NIAGARA Study Insights: Durvalumab and Chemotherapy in Bladder Cancer Treatment | Dr. Petros Grivas

In this episode of OncoDaily, Dr. Petros Grivas joins host Chandler Park to discuss the groundbreaking NIAGARA study presented at ESMO 2024. This global, multicenter trial investigated the perioperative use of dr combined with chemotherapy for localized muscle-invasive bladder cancer, enrolling over 1,000 patients. Dr. Grivas highlights the study’s promising results in event-free and overall survival, while also addressing critical questions about the necessity of both neoadjuvant and adjuvant treatments.

Chandler Park MD, FACP is an haematologist oncologist, medical journalist, and clinical researcher. He is the Advisory Dean and Clinical Professor at University of Louisville School of Medicine. He is the Kentucky Physician Representative of the ASCO State Executive Council. He is also the Medical Oncology Board Examiner at  American Board of Internal Medicine.

Petros Grivas, a board-certified medical oncologist, serves as Clinical Director of the Genitourinary Cancers Program at the University of Washington and Seattle Cancer Care Alliance. He’s an Associate Professor at the Dept. of Medicine and Associate Member at Fred Hutchinson Cancer Research Center since January 2018. With extensive training and experience, he’s led clinical trials, contributing to FDA approvals for bladder/urothelial cancer treatments. 

Chandler Park: You know, I tell you, Petros, you know, I know that Niagara’s got the big headline, but there were so many interesting bladder studies at ESMO 24. I mean, if you think about it, like, you know, like we had the CTDNA with the Tombola study. I mean, the Volga study.

I mean, you had in the metastatic setting, we had our colleague, Dr. Golski, talk about first-line metastatic for, you know, for HER2 study. I mean, there’s so much, but like, we want to kind of focus on the Niagara study. And I tell you, all the friends and colleagues that we talked to, superb, outstanding job at the discussing, very well balanced.

I felt like you put in a lot of information about not just the point that we got to the Niagara study, but also future studies, things that we can kind of look forward to because it answered questions. Yes, we had that DFS and overall survival, but it also raises more questions. So what are your thoughts about the Niagara study, Petros?

Petros Grivas: Thank you so much, Chandler, for the kind words. You know, I always want to receive feedback and always looking forward to do things better in the future. So thank you for the kind words.

I think Niagara trial was one of the biggest highlights at the ESMO 2024 Congress. What a great effort, right? More than a thousand patients accrued in a localized massive laser bladder cancer study.

Kudos to Professor Powles and all the study team. And of course, to the patients and families, right, and caregivers who contributed to that study. You know, we traditionally had challenge, right, accruing in these bladder cancer trials.

We know back in the day challenges in accruing in adjuvant trials, despite all the best efforts. So definitely an important milestone showing the feasibility of accruing in more than a thousand patient trial when we work together in a multi-center, you know, global international manner. And I want to underline this global international approach.

That’s very important. I think everything we do, you know, in different organizations, societies, it’s great to see this global perspective and global collaboration. But going back to the study, I think this is a very, very interesting approach with a perioperative strategy.

You have a neoadjuvant component, you have durvalumab added to the standard of care gemcerapine cisplatin. So GEMCIS plus durvalumab, there were four doses of durva preoperative, neoadjuvantly, and then up to eight monthly doses adjuvantly. So it was kind of a sandwich approach, let’s say.

And the control arm was GEMCIS four cycles neoadjuvant only with no adjuvant component. So that trial accrued, as I mentioned, over many years. It finished accrual in July 2021.

That was very, I would say, close. But before, the adjuvant nevolumab got approval by FDA in August 2021 and by EMI in April 2022. And I make this point because of the timing.

Patients who are in the control arm, like the neoadjuvant GEMCIS, many of them, probably most of them, did not have access to adjuvant nevolumab. And of course, that may impact the performance of the control group. And I made this point to the discussion.

And of course, the other point is that, you know, subsequent therapies, right, what people have access to in metastatic disease may also impact overall survival. So we have to keep that in mind as we interpret and dissect the data. Having said that, this study was well balanced in terms of the characteristics in the two groups.

I want to give congratulations to the investigators for including divergent histologists. About 15, 1, 5 percent of patients had histology subtype. Of course, the primary histology had to be urothelial.

And about 5 percent, small proportion, had clinically N1 stage. And the interesting thing was that there was about 20 percent of patients or so that had creatinine clearance below 60. It was, they went down to 40 mL per minute as a cutoff.

And they used split-dose cisplatin for those patients who had GFR below 60 mL per minute. So we saw some patients who traditionally were deemed ineligible for cisplatin that were included. The pathologic complete response rate, 37 percent with GEMCIS DURVA, 27 percent with GEMCIS alone, a little bit lower than expected.

And we can have some hypothesis why this happened. You know, it’s hand-waving a little bit. But one potential approach is that in the denominator of that proportion, there were patients included who did not undergo radical cystectomy because they chose to.

About 6 percent, single digit, 6 percent of patients in both arms or so did not undergo cystectomy because of their choice. And these were included in the denominator but not in the denominator. So this can lower a little bit the proportion.
The other natural question is split-dose cisplatin, does it perform the same with the classical dosing scheme intensity? We have some retrospective data about that, but we don’t have, you know, level one prospect evidence. I think it’s a reasonable approach.

We do it in the clinic with borderline GFR. I have done it. We have a prospective data published with Dr. Koskin and others. But that’s another question there that may or not have impacted pathologic CR8. And of course, you know, pathology review, you know, plays a role. They had central pathology review there.

And of course, you know, if you look at the actual statistical analysis and statistical plan, initially they had 59 patients who were not included in the initial path CR analysis. And those 59 patients were included in a subsequent analysis that was done and ended up having this delta of 10 percent in path CR, 27 to 37 percent path CR8 favoring the DURVA arm. And the question I had is, is that 10 percent delta in path CR adequate enough to explain the significance in EFS, event-free survival, and OS, overall survival?

In my mind, this seems unlikely, which, in other words, I think the adjuvant component is adding value there. And we have seen data from Ambassador, Dr. Apollo, so the data at ESMO, New Zealand Medicine paper, and the TECMED 274 that we know that adjuvant I.O., adjuvant anti-PD1, prolongs the history survival. So, I think overall, putting everything together, the take-home message for me is the addition of DURVALUMAB to GEMCIS did not compromise the ability of patients to get curative intent radical surgery.

The toxicity was very similar in the two arms. So, that’s reassuring. Of course, we have to think about immune-related adverse events, educate our patients, of course.

And the significant difference in event-free survival has a ratio of 0.68, and overall survival has a ratio of 0.75. Those endpoints make Niagara the only, I would say, localized MIBC trial evaluating checkpoint inhibitor with OS benefit. So, I think it’s practice-changing, despite the caveats and limitations we discussed before. It’s a new paradigm, I would say, and changes everything, right, because we use checkpoint inhibitor up front in the neoadjuvant setting.
There are many questions that remain, right. For example, do we need both neoadjuvant and adjuvant component? Do we need either?

I don’t think we know the answer to this question because of the Niagara trial design. For now, I would say that I would use both neoadjuvant and adjuvant until we know better. Of course, we’re going to over-treat patients, and, you know, it’s a question of how do you select out those who do not or do need, you know, adjuvant treatment.
But these are questions for the future. And, of course, what do you do subsequently if a patient has a subsequent progression? Is there a role for checkpoint inhibitor retaliants?

What about bladder preservation? And, of course, the role of ctDNA. Many unanswered questions, and hopefully the future trials will help us answer those.

Chandler Park: Absolutely. You know, and I think, you know, just I think that was a wonderful discussion of what you just mentioned. Like, for us, here in September 2024, standard of care.

But it does raise some questions, like from the patient’s journey, right? So, we have a brand new patient, T2, T3. We’re talking about it on our tumor board.

There’s some patients, in fact, a lot of my patients, Petros, I use Dostin’s Impact. I mean, based on the VSEPR, I do four cycles. You get done in 56 days.

You do surgery in five or six weeks later. And, you know, as long as they don’t have cirrhosis, because you have to think about the methotrexate, always check the echo. But I do consider Dostin’s Impact.
So that, you know, should we still consider that? I mean, do you do that as well, Petros? Do you consider Dostin’s Impact for a neoadjuvant approach?

Petros Grivas: Great point, Chandler. I agree with you. And I actually mentioned in my discussion to your point that, personally, myself in clinic, I use Dostin’s Impact with growth factor support as primary prophylaxis for four cycles for node negative patients.
And the big question to me is how the data from Niagara impact that practical pattern. Of course, you can argue that XemSys is a very acceptable, reasonable, and the most controlled arm in the Niagara study, and is the most commonly used regimen in the neoadjuvant setting, you know, across the board. So I think it was okay that they used that.

It was very acceptable and reasonable. Having said that, people like you and me who use those XemSys in clinical practice, what do we do? I think there are interesting data we saw from the AURA trial, A-U-R-A, that was presented at ASCO 2024.
And that trial was a phase two study looking at Dostin’s NVAC plus Avelumab and also XemSys plus Avelumab in the neoadjuvant settings. The trial, of course, was not powered to compare those two combinations, but numerically showed higher path CR rates with Dostin’s NVAC plus Avelumab. And of course, the safety data overall, toxicity data, were reassuring that, you know, you can combine Dostin’s NVAC plus sigmoid inhibition.

The other interesting point is that there’s some preclinical data that people talk about. We have, of course, to see more data on that, but adriamycin may be more immunogenic. And so is that potentially having, you know, some impact there?

Is that Dostin’s NVAC potentially? We don’t know, but is it a better partner with sigmoid inhibition? I can share with you, stay tuned, because we just completed the phase two trial here at the University of Oshkosho and Farnsworth Heart Cancer Center, looking at Dostin’s NVAC plus sigmoid inhibitor in patients with histologist subtypes.

And we’re hoping to present the data very soon. I think this data will generate some good discussions and, you know, complement the discussions we have today. And of course, we have in the upper tract disease, which is a separate question, and I think merits its own trial, I want to give a shout out to the E-Durvalumab.
Exactly that question. That trial has also, it’s a splatting ineligible cohort with Jamshedab and Durvalumab. And Ginny Hoffman Dr. Hoffman from Johns Hopkins is the chair, and I’m honored to be the co-chair in that study. So hopefully we’ll answer the question in upper tract disease in the next few years.

Chandler Park: Absolutely. And, you know, the other thing is, if you think about the Dostin’s NVAC, and then if you look at the ambassador study, you look at the Checkmate 274, we have another point where we can kind of evaluate the patient. So if you look at the adjuvant study, T2 or higher, so if they have a T0, T1, they’re not getting immunotherapy adjuvant. So I feel like some of these patients might be overtreated there.

What are your thoughts about that, Petros?

Petros Grivas: It’s a great question, Chandler. I think you’re right. I think we’ll end up overtreating some patients.
The problem we have right now is we do not have fully validated, reliable biomarkers with clinical utility that can help us select the patients who need adjuvant therapy. And, of course, this is an ongoing effort. It was part of my wish list to Professor Powles and the study team, give us more data down the road, give us outcomes, ad hoc exploratory analysis, hypothesis generating, but give us those outcomes with disease-free survival and overall survival based on pathologic states, path CR, path downstaging, pathologic residual muscle invasive disease.

I would like to see how these patients do, because it’s interesting to see whether we can have in the future more granularity about which patients need adjuvant therapy. And the data from the Tombola trial that we saw by Dr. Jensen at ESMO and the ongoing MODERN trial by Dr. Galsky Alliance in the U.S. and the INVIGOR-011 trial by Professor Powles and others, all those trials will help this dialogue, right? We’ll get bits and pieces of data sets that can help inform the answer.

I think we’re going to over-treat patients at the same time. We want to avoid under-treating as well. So, it’s that fine balance.
And it makes a discussion with the patient. The last point I will make is, in the same presidential discussion that I was honored to be part of at ESMO, there was a great presentation by Dr. Smith from Keynote 522 trial in breast cancer. Very similar story.

And Dr. Marlene Koch did the discussion. And we had very similar themes, similar concepts, and similar questions between breast cancer and bladder cancer. And one of the questions was, in the pathologic complete response subset, do we need to continue with adjuvant I.O.?

And in the breast cancer study, if I remember correctly the data, you can double-check me, I think for the path CR subject, there was still a hazard ratio 0.69 in those who continued adjuvant PEMBRO versus not in the breast cancer study. Of course, this was a wide confidence interval overlapping, you know, crossing one. So, the question is still out there. You know, I don’t think they have answered the question even in breast cancer with a much longer follow-up.

So, the question is, are we going to ever find out, right, in our study in Niagara, in our bladder cancer field? However, we have many trials going on. We have, of course, NIAGARA with longer follow-up.
We have Keynote 866 with GEMCIS plus minus PEMBRO. We have GEMCIS plus minus NIVO. And we have the AV PEMBRO trials, Keynote B15, Keynote 905, the Volga trial.

All of those will contribute to this dialogue. And I think in the next few years, I think localized MIBC will be completely different disease and different outcomes, better outcomes for our patients. We’re going to cure more patients.

And the question is escalation, de-escalation, biomarkers. That will be an ongoing effort.

Chandler Park: I love it, Petros. I mean, we’re so fortunate in the bladder where we’re the golden age for treatment. And, you know, for right now, standard of care, it’s wonderful.
Congratulations, Dr. Tom Powles, all of the patients, all of the support group, all of the PIs. I think it’s great. And now we can build on this.
It’s a great foundation. So, really enjoyed our conversation, Petros.