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Kriti Mittal: Hello, and welcome to this online session on updates in non-muscle invasive bladder cancer. My name is Kriti Mittal. I'm an assistant professor and GU medical oncologist at the University of Massachusetts.

Guru Sonpavde: And I'm Dr. Guru Sonpavde. I'm the GU oncology and phase one director at the AdventHealth Cancer Institute, and I'm also a professor of medicine at the University of Central Florida, in Orlando, Florida. Kriti, there have been a number of recent advances in non-muscle invasive bladder cancer. Do you want to start by telling us about intravenous immune checkpoint inhibitors?

Kriti Mittal: Sure. In January 2020, the FDA approved pembrolizumab for patients with high-risk BCG-unresponsive non-muscle invasive bladder cancer. This approval was based on the KEYNOTE-057 study, specifically from cohort A, which enrolled patients with carcinoma in situ, with or without papillary tumors. These were patients who were either not eligible for or declined radical cystectomy. Patients were treated with pembrolizumab every three weeks, until either progression, toxicity, or up to two years. In this study, the primary endpoint was clinical complete response at three months, which was seen in 41% of patients, but more meaningfully, about 20% of patients remained in complete response at the 12-month mark.

We also recently saw data from cohort B of the KEYNOTE-057 study. This was for patients who did not have CIS. They had papillary tumors without CIS. And from this cohort, we saw that the 12-month CR rate was about 43%. The other agent that has been evaluated in this setting is atezolizumab. The SWOG-1605 study in patients with CIS, who, in a single-arm study, received intravenous atezolizumab for up to a year. In this study, 27% of patients were in complete response at six months, and 13% of patients at the 18-month mark. Unfortunately, this study did not meet its pre-specified threshold. With this background and case, Dr. Sonpavde, what are some of the trials in progress that you're excited about?


Guru Sonpavde: Immune checkpoint inhibitors continue to undergo investigation, as you know based on these data. Intravenous pembrolizumab was approved in BCG-unresponsive non-muscle invasive bladder cancer. But the one-year CR rate, like you said, was approximately 20%. Can we do better? There are a couple of phase III trials going on, that are looking at pembrolizumab, and the other one looking at durvalumab. The pembrolizumab trial is the KEYNOTE-676 phase III randomized trial. This is being done in patients who are post-BCG, with persistent high-grade disease, or CIS, could be and/or CIS, actually, which is comparing BCG versus BCG plus pembrolizumab. And the second study is called the POTOMAC study. This is a study in BCG-naive patients, which is being looked at in a three-arm trial, with BCG alone, versus durvalumab plus BCG, but the durvalumab plus BCG has two arms. One arm gets BCG induction only, and the other arm gets induction plus maintenance to try and tease out whether the maintenance is necessary or not.

And then, there is an interesting third cohort in the KEYNOTE-057 study, that's a non-randomized study that you previously described, which actually led to the approval of pembrolizumab in the CIS cohort. Now, this has a third cohort, which is looking at the CIS group of patients, and it's combining pembrolizumab plus either a TIGIT inhibitor, in a co-formulated compound, or a LAG-3 inhibitor, which is... Again, both of these are different immune checkpoint inhibitors, so this is an interesting next step for immune checkpoint inhibition. And then, there is another study I wanted to highlight, which is a study called the BLADDER-ADAPT study, which is a randomized phase II study, which is looking at BCG-unresponsive patients, where the investigators are looking at durvalumab combined with BCG, or durvalumab combined with radiation, or durvalumab alone. This is interesting because there are some interesting data to suggest that radiation therapy might have a role, combined with chemotherapy, so would it have a role combined with immune checkpoint inhibition? That is something of interest. Kriti, based on these data, do you have any thoughts?


Kriti Mittal: Yeah. I think these are very exciting times, both for the treatment of non-muscle invasive bladder cancer, as well as advanced urothelial carcinoma. At ESMO, recently, we saw some paradigm-shifting presentations from EV-302 and CheckMate 901. For patients enrolled in those trials, these were patients either with de novo metastatic disease or patients who had progressed beyond 12 months of neoadjuvant therapy. As we start to think about increased utilization of immunotherapy in the non-muscle invasive disease case, either as monotherapy or in combination with other treatments, how do you think prior exposure to IO in the non-muscle invasive disease space might impact the treatment of advanced disease? Because one would presume these patients may have either IO resistance, or at least to monotherapy, and potentially more aggressive disease biology.

Guru Sonpavde: Yes, this is an interesting question, Kriti, and this needs to be further teased out in more investigation of this issue, essentially, given that immune checkpoint inhibitors might be used more in the earlier disease settings, not only non-muscle invasive bladder cancer but also the emerging data, of course, in the neoadjuvant setting of muscle invasive disease, and of course, adjuvant therapy, where nivolumab is already approved for the adjuvant therapy of muscle invasive bladder cancer. Really, the data here are not clear. Should we use a three-month treatment-free interval, from previous PD-1 inhibition, to reinstitute, let's say, EV pembro, or gem/cis nivo, if they both come into the first line metastatic disease space? It's not clear what the right cutoff is. There are some emerging data in the lung literature to suggest that maybe six months is a good idea. I think that these data need to be further hashed out with more accumulation of experience.

Kriti Mittal: Certainly. This is indeed a data-free zone. What is clear, however, is that science is moving forward quite rapidly. These are certainly exciting times for GU medical oncologists. We saw some data from novel agents presented at ESMO. Would you like to discuss some of those data, please?

Guru Sonpavde: Yes. Thank you, Kriti. And even before the novel data at ESMO, I do want to highlight that intravesical nadofaragene firadenovec, which is a replication-deficient recombinant adenovirus that delivers the interferon Alpha-2B gene, is actually approved for BCG-unresponsive non-muscle invasive bladder cancer, where it induced complete remissions in, approximately, 53% of patients. And approximately, half of them were durable to one year, so that's approximately a 25% one-year CR rate. The USFDA actually approved this agent back in December 2022. And this agent is given intravesically only once every three months, so it's a rather convenient agent without any significant event. This agent is actually out there already. Now, coming to the new agents, we have some recent data at both ESMO and SUO. At SUO, just earlier in December, and late November, there was data presented for CG0070. It's got a long name that is a little bit tough to pronounce, cretostimogene grenadenorepvec.

This is actually a cancer-selective oncolytic adenovirus, which has the insertion of the E2F promoter, along with GMCSF. And it preferentially replicates in these tumor cells, which are RB deficient. That's where it replicates. This oncolytic virus had interesting data earlier in AUA this year, where monotherapy, in the phase II BOND trial, showed a CR rate of 65%, and a durable CR of 28% at one year. There was a second study called the CORE1 trial, also at AUA, which showed that the CG0070 plus intravenous pembrolizumab actually showed a very high complete remission rate of 85%, at any time, with a 12-month CR rate of 68%. Now, what was shown at SUO was actually the phase III BOND-003 trial. This is somewhat earlier analysis; the trial is not complete. This was 66 patients. And this was BCG-unresponsive patients with CIS.

This was very heavily pretreated BCG-unresponsive patients. At the end of the day, these data looked very interesting for CG0070 in BCG-unresponsive patients, with a CR at any time of around 78%, and with CR at six months of approximately 64%. Again, we don't have 12-month CR rates from this phase III trial, but CG0070 clearly looks like an interesting agent that we need to keep an eye on based on these data. And the toxicities were highly manageable. There were no grade three toxicities. That gives these agents a high therapeutic index, given the intravesical administration. And then, there is an agent called N-803, which is an IL-15 superagonist. This has been given intravesically in combination with BCG, in BCG-unresponsive patients. This is not monotherapy, this is combined with BCG, in post-BCG patients, BCG-unresponsive patients.

And this also has looked very promising, with a one-year CR rate of, approximately, 45%. This agent awaits regulatory review at the USFDA, and could, potentially, also be available. Now, getting quickly to chemotherapeutic agents, as you know, there is interesting data out there for intravesical docetaxel plus gemcitabine. And just to quickly highlight this before I go onto the novel TAR-200 agent, which I will discuss in a second, there is a first-line trial, but done by the cooperative group, which is going to look at first-line BCG, versus the combination of docetaxel plus gemcitabine. This will, potentially, alleviate some of the problems we are having with intermittent BCG shortages. Now, going to the new agents, TAR-200 is an interesting way of delivering intravesical gemcitabine. This is a pretzel-shaped device that is inserted intravesically into the bladder by the urologist, every three weeks.

And the way it's given is, every three weeks insertion for, what, six months, and then you taper it to an every three month maintenance schedule. And this regimen looked very interesting in the SunRISe-1 trial, which was presented preliminarily at AUA earlier this year, which had many amps. But essentially, they showed the comparison of TAR-200 and cetrelimab. Cetrelimab is an intravenously given PD-1 inhibitor. And the TAR-200, of course, is an intravesically delivered device, every three weeks, that delivers slow release gemcitabine. The CR rate was very interesting, around 73% for TAR-200, and around 38% for the cetrelimab, which is what, historically, has been seen with intravenous pembrolizumab. Now, at ESMO, there was an update of the SunRISe-1 trial, where the study was updated with 80 patients this time, again, BCG-unresponsive carcinoma in situ.

And interestingly, the response rate held up what was shown earlier in AUA. Approximately, 76.7% CR rate in patients with high-risk non-muscle invisible bladder cancer, with carcinoma in situ. Many of these patients had durable responses. We still need to await their long-term data, but it's looking interesting for long-term outcomes. Also, the median duration of response has not been reached. The toxicity profile was highly manageable. Of course, the gemcitabine is only delivered intravenously. With this, there is no systemic delivery. I did want to mention the SunRISe-3 trial, which is a trial looking at first-line TAR-200, with or without cetrelimab, intravenous PD-1 inhibition in BCG-naive patients. Really, it's a three-arm phase III trial, in BCG-naive patients, comparing standard of care BCG, versus the TAR-200 alone, or TAR-200 plus intravenous cetrelimab, which will, hopefully, give us this agent in the first line disease space of higher risk non-muscle invasive bladder cancer.

Now, last quick word on intravesical enfortumab vedotin. There is a small dataset out there, that has given intravesical enfortumab vedotin in BCG-unresponsive non-muscle invasive bladder cancer. And the data looked very interesting. There was a complete remission seen in three out of five evaluable patients. The future of this agent would warrant further investigation of this regimen. We need to wait and see what happens with further development of this agent. Coming to a new class of agents, targeted therapy, erdafitinib for FGFR inhibition, Kriti, so we know that erdafitinib is already approved for metastatic disease, with tumors harboring FGFR3, FGFR2, activating mutations or fusions. Do you think this agent may have a role in non-muscle invasive bladder cancer, given the prevalence of these alterations in, especially, low grade non-muscle invasive bladder cancer?

Kriti Mittal: Yes, indeed. Erdafitinib heralded the era of precision oncology in patients with urothelial cancer. And we did see some interesting data in a randomized trial in high-risk non-muscle invasive bladder cancer patients with recurrent BCG-treated disease with eligible FGFR mutations. This was the THOR-2 study, in cohort one, in which patients were randomized in a two-to-one manner to receive either oral erdafitinib, six milligram dose, versus investigator's choice of intravesical chemotherapy with gemcitabine, intravesically, or intravesical mitomycin. The primary endpoint of this study was recurrence-free survival. The median RFS was not reached for erdafitinib, and it was 11.6 months with intravesical chemotherapy. And the estimated hazard ratio was 0.28, favoring erdafitinib. The toxicity profile was also consistent with previously published data, as per the authors. I think this was a very interesting study. Now, in both targeted therapy, I do believe there was another study presented, looking at the role of intravesical FGFR inhibition. Would you like to discuss those data, Dr. Sonpavde?

Guru Sonpavde: Yes. Thanks, Kriti. Essentially, oral erdafitinib, of course, in these oral trials of erdafitinib in non-muscle invasive bladder cancer, the investigators used a lower dose than used in metastatic disease. They used six milligrams daily because of the toxicities that we know are associated with this drug: the dry eyes, dry mouth, dermatitis, diarrhea, the eye toxicities, the retinal toxicities. Six milligrams was used. Now, however, can we use this drug intravesically, with the slow-release device that was used in the TAR-200 regimen, using the pretzel-shaped device? Really, the company has looked at the same pretzel-shaped device to deliver erdafitinib intravesically. This is TAR-210. And in fact, there were data presented at ESMO this year, in a couple of different cohorts. These were small cohorts. The first cohort was of high-risk non-muscle invasive bladder cancer, Ta/T1, no carcinoma in situ.

And remember, it's the lower grade cancers that have a higher proportion of these alterations. And then, there was a second cohort of intermediate risk non-muscle invasive bladder cancer. Again, this agent, TAR-210, is intravesically inserted once every three months. It's not every three weeks. So, kind of a slow, steady delivery over three months, that this device can deliver erdafitinib. In the high-risk non-muscle invasive bladder cancer cohort one, there were 16 patients. And actually, 11 patients had a response. And nine were recurrence-free, so an 82% recurrence-free rate in this cohort of the high-risk non-muscle invasive bladder cancer, no carcinoma in situ. In the second cohort, which was intermediate risk non-muscle invasive bladder cancer, they had 27 patients.

And actually, 15 patients had a response. And there was a complete response in 87% of patients. High activity shown with this intravesical, slow-release delivery of erdafitinib. Really, given all of this, and also the high tolerability of the intravesical agents, I think that the future for non-muscle invasive bladder cancer, with all of these new agents, the N-803, the TAR-200, the TAR-210, the CG0070, all of these new agents on top, of course, of intravenous pembrolizumab, and the intravesical nadofaragene, interferon Alpha-2B gene delivery, I think that we are making lots of huge advances. And we need to continue to accrue to trials to make further advances. With that, I thank you, and I will ask Kriti to say a few words.

Kriti Mittal: Thank you for those exciting updates. We'd like to thank BCAN and Pfizer for supporting this symposium through the grant, as well as UroToday, for hosting our informational session. Dr. Sonpavde, thank you very much for joining me today. And we look forward to many more sessions in the future. Thank you.

Guru Sonpavde: Thank you.