Ashish Kamat: Welcome everybody to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston, at MD Anderson Cancer Center. And I'm joined today by Dr. Shilpa Gupta, who's a medical oncologist at the Cleveland Clinic, and a true expert in everything to do with bladder cancer. Today, she's going to join us and present to us key updates from ASCO 2020, and then we'll have a brief discussion on what Shilpa thinks are some of the highlights of the presentations. So with that, Dr. Gupta, take it away.

Shilpa Gupta: Thanks Dr. Kamat. Thanks for the opportunity for sharing the key ASCO updates. There's a lot going on in the bladder cancer field, and I'm delighted to share the key updates.

Starting with the neoadjuvant immunotherapy approaches in muscle-invasive bladder cancer. We saw the study, NABUCCO, that was presented at ASCO this year, the updated bio market analysis, and clinical follow-up. This was a study of preoperative ipilimumab and nivolumab in stage III urothelial cancer. Patients received ipilimumab loading dose, followed by Ipi Nivo, and one dose of nivolumab. And these were high-risk cisplatin-ineligible patients. And the primary endpoint was feasibility, which is a key concern in these patients. We don't want any therapies that could hamper that. And very encouraging clinical results were shown: complete responses in 46% patients, and down-staging in around 58% of patients. Most patients received all three cycles, and immune-related adverse events did occur in around 54% of patients.

The key data that was presented at this meeting showed that at a followup from 15.9 months, only about 8% of patients had relapsed. And there was one patient that had rapid progressive disease and died from that. But overall, the relapse-free and overall survival looks good from this followup.

They also looked at several biomarkers, like tumor mutational burden, intratumoral TDH, and TGF data associated genes. And we saw that TGF beta was associated with resistance to immunotherapy like human mutational burden was felt to be correlating with responses.

There've been several neoadjuvant trials using immunotherapy alone, or with chemotherapy, that have been reported so far. This table primarily outlines the fact that it is looking encouraging and doable with no delays to cystectomy in majority of patients and encouraging responses in both cisplatin-eligible, as well as cisplatin-ineligible patients.

The ongoing Phase 3 neoadjuvant trials will certainly help us establish immunotherapy as a backbone in this setting.

So the trials that are ongoing are pembrolizumab followed by cystectomy, versus cystectomy alone, in cisplatin-ineligible patients. Another trial is looking at nivolumab in these patients. And there's a combination trial of nivolumab and a CD122 agonist, NKTR-214, versus cystectomy in cisplatin-ineligible patients.

And for patients who are eligible to get cisplatin, we have several trials, which KEYNOTE-866 is looking at Gem/Cis plus pembrolizumab versus Gem/Cis, followed by cystectomy. Then the NIAGRA trial is looking at Gem/Cis plus durvalumab, versus Gem/Cis. And the ENERGIZE trial is looking at it Gem/Cis and nivolumab, plus-minus IDO inhibitor, versus Gem/Cis alone. So these trials are really interesting, and over the next few years will provide insights on where immunotherapy stands alone, or in combination in neoadjuvant setting.

Moving on to adjuvant immunotherapy approaches in muscle-invasive bladder cancer. The key study that was presented at ASCO this year was the IMvigor010. This was the primary analysis from the Phase III randomized trial of adjuvant atezolizumab versus observation in high risk muscle-invasive urothelial carcinoma. Dr. Miles and I presented this data.

This was a one to one randomization of high risk muscle-invasive urothelial cancer patients, including upper tract disease, who were randomized to atezolizumab or observation. It was around 800 patient trial... The primary endpoint was disease-free survival in the intention-to-treat population, and key secondary endpoint was overall survival. And it was stratified based on several factors like prior new adjuvant chemotherapy, lymph node involvement, number of lymph nodes resected, stage, and PD-L1 one status.

Unfortunately, this was a negative trial, as we can see here. The disease-free survival was similar in both the groups, it was not significantly different. And neither was the interim overall survival, in the intention-to-treat population.

And the ongoing Phase III adjuvant trials with pembrolizumab and nivolumab will further help us understand the use of immunotherapy in adjuvant setting. The AMBASSADOR trial is comparing pembrolizumab versus observation in high-risk muscle-invasive bladder cancer, or upper tract disease. The only difference from the IMvigor trial is that this does allow positive margins, IMvigor010 did not.

The CHECKMATE-274 trial is again, similar setting, randomization to nivolumab versus observation, and the primary endpoint is disease-free survival in PD-L1 positive patients and all patients.

Next is the maintenance immunotherapy setting in metastatic urothelial cancer. And the plenary presentation this year was the JAVELIN 100 study, presented by Dr. Tom Powles. This was maintenance avelumab, and best supportive care versus best supportive care alone, after platinum-based first-line chemotherapy in advanced urothelial carcinoma.

So this is the study design, any patient who got first-line platinum-based chemotherapy, either carboplatin or cisplatin, and did not have progressive disease, was enrolled in this study, was eligible, with unresectable locally advanced or metastatic urothelial cancer. And after completion of chemotherapy, if patients had stable disease, fascial, or complete responses, they were randomized to avelumab and best supportive care, versus best supportive care alone. And the primary endpoint was overall survival. And the primary analysis populations were all intention-to-treat patients, as well as PD-L1 positive population. Secondary endpoints for progression-free survival, objective response, safety, tolerability, and patient-related outcomes. Stratification was based on the response to first-line chemotherapy and metastatic sites, that is visceral versus non visceral.

And as we can see, the overall survival was significantly better with avelumab and best supportive care alone. At 21.4 months, compared to 14.3 months with best supportive care alone. And this is the first time we have seen positive overall survival results in maintenance setting. And in the PD-L1 positive population, the results were even more pronounced. With overall survival, not reached in avelumab and best supportive care arm, and 17 months in the best supportive care arm.

The subgroup analysis favored avelumab across the board. The key thing here that I would highlight is that patients with visceral metastasis seem to benefit if they had PD-L1 positive, and otherwise the benefit was not as pronounced as other categories.

The progression-free survival was also significantly better with avelumab and best supportive care. In the overall population, it was 3.7 months in avelumab arm, versus two months in best supportive care arm. And it was more pronounced in the PD-L1 positive arm, being 5.7 months with avelumab, versus 2.1 months in best supportive care arm. And based on these positive results in June, the FDA approved avelumab for maintenance treatment of patients with locally advanced or metastatic urothelial cancer, that have not progressed with first-line platinum-containing chemotherapy.

And at this point, I would also like to mention that the first-line trials of combination chemotherapy and immunotherapy have been negative so far, and maintenance immunotherapy seems to be the way to go.

Last year, I touched upon the key study that was presented in the BCG-unresponsive non-muscle invasive bladder cancer. This was the SWOG S1605 study presented by Dr. Peter Black. This was a single-arm Phase II trial with BCG-unresponsive, high risk, non-muscle-invasive bladder cancer patients. The arm with carcinoma in situ, plus-minus Ta/T1 data was presented. The primary endpoint was pathological complete response rate at six months in CIS patients. It was determined by mandatory biopsy.

Of note, the other trials in this space did not have a mandatory biopsy and the FDA mandated a futility analysis after 25 eligible CIS patients reached the six-month endpoint. And seven patients were required to have a complete response, however, it was only seen in five patients. So it did not meet the primary endpoint.

This is the study's schema, it did not meet the primary piece specified endpoint, but interestingly, the three month CIS patient complete response rate was 42%. The safety was reasonably in line with what we see, however, there was a treatment-related death on this study.

Comparing this across other agents. We know that based on the KEYNOTE-057, pembrolizumab is approved in this setting, and the treatment complete response rate with that is 41%. And this shows comparable results. It will remain to be seen if this will become an approved option.

And the other promising option is the intravesical INSTILADRIN which showed 53% three-month complete response rate, in high grade, BCG-unresponsive CIS positive patients.

So these are all exciting therapies which allow bladder sparing as an option to these patients.

Ashish Kamat: That was great, Shilpa, thank you so much for doing this. I have a couple of questions for you. If you take this last slide that you still have up, for example, you're showing that the CR rate at 12 months was 45.5%, but that's 45.5% off the 53% at three months. Correct? So that would actually be similar then to about 24, 25%. Correct?

Shilpa Gupta: Yes. That's correct. Yes.

Ashish Kamat: Because looking at this, it looks like INSTILADRIN, which again, full disclosure, was developed at my place, is almost twice as better as the immunotherapies, but I just want to caution our audience that that's-

Shilpa Gupta: Yes, that's true Ashish, I should have clarified that on this.

Ashish Kamat: 45% of 53%. Great. And then, in moving back to the other studies that you mentioned. What do you suppose the biologic rationale would be for IMvigor010 being a negative study, and JAVELIN-100, even though it's obviously different patient populations, they're in the spectrum of the disease. Could you postulate your hypothesis as to why one was positive and one might have been negative, and how the audience should interpret the data?

Shilpa Gupta: Yeah, that's an interesting question, Ashish. I think, from what we see, it appears like some tumor burden may be required to see a response from immunotherapy in the adjuvant setting, given there is no visible or active disease. Perhaps that's what failed to get a response. While in the maintenance setting, these patients started out with metastatic disease, and most of them had some residual disease at the time of enrollment. So I'm thinking maybe we do need some tumor burden for the immunotherapy to work in bladder cancer.

Ashish Kamat: And then based on all the data that's been presented, in 2020 to date, it's been a crazy year, but a lot of data coming out. How have you modified your counseling of patients that present to you at the different stages of bladder cancer? What does your discussion with them look like now?

Shilpa Gupta: Yeah. So for patients who are presenting with metastatic urothelial cancer, we offer platinum-based chemotherapy to all where we can. In the rare circumstance where they cannot get carboplatin, we treat them with single-agent immunotherapy, or if they have high PD-L1 expression in their tumors, and they are cisplatin-ineligible, then they also meet the criteria. But other than that, platinum-based chemotherapy is our treatment of choice. And if they do not progress after four to six cycles, six cycles is preferable, if they do not progress, then we talk to them about considering avelumab maintenance, and have an in depth discussion about the pros and cons.

Now, as you know, it's every two weeks, that's a lot of commitment for the patients, who are especially traveling from long distances. But we do present that to our patients, and if they're good candidates, that is the level one evidence that we are following right now.

Ashish Kamat: Would you caution against using any other IO agent in the place of avelumab to people? Or do you think that they're interchangeable enough that practices that have more familiarity with one of the other agents could use that as maintenance therapy?

Shilpa Gupta: Yeah, that's a great question, Ashish. We also participated in the pembrolizumab Hoosier study led by Dr. Matt Galsky, which also utilized the switch maintenance approach. In fact, it was presented last year at ASCO. It showed progression-free survival benefit with pembrolizumab compared to placebo. It was a Phase II trial, and it's not FDA approved in this setting. But I think in the community, I foresee that it may be interchangeable because pembrolizumab is given every six weeks and it's more convenient. But if he were to follow level one evidence, I think the label is only for avelumab, and that is what we should stick to when possible.

Ashish Kamat: Yeah. That's a good point. If you follow [inaudible] evidence, you obviously have to stick with the data that was presented in Tom Powles' study.

A quick question about the dosing schedule. So you mentioned obviously pembro has moved to 400 every six weeks. Is that a dose that you're now using across all patients or in selected patients? Have you gone to six weeks for everybody for pembro?

Shilpa Gupta: Yes. I have gone to six weeks, especially with the COVID logistics. But we are making sure we check in with them virtually at three weeks to make sure they don't have any subtle side effects, which need to be worked up. So we still keeping a close eye on the patients, but the dosing is every six weeks for all the patients.

Ashish Kamat: And since many of the studies were actually done before the six-week schedule was established. Do you have any concerns or any words of caution for people that are extrapolating results from one study to a different dosing schedule?

Shilpa Gupta: No, I think, you're right. All the studies that use the two, three weeks schedule, and we just have to go by what basis was for changing the dosing. As we have also enacted with nivolumab, all original studies were every two weeks, but we are using the flat dose every four weeks. So I think going by the mechanism and the pharmacokinetic dose distribution data, it's safe to say that it's probably okay to use the six weeks study.

Ashish Kamat: Okay.

Shilpa Gupta: Six-week dosing. I'm sorry.

Ashish Kamat: Six-week dosing. Correct. Correct. Correct. Now, this has been great, a great discussion and lots more I could ask you, but in the interest of time, let me ask you one last question. Let me have you put on your predictive hat and maybe you could tell us what you predict will be the breaking news when it comes to bladder cancer therapies at ASCO 2021. What are you most excited about?

Shilpa Gupta: I think it would be great to see some neoadjuvant immunotherapy trials readout, or at least in trend data available so we can start using it. You know, right now that is a setting where we know immunotherapy works, but there is no substantially randomized trial data. I think that would be what I'd be most excited about.

Ashish Kamat: Thank you so much, Shilpa. It's always a pleasure chatting with you, and thanks for taking the time and sharing your thoughts and the updates with our audience. Stay safe, stay well, and hopefully, we'll actually see each other in person sometime soon.

Shilpa Gupta: Thank you, Ashish. I appreciate the opportunity. Have a great day. Stay safe.