levels. If we think about ... We don't usually have time in these patients, and that's probably a poor prognostic sign overall which we've known for a while, but might we intervene in that setting and try to help support patients with other modes and see if that can be useful. I would imagine probably not, but these are all things that you think about as you're trying to support these patients. What are your thoughts about why the older patients may not have responded as well as the younger patients?

Andrea Apolo: Yeah, that's hard to tell. You don't know if it's the biology of the tumor or the it's the comorbidities of the patients. We didn't take into consideration their performance status with that, so it's hard to tell why the patients that were older didn't have as good of a response.

Alicia Morgans: But definitely something for us to think about-

Andrea Apolo: Yeah, to look into, yeah.

Alicia Morgans: But also, to recognize that there were still patients who had responses, so-

Andrea Apolo: And that was what was encouraging from this poster was that even though the high risk patients had lower responses, everybody responded, so that was encouraging.

Alicia Morgans: Absolutely, and you have I think at least one other abstract that I wanted to touch on.

Andrea Apolo: I do, so I have another abstract that my fellow is presenting. This is a correlative trial, a trial that I've been running for a while combining cabozantinib, nivolumab, and ipilimumab in bladder cancer patients, kidney cancer patients, and rare GU histologies. So we took the first 50 patients, 52 patients, and we looked at the circulating tumor cells using the Epic platform, and we looked at baseline, cycle two day one and cycle three day one, and we say, you know, does it change, and they were pretty consistent among the three time points, but we did find a prognostic significance if you have CTCs and they did not decline at cycle two day one, so that was interesting. There was a trend toward a survival difference. It was poor outcome if they didn't decline. 

Also, the morphology of the CTCs seemed to be important, whether it was elongated, the nucleus shape-

Alicia Morgans: Interesting.

Andrea Apolo: So I thought that was very interesting and we're looking a little bit more into that, but the morphology differences among the CTCs made a difference. What we're really looking at now and I'm very excited about is the genomics of the CTC and how that correlates with outcome, and it gives us an opportunity to sequence the CTCs and kind of see, especially the different morphologies, what do they carry, why do they look so different.

Alicia Morgans: Interesting. It's so useful too, because with these drugs, we need to have a good understanding of whether the drug is working or not, and it would be lovely to have it by cycle two, because we don't want to waste time on a treatment that's not working. We'd love to move on to the next, whatever the treatment is or a clinical trial.

Andrea Apolo: Agreed.

Alicia Morgans: So, if you can help us figure that out by having funny looking CTCs or even combining some of these factors to make a score, perhaps that would be really, really useful clinically, so excellent.

So what's your take home message? You're really defining new paths forward in the area of bladder cancer, and I'd love to hear what's your take home messages for the viewers?

Andrea Apolo: I think it's a very exciting time to be doing bladder cancer research. Having a therapy that works, having immunotherapy with checkpoint inhibitors has been altering in terms of the treatments that we are able to offer patients. There's so many exciting trials. Combination trials are very exciting. I mean, I have a lot of interest in combining the checkpoint inhibitors with TKIs, moving the therapies forward, of course, to earlier states of disease like we're doing with the AMBASSADOR Trial, that's very exciting, and biomarkers, seeing if we can find a good biomarker that can predict response. I mean, prognostic biomarkers is one thing, but if we can find a predictive biomarker, I think that's going to be very important.

Alicia Morgans: Absolutely, and I just want to emphasize, you know, this is your life. You've committed to bladder cancer and to clinical trials, and I encourage clinicians and patients to engage in these trials because it's only through engaging in these kinds of opportunities that we answer the questions that we have and we make the therapeutic discoveries that have dramatically moved the field of bladder cancer forward in the last few years, so thank you for time.

Andrea Apolo: Oh, thank you. It was my pleasure to be here. Thanks for having me.

Alicia Morgans: Of course.