Michiel Simon Van Der Heijden: Yeah, thank you Ashish. And also thank you for inviting me here again for UroToday. So, indeed, at ESMO, I presented the results for the health related quality of life outcomes from the NIAGARA trial, a trial we all know pretty well, I think, and this was of course on behalf of all my co-authors. Disclosures here. So as a reminder, and I'm sure the audience of UroToday knows this very well, but the NIAGARA trial was a trial that compared chemotherapy with or without durvalumab in the neoadjuvant setting and then in the adjuvant setting continued in the experimental arm with durvalumab, and it showed that there was a significant improvement in event-free survival and overall survival at the first analysis for perioperative durvalumab added to neoadjuvant chemotherapy. There was also a numerical improvement in pathological complete response rate, and the treatment has now been approved for muscle invasive bladder cancer, cisplatin eligible muscle invasive bladder cancer in both the US and the European Union and many other countries around the world.
So in this presentation, we will present patient-reported health related quality of life results from NIAGARA. This is the study design of the NIAGARA trial. Over a thousand patients were randomized in this trial to receive either cisplatin gemcitabine with durvalumab or without and then adjuvant durvalumab or no further treatment in the control arm. So the primary endpoints event-free survival and pathological complete response, and the key secondary endpoint was overall survival. And the pro-secondary endpoint was the EORTC QLQ-C30 scale, and an exploratory endpoint was the EQ-5D-5L visual analogies scale. And they were both assessed by electronic device at baseline and then every four weeks until disease progression.
So the compliance of these questionnaires was pretty good. So for the EORTC QLQ-C30 questionnaire compliance was a baseline over 80% and then slightly below 80% at post-baseline visit or at least one post-baseline visit. And the EQ-5D-5L was slightly lower. So the general health status, physical fatigue and pain questionnaires subscales were pre-specified priority subscales in this study. And in these subscales, a 10-point change in score compared to baseline was considered clinically meaningful.
And the key analysis in this study were changed from baseline and time to definitive deterioration. For the exploratory endpoint of the EQ-5D-5L visual analog scale, patients could rate their current overall health, and a change from baseline is reported here. So these are the curves for the general health status, quality of life and physical functioning, so two of the priority subscales. And as you can see, there is a decline in these scores in the neoadjuvant period around radical cystectomy, which then returns to baseline in the adjuvant part of the study. And for both these scales, the difference between the arms was actually minimal and non-significant. So there was no difference in quality of life for these two scales between the durvalumab arm and the control arm.
So a similar picture for fatigue and pain. So here the curve should be seen in the reverse because going up means deteriorating and going down means improving. And once again for fatigue, we see deterioration during the neoadjuvant period for pain. The deterioration peaks around surgery and then goes back to baseline and has no differences between the experimental arm with durvalumab and the control arm. So these are the Kaplan-Meier curves for the time to definitive deterioration for two important subscales. And on the right hand side is a forest plot with subscales and some showing a trend toward perhaps some improvement with durvalumab, but overall, there's no significant difference between the two arms in these subscales in time to definitive deterioration.
Finally, the EQ-5D-5L visual analog scale, there was also, again, no difference between the experimental arm and the control arm in this scale. So in conclusion, I think this study is important because we hear report a large prospective analysis of health-related quality of life in patients with muscle invasive bladder cancer receiving perioperative treatment. So in the neoadjuvant and radical cystectomy period, both treatment arms had worsening quality of life scores, which improved in the adjuvant treatment periods. No clinically meaningful differences were observed between the treatment arms for QLQ-C30 across the study period, and comparable time to definitive deterioration was reported across all subscales. Finally, there was no adverse impact on the EQ-5D-5L visual analog scale score with no differences between treatment arms across the study periods.
So the addition of perioperative durvalumab to neoadjuvant chemotherapy significantly improved event-free survival and overall survival without adversely impacting patient-reported outcomes. I'd like to thank all of the patients and their families and caregivers for participating in this study and also would like to thank all my colleagues who made the NIAGARA Study a success. Thank you.
Ashish Kamat: Thanks, Michiel, for presenting this very important data that's really quite relevant. I'd like to pick your brain on a few things because one of the things we heard about when we had the data from the NIAGARA study that came out initially was that what's the contribution of the different components? Is the adjuvant relevant? Then we saw the path CR data. We saw that patients benefit despite the path CR for certain groups of patients and a lot of discussion around that. And then ultimately, even though on the study everybody got adjuvant therapy, a lot of people in clinical practice were saying, "Well, I'm going to discuss it with my patient, and the patient has had side effects, or if they have any reluctance to continue, I might not offer it."
Would you use this data that you presented to try to convince people to stick to the protocol with their patients? How would you use this in the real world?
Michiel Simon Van Der Heijden: Yeah, so thanks for that question. I think that these are all very important questions. So I think this data, what it adds here is, so this quality of life data is mainly that there's no deterioration. I think it shows that what we were already expecting is that in the neoadjuvant periods, quality of life deteriorates a bit and also during cystectomy, but then it goes back to baseline. So that's good news. So in the end, patient's quality of life returns to normal basically. And it seems that durvalumab doesn't really have an impact on that in a negative way at least. It also doesn't seem to have an impact in a positive way, which actually turned out to be very difficult to show in bladder cancer trial in my experience mainly I think because the state of the disease is mainly determining quality of life here.
So how would I use that? Well, if patients are reluctant to see their quality of life deteriorating, I can at least reassure them with this data. I think you had questions about what are the contribution of components of the neoadjuvant, the adjuvant parts, the NIAGARA study was not designed to answer those questions. It's already hard enough. You need a thousand patients to show that there is improvement for peri-operative therapy, and this would require a second randomization to see if the adjuvant portion would add to the neoadjuvant portion. So we really don't know. Path CR is not distinguishing patients who will or will not benefit.
And I think it is tempting to use that data to say whether it is or is not helping to give the adjuvant period, but it really doesn't because the effect of the neoadjuvant portion is already in the path CR basically. So it is a bit difficult to use that data to answer those questions I think. I think for now, if patients tolerate it well, I would just continue the full regimen. And if patients are struggling to continue because of immunotherapy side effects, for example, it's just the conversation I think between patient and their physician whether to continue all the way or not. And I think there's at this point, no data to really guide us there.
Ashish Kamat: Absolutely. And that's what I've been doing. If the patients have done well with it, then continue. Right? I mean, why not? If they're not doing well, if they're struggling and especially if they have path CR, then I think we can make clinical judgments. But the other thing that really was surprising, pleasantly surprising to me, and I'd love to hear your thoughts on it, was how well the patients recovered their quality of life reports. And this is self-reported after radical cystectomy, after neoadjuvant therapy, radical cystectomy, multimodal therapy because we often hear from people that patients who undergo radical cystectomy, they're miserable after their surgery. Patients undergo neoadjuvant therapy and then radical cystectomy, they're miserable. And you've seen data from the CISTO trial that suggests that patients do just as well, if not better, after radical cystectomy compared to intravesical therapy where they're trying to save their bladder for non-muscle invasive disease. So any thoughts from your perspective on how remarkably well patients did in their quality of life after multimodal therapy?
Michiel Simon Van Der Heijden: Yeah, so I think that in most of the quality of life analyses we see that one of the fields that is maybe the only field that is really deteriorating is sexual function. I'm not sure if this was really, these are global quality of life scales. I'm not sure if this is really captured well here. And I think it's just my personal opinion, but I think a lot of these patients, they have a diagnosis that is life-threatening, they're glad that their treatment is over with, and they're happy to pick up life again and glad that everything went well, and I think that's what we're seeing here in these scores. And it's very hard to show a deterioration and, in fact, baseline scores actually in the study we're already really good. So patients with baseline with bladder cancer still there and starting treatment had pretty much normal quality of life scores. So that already underscores that this patient population is probably highly motivated and going into this treatment maybe quite positively, I would say.
Ashish Kamat: Yeah, and of course sometimes we have to also recognize that patients on clinical trials or even in our clinics, don't want to disappoint themselves and their team. Right?
Michiel Simon Van Der Heijden: Exactly.
Ashish Kamat: Sometimes they don't report quality of life. But I really still think that these data are very encouraging, not just for us, but for us to be able to counsel our patients. So I want to congratulate you once again, and thank you for taking the time.
Michiel Simon Van Der Heijden: Thanks. It was a pleasure.