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Shilpa Gupta: Hello, everyone. I'm Dr. Shilpa Gupta from the Cleveland Clinic in Cleveland, Ohio, and I'm delighted to be joined by my good friend and colleague, Dr. Petros Grivas from the Fred Hutch Cancer Center in Seattle, Washington. Hi, Petros, how are you?

Petros Grivas: Hello, Shilpa. Thank you so much for having me. Always a great pleasure to see you and discuss with you. So much going on in the field of GU cancers and bladder cancer specifically, so always great to interact and exchange ideas.

Shilpa Gupta: And Petros, today we want to discuss this wonderful session that you led, which was called Lessons Learned from Other Cancers and How We Could Apply Them to Urothelial Cancer. And I really loved how you had a great theme going there about the clinical lessons learned from kidney cancer, where Dr. Brian Rini spoke from the experience of immunotherapy, and then from melanoma, your colleague Dr. Shailender Bhatia spoke about their experiences about immunotherapy.

And then we also had a nice segue into the preclinical and the translational aspects of immunotherapy and how we can utilize it in urothelial cancer. So I would love to get your thoughts, Petros. In the kidney world, it's very clear that IO after IO is not recommended. Now we have two negative trials—TiNivo-2 and the CONTACT-03—which have shown that really there's no benefit of IO after IO.

And we heard from Dr. Bhatia, in the melanoma world, they are totally OK with rechallenging the same IO or a different IO. And he presented such beautiful cases. So I would love to ask you what you think is the thing that we can see in bladder? We don't have any such studies going on, and I know you're leading some efforts through the cooperative group. So would you love to share some thoughts?

Petros Grivas: Absolutely, Shilpa. Thank you so much, first of all, for the question and also for being part of this wonderful session at the Bladder Cancer Advocacy Network Think Tank in August this year. 2024 was a fantastic meeting. And to your point, we had a packed room in that particular breakout session named Lessons Learned from Other Tumor Types and How We Can Think About Immunotherapy in Particular for Patients with Bladder Cancer/Urothelial Carcinoma.

And thank you for doing a great job in that session yourself. You summarized so well the landscape of immunotherapy right now across the stages of disease—localized disease, BCG-unresponsive carcinoma in situ, role of adjuvant immunotherapy, as well as role in metastatic disease with checkpoint inhibitors.

And as you said, there is a lot of interest in the field and a lot of discussions about ongoing trials, combinations between checkpoint inhibitors and other checkpoint inhibitors, and, of course, with antibody-drug conjugates, and, of course, with chemotherapy.

So we tried to, as you said, learn from other tumor types. And we had, of course, Dr. Shailender Bhatia from the University of Arizona Cancer Center, one of my colleagues here who is an expert in cutaneous malignancies. And of course, we had Dr. Brian Rini, who is at Vanderbilt and a known expert in the field of kidney cancer. And they shared with us lessons learned from those tumor types and how this can apply to bladder cancer.

And I think that there was definitely a lot of interest, as you mentioned, in metastatic RCC (Renal Cell Carcinoma). We have two clinical trials, phase III CONTACT-03 and TiNivo-2, that both showed that there is no benefit of rechallenging with a checkpoint inhibitor in patients with metastatic RCC who have progression on a prior checkpoint inhibitor.

And there were some differences in the design in the two trials. For example, one of them allowed that the most immediate prior therapy could not be immunotherapy, and so there's some immunotherapy-free interval, let's say. And of course, there are different drugs—atezolizumab/cabozantinib in CONTACT-03, tivozanib and nivolumab in TiNivo-2. So there are differences.

And obviously there are some discussions about the dose of tivozanib used in the TiNivo-2 trial. With all those nuances in mind, the message was that if someone has progression on a checkpoint inhibitor while on treatment, there is no benefit of rechallenging those patients.

Of course, this is different, as you and I discussed, if someone, for example, gets adjuvant nivolumab for bladder cancer after radical cystectomy or they got pembro for BCG-unresponsive CIS, and they complete treatment, and they have progression later. That's a different scenario. And the question is, of course, how later is enough?

What is your immunotherapy treatment-free interval between completion of checkpoint inhibition and recurrence to consider doing a checkpoint inhibition strategy, for example, pembrolizumab with enfortumab in metastatic urothelial carcinoma? And I don't think we know for sure. I know we asked in the room, and people may have different thoughts about the optimal treatment-free interval—three months, six months, nine months, 12 months. Nobody really knows.

And you and I are part of the SITC, Society for Immunotherapy of Cancer, guidelines, and there are some guidance there about that question, but it's hard to know how this applies specifically to bladder cancer. So I think overall, the take-home message from the kidney cancer arena is, if you have progression on a checkpoint inhibitor, no benefit of rechallenge. We do not know whether that's true or not in metastatic urothelial carcinoma.

On the cutaneous malignancies world, Dr. Bhatia took a different approach. And he is an immunotherapy expert, to your point, Shilpa. He is dedicated to research immunotherapy, is very bright. And his approach was to find the right partner of immunotherapy and keep trying the immunotherapy approach, but switching maybe the partner and try to desensitize the cancer to the immunotherapy approach.

I think the challenge we have is different tumor types have different biology, different tumor microenvironment, different responsiveness, different potential biomarkers. So, in my mind, it's a little bit hard to extrapolate from one tumor type to the other. And to conclude my thought, Shilpa, tell me what you think, it will be nice to have a dedicated clinical trial in metastatic urothelial carcinoma asking this question.

And on that note, we have been working on a clinical trial with the cooperative groups, the ECOG-ACRIN EA8231 with Dr. Monica Joshi from Penn State. And we're trying to do the IO rechallenge question. That trial had a design of sacituzumab govitecan plus pembro, based on the cohort 3 of the TROPHY trial, versus sacituzumab govitecan alone.

And right now, we're of course in discussions to see how we evolve this because of the announcement, press release by the company Gilead, that they're going to withdraw the indication of sacituzumab govitecan in urothelial carcinoma. So I think the question is still open, and I would love to hear your thoughts. But I think we ideally need a dedicated trial.

We have a little bit of retrospective data in a few datasets. We published this recently. There's maybe a small proportion of patients who may benefit from a rechallenge, but for sure, for now, we do not know. And personally, I'm not using an IO monotherapy rechallenge if a patient had progression before.

In other words, if someone has progression on metastatic disease, let's say on pembro, I'm not using another single-agent checkpoint inhibitor. But I'm open to doing trials with combinations. What do you think?

Shilpa Gupta: Yeah, I think totally. In fact, you nailed it on the head, as usual. I think even when we were designing the MAIN-CAV trial, which you're a part of, which was a maintenance avelumab and cabozantinib as maintenance strategy post-platinum. Initially, we had excluded all prior IO therapies. But then we had adjuvant nivolumab approval. We also had the use of pembrolizumab in BCG-refractory disease.

So we had to amend the protocol and say, as long as 12 months had passed, which, again, like you said, it's arbitrary. It's not based on real science. But I think that's how historically we have designed the trials in bladder cancer, where prior platinum use, even for the immunotherapy trials, was considered 12 months.

So I think you're right. We need a dedicated trial. And more importantly, we want to see how is it different. Let's say, if somebody got immunotherapy in non-muscle-invasive disease and then progressed, and now has metastatic disease versus somebody had adjuvant immunotherapy in MIBC and then progressed, and what would you do?

And coming from your elegant discussion at ESMO for the NIAGARA study, if that were to become the new standard in localized disease durvalumab and chemo followed by durvalumab, and if those patients are recurring later, then are we really going to give them pembrolizumab with EV?

So I think all these questions are very important to address, and we should keep working with the cooperative groups to discuss. And I think the other thing that I'd taken away from this session was all the translational work that is going on, especially in the BCG-unresponsive disease. And there's so many agents. Where do we use systemic therapy?

I would love to hear your thoughts. Now that we have so many novel intravesical agents, would you really spare the use of pembrolizumab? Because, in any case, it has modest activity in NMIBC. And why give it? What do you think?

Petros Grivas: Great question, Shilpa. As always, you have very useful insights. I think in the context of BCG-unresponsive, non-muscle-invasive bladder cancer, we now have more options, to your point. And back in the day, it was only intravesical valrubicin, based on, I would say, modest benefit back in the day, as a bladder-sparing option for those patients who are not fit or declined radical cystectomy for BCG-unresponsive NMIBC.

And as you said, a few years ago, intravenous systemic pembrolizumab became FDA-approved based on the clinical complete response and clinical response rate in that context of the KEYNOTE-057 trial. That was published a few years ago, and this medication, intravenous pembro, has now been approved in this disease for the last few years.

However, the utilization seems to be low or lower than expected. And the question is why? And I think to your point, maybe because of the availability of other intravesical therapies, there has been utilization, at least speaking to colleagues in the urology setting, of intravesical chemotherapy. For example, intravesical docetaxel, gemcitabine has been utilized based on very interesting and promising retrospective data.

And also we have two recent FDA approvals in BCG-unresponsive NMIBC. One is nadofaragene firadenovec, this adenovirus that carries the interferon gene. And also we have the most recent approval of the drug that used to be called N803, an interleukin-15 superagonist in combination with BCG. And this also got FDA-approval recently and I know both those agents are now available.

And of course, manufacturing needs to help with the availability of the drug. But also the cost of those drugs may be an issue, and the real availability in different community and academic centers is evolving. So I think because of the availability of intravesical agents that may have less systemic toxicity in a disease which is early-stage, and maybe the tolerance of systemic toxicity is less in that early-stage disease, I think the availability of intravesical options may be explaining, at least partially, why the intravenous pembro is not used as much as we had expected before.

Shilpa Gupta: Thank you, Petros. I really appreciate that. And I think that's a wrap for this. This was really an exciting session and I hope you will contribute again at next year's Beacon Meeting, because we'll have so many new antibody-drug conjugates, we can actually move beyond immunotherapy and move from there. So thank you.

Petros Grivas: Thank you so much, Shilpa. And I just want to say, overall, it's great to have options for our patients. Intravenous pembro, of course, is still an option for BCG-unresponsive NMIBC. And I was really pleased to see this interest in the session that you participated in and contributed to, that was co-chaired by Dr. Neela Mukherjee. She's at UT San Antonio, and I think this was a great session.

And we appreciate Bladder Cancer Advocacy Network for their support and the advocacy that the patients and the advocates provide. I think it helps us—you and me and others—design patient-centered trials. And as you said very correctly, we all try to move the field forward. Thank you.

Shilpa Gupta: Absolutely. Thank you, Petros. Have a great day.

Petros Grivas: Thank you.