The NIAGARA Trial, Cisplatin Regimens, and the Potential of Durvalumab With Gem/Cis for MIBC

A roundtable moderated by Karine Tawagi, MD, of the University of Illinois, featured discussion on the treatment landscape of muscle invasive and non-muscle invasive bladder cancer.
Panelists Petros Grivas, MD, PhD, of Fred Hutchinson Cancer Center, and Vadim Koshkin, MD, of the University of California, San Francisco discussed some of the latest practice-changing trials in the treatment landscape, as well as the potential of bladder-sparing treatment approaches and the use of ctDNA.

In part 3 of this roundtable, the NIAGARA trial is discussed, along with cisplatin regimens and the potential of durvalumab.

Watch the next segment: Exploring Bladder-Sparing Treatment Approaches in MIBC

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Dr. Tawagi:
You did mention the creatinine clearance was down to 40 in terms of eligibility. I feel like when I have discussions with patients, because they’re coming for day one, day eight anyways for Gem/Cis, I often just give split dose, but I’m wondering what your preference is. Do you normally just do the regular regimen or do you do split dose?

Dr. Koshkin:
As much as possible, I try to do the regular regimen, and regular regimen meaning you give full dose cisplatin, 70 milligrams per meter squared on day one as opposed to splitting it 35 and 35. But for patients, I mean, if you’re like I would say GFR 50 and under, that’s really where you start thinking about split dose, right? And for many of those patients I think that’s probably safer. But I think, Petros, you brought up an excellent point about this study and, well NIAGARA, and potentially slightly lower response rates with chemotherapy than I guess what we would expect, what we’ve seen in some of the other studies. And I wonder, I would be very interested to see that subset in the study who actually got split dose, and then this will be a way to potentially look at more robust data maybe in this perspective setting.

I also wonder, we talked about dose-dense MVACs, I also try to give it to patients who are more fit and I think can tolerate it, because I think it is a tougher regimen. I know there have been some clinical trials somewhat indirectly comparing the two that suggest the side effects are similar. I don’t know if that’s really kind of what I’ve seen in practice. Maybe in trial patients that are relatively more fit they can do both, but in practice, I really, dose-dense MVAC, I think is a very select group of patients that I would apply that to.

But I wonder if, based on this data, based on NIAGARA data, whether certain physicians would even extrapolate and give IO or like durvalumab with dose-dense MVAC. Because, I mean, really what we’re seeing here, what we’re hoping we’re seeing here, is the synergy of immunotherapy and chemotherapy and in this muscle invasive setting. So in theory, it should work with the other Cisplatin-based regimen, too.

Dr. Grivas:
And actually, it’s interesting you mentioned that. I was discussing with some colleagues in the laboratory, and there is some early discussion that Adriamycin may be more immunogenic, and even this is discussed in breast cancer as well. So I think in the context of that pre-clinical data, the ORRA trial that we talked about before, the phase two study with dose-dense MVAC, ramucirumab looking very promising. And again, some we’re hopefully going to contribute to this dialogue by our investigative trial in the future.

Personally, again, this is not the NIAGARA trial, but personally I’m very compelled and intrigued about the idea of dose-dense MVAC plus checkpoint inhibitor. To generate more data, we have a phase three trial in upper tract disease, neoadjuvant upper tract, kidney pelvis or ureter, with Dr. Ginny Hoffman Sanchez, who’s the chair, I’m the co-chair. This is cooperative groups. This ECOG-ACRIN AT192 trial. Definitely recommend to open it in your sites if you can. This is neoadjuvant dose-dense MVAC plus minus durvalumab. So we’re going to answer this exact question in the prospective phase three trial. And we have a cisplatin ineligible cohort with some set-up in durvalumab for, again, in the upper tract only. So we’re going to find out in that subset as well.

Dr. Tawagi:
Absolutely. I think that’s going to continue to answer more questions about the role of dose-dense MVAC with immunotherapy in the perioperative space. The PD-L1 expression for patients on both arms of the trial was over 70%. Are you routinely checking for PD-L1 in this setting, and do you think that that’s higher than what you’re seeing?

Dr. Koshkin:
I don’t check for PD-L1 in this setting. And most settings, I would say I don’t check for PD-L1 for at this point. I used to do it more in a metastatic setting. In muscle-invasive, not so much. I would say, well, one exception may be for actually consideration of adjuvant in durvalumab, there was a suggestion actually based on the Checkmate 274 data that the higher PD-L1 patients, patients with higher PD-L1 expression, do better. But no, so certainly in the neoadjuvant setting, I don’t use it as a biomarker. I don’t know if you do.

Dr. Grivas:
I agree 100% with Vadim. Back in the day, almost 10 years ago, we’re very excited about, of course, PD-L1 as a biomarker. I think this promise fell through in terms of the PD-L1. I do not find it clinically useful like Vadim said. I do not use it in bladder cancer in any setting. I think the data so far, and of course the confusion with multiple different assays and different settings, I have not found useful at all.

Dr. Tawagi:
That’s definitely a great point. And one other thing that we kind of touched on earlier was immune-related adverse events. So they weren’t explicitly reported in the NIAGARA. It was more AEs from systemic therapy. It looks like there were about 80% of patients that discontinued durvalumab due to the toxicity. It would be great to get more information on what those toxicities are so that we can appropriately have these discussions with patients.

Dr. Grivas:
I think it’s a great point. I had this wish list in my discussion that I provided to Professor Pauls and the study team, and one of them was to look at the immune-related adverse events, especially the long-term endocrinopathies. We can get some data about healthcare utilization, maybe hospitalizations. Of course, it’s hard to capture sometimes those data sets even in large studies, but I think it’s an important point.

A couple of thoughts. Number one, if we look at the patients who discontinued durvalumab neoadjuvantally minimally was maybe a very small proportion. And I think that overall safety toxicity profile showed that the addition of durvalumab to Gem/Cis did not compromise the ability of patients to undergo curative intent radical cystectomy, which is encouraging. It seems to be a safe combination as we have seen in other tumor types, in metastatic disease with gem-cis-nivo, at least this is some reassurance in neoadjuvant curative intent setting that the addition of checkpoint inhibition to chemo did not compromise the ability to get curative in surgery.

The other thing, if you look at the adjuvant therapy component, I think you’re right, Karine, if I remember the numbers, it was only about eight single digits. 8% of patients who stopped durvalumab for treatment-related adverse events. And they had up to an eight-month period in the adjuvant phase. So overall, no new safety signal, no new toxic signal. But of course, I think education and vigilance for IRAEs is always important.

Dr. Koshkin:
And of course, it’s also a question of whether the patient who stopped durvalumab, I think presumably most of them stopped it in the adjuvant portion, right? Not neoadjuvant. And it’s a question, well, again, that comes up whether all patients actually need to complete the entire adjuvant portion. And I think here we actually, we may be seeing some patients and/or investigators voting with their feet so that if you are in month six of durvalumab and you’re getting even sort of mild side effects, you really need to continue with it.

Dr. Grivas:
And that’s the big question. You have to monitor these patients very closely and then educate them, make sure they report. They do not under-report which happens sometimes with patients, they go into stem therapy.

Dr. Koshkin:
Especially in trials.

Dr. Grivas:
Exactly. And then you adjust according to the toxicity profile, and you may stop if needed based on the grade and the attribution of adverse events. The last quick point, I think it came up at the discussion was the utility of the CTCAE criteria as a tool to capture immune-related adverse events. It’s not designed for that. It was designed for chemotherapy. It’s being adapted, of course over time, but I think we need to be vigilant about which tools we use to capture those AEs.

Dr. Tawagi:
I absolutely agree. And so I think NIAGARA overall is practice-changing, extremely exciting. Hopefully, we’ll have regulatory approval, and it’s changing the perioperative space for patients that are cisplatin eligible.