The Role of Avelumab Switch Maintenance Immunotherapy in the Front-Line Space of Patients with Advanced Urothelial Cancer - Srikala Sridhar

March 7, 2023

Srikala Sridhar joins Petros Grivas in a conversation about the JAVELIN Bladder 100 phase III trial in the front-line setting using immunotherapy to treat advanced urothelial cancer. The study involved patients who received upfront platinum-based chemotherapy and were randomized to receive avelumab every two weeks or supportive care if they had no evidence of disease progression. The trial showed that maintenance therapy with avelumab resulted in a 6-month improvement in overall survival. This was a clinically significant result and a major advancement in treating this type of cancer, which had previously seen negative results in other phase III clinical trials. 


Srikala Sridhar, MD, MSc, FRCPC, Professor, Department of Medicine, University of Toronto, GU Medical Oncologist, Princess Margaret Cancer Center, Toronto, ON

Petros Grivas, MD, Ph.D., Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center.

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Petros Grivas: Hello, I'm Dr. Petros Grivas. I'm a medical oncologist and associate professor at the University of Washington and Fred Hutchinson Cancer Center. I'm really excited I'm here today to host Dr. Kala Sridhar. Dr. Sridhar is a very well known medical oncologist internationally. She's a full professor at the University of Toronto, and she's the director of the GU Medical Oncology Program at the University of Toronto British Margaret Cancer Center there. She's also serving as the head of the GU Medical Oncology Program in Canada. Kala, thank you so much for joining me today.

Srikala Sridhar: Thank you for having me, Petros.

Petros Grivas: It's exciting to see you ASCO 2022 meeting in person after 3 years with safety measures, of course, and we had that chance to interact and watch the amazing developments in GU medical oncology, in which is a field you have made wonderful and meaningful contributions globally.

I want to talk to you today, specifically about the role of avelumab switch maintenance immunotherapy in the front-line space of patients with advanced urothelial cancer. As we know, Kala, we have seen four other phase III clinical trials which did not meet the primary endpoint. That makes me think how difficult it is to improve outcomes in patients with urothelial cancer in general, and specifically the front-line setting.

JAVELIN Bladder 100 is the only positive phase III trial in the front-line setting using immunotherapy. And we haven't seen improvements in this disease for a long time, especially in the metastatic setting. I want to start asking you about the design of the JAVELIN Bladder 100 trial, why we did this trial to begin with, what were the main take home messages, and how the data presentation has evolved over the last 2 years to include updates on the clinical endpoint, as well as biomarker data and quality of life PRO data.

Srikala Sridhar: Absolutely. I think the JAVELIN Bladder 100 study is an important study and has been a really important study for the field. Let me set it up for you. We know that front-line chemotherapy is highly effective, high response rates with Gem-Cis, or even Gem-Carbo for that matter. But the problem is one of durability. So, we get the response, but often the disease does not continue to stay controlled. And so, immunotherapy currently approved in the second-line setting may offer a little bit of that durability.

And so this sets the stage for the JAVELIN Bladder 100 study where patients received upfront platinum-based chemotherapy, and if they had no evidence of disease progression, they were randomized to receive avelumab every 2 weeks or best supportive care. We saw these results initially presented and also published and really showed that there was about a 6 month improvement in overall survival with the use of maintenance of avelumab. So, that was on the initial evaluation of the study. And, of course, it's very exciting, because as you mentioned, we'd had a number of negative studies up until that point.

This year at ASCO, we saw the updated analysis after 38 months of follow up. And the good news here is that what we saw initially holds true in the updated analysis. Further sub-studies have looked at things like whether patients receive Gem-Cis or Gem-Carbo, depending on their PD-L1 status, looking at the time from the end of chemotherapy to the beginning of maintenance therapy within the 4 to 10 week period, and even site of the primary. And all of those factors did not impact on the benefit of maintenance avelumab. So it's a pretty consistent finding across the board.

Petros Grivas: Kala, I agree with you a hundred percent. It's really exciting to see a positive phase III trial and oncology, let alone in advanced urothelial cancer where the field has been stagnant for probably two or three decades and see a very significant statistically and clinically meaningful overall survival benefit. Hazard ratio 0.69 with avelumab maintenance versus best supportive care alone after response to the use chemotherapy, platinum-based chemo. And with a longer follow up, as you mentioned, hazard ratio went to 0.76, still clinically significant and statistically significant with the median overall survival difference of many months. And this was despite the fact that you alluded to that many patients, about three-quarters of the patients, on the best supportive care arm, the control arm, received second-line therapy, which is the largest proportion I have ever seen, retrospectively or prospectively, of patients in the front-line setting getting second-line therapy. So I think this is adding a value in the study.

Do you want to briefly talk about the hypothesis-generating biomarker translational data that you presented, I think, a year ago or so, and now we have a publication in Nature Medicine.

Srikala Sridhar: Yeah, for sure. We had looked at a number of the biomarkers. This was presented at ESMO 2021 in Paris, and we had looked at number of the biomarkers to see if we could figure out who should be getting this treatment versus who shouldn't, perhaps. And I'd say that we actually didn't see any specific biomarker coming out. So we looked at things like PD-L1, we looked at tumor mutation burden, we also looked at a number of signatures, but nothing clearly identified that we should be treating some patients but not other patients. So I think it brings us back to the patients who were included in the study. Those who'd had front-line platinum based chemotherapy and had not had progressive disease and subsequently received avelumab. So I think that it is important information. We're collecting this biomarker data and I think it'll be important looking forwards maybe to tell us who will have the long term benefits with these treatments. But for now, I think it's really sort of an all-comer type of approach that we take.

Petros Grivas: I agree totally with you, Kala. And the paper is very interesting to your point, that Nature Medicine published by Dr. Powles and our team about a year ago, and I think you're right. I think, right now, these data are very interesting hypothesis-generating, mainly for future trial designs, but so far have no clinical implication where are treating patients with avelumab maintenance regardless of any clinical or molecular biomarker, regardless of any subset, you'd pointed out that the benefit is across the board across different subsets of patients based interaction test that was done. And certainly, patients who have a complete response, partial response, or stable disease, any of those subsets had benefits. Significant benefit, I would argue. So, if you have no progression and no contradiction to immunotherapy, avelumab has level 1 evidence of maintenance therapy.

And recently we published in the European Urology about a week ago that the quality of life of those patients is not impacted negatively. The impact on quality of life is minimal. So this overall survival, progression-free survival benefit comes at a minimal impact on quality of life, which is encouraging that these patients maintain a good quality of life. It's important to cure what patients think and patient-reported outcomes.

Now, in my mind, Kala, is the issue of implementation of life-prolonging therapies across the globe. I come from Greece, a country with definitely less resources compared to the US and I'm talking to colleagues in multiple different countries and the issue of healthcare disparities and access to care access to life-prolonging treatments comes all the time. So, regarding implementation, this, of course, requires regulatory approval by different agencies across countries, and of course, access to care and access to those treatments based on any potential financial burden or any other parameters. So I want to ask you, how was the translation implementation of the JAVELIN Bladder 100 data in Canada? You have a leading role in Canada as a whole country. How was the uptake, and any barriers you identified?

Srikala Sridhar: Yeah. This is a really good question and I think it's important to consider the disparities across the world. Certainly in Canada, we do sometimes lag behind in terms of access to new treatments. I think there's a lot of efforts underway to try to overcome that. JAVELIN Bladder 100 led to the approval of avelumab in January 2021, that was a Health Canada approval, and then we're very fortunate to have a company sponsored program really to give us access to of avelumab fairly soon thereafter. And then more recently, we've received notification of public funding. So, that then allows it to be given quite broadly across many of the cancer centers.

I would say, reflecting on Canada as a whole, that we've really had pretty good uptake of avelumab across the board. In Canada, we have also not had the availability of front-line immunotherapy, so Pembro or Atezo has not been available to us in the front-line setting, which means that most of our patients are getting treated with Gem-Cis followed by avelumab or Gem-Carbo followed by avelumab. So I think, overall, the uptake has been good, and perhaps lack of availability of upfront immunotherapy has increased the use of avelumab in the maintenance setting for our patients. So I think it's been great and I think our patients have really benefited and really been happy to have had access to this treatment in the front-line setting as a maintenance.

Petros Grivas: It's great to hear that, Kala. And, obviously, as you mentioned, there are differences across standards, but it sounds like in Canada, the adoption and implementation has been relatively smooth compared to some other countries, so it's great to hear that. It sounds also that you do not have the ability to use checkpoint inhibition in the front-line setting because they're not approved based on the totality of the data we have seen in phase II and phase III trials. Let me ask you this quick question. If you had the option to use checkpoint inhibitor in the front-line setting, if, for example, you were practicing in the US, for cisplatin-ineligible patients or platinum-ineligible patients, in which population would you use checkpoint inhibitor in the front-line setting in the context of the JAVELIN trial?

Srikala Sridhar: Right. I'll start by saying I'm a pretty big believer in chemotherapy up front. And when we look at things like cisplatin eligibility, my creatinine clearance cutoff is around 50. So anyone with the creatinine clearance of 50 and above will Gem-Cis or split-dose Gem-Cis. I find that a very helpful regimen, well tolerated. And then between 45 and 50, I'm using a lot of Gem-Carbo in that setting. And then it's only in that group where less than 45, 40 or less that I may consider using an upfront immune checkpoint inhibitor. And prior to that, I will get my nephrologist involved, my onco-nephrology team to see if we can optimize renal function to allow the use of upfront platinum-based chemotherapy. I still feel that this cancer needs some chemotherapy, so I really try my best to get some chemotherapy into these patients. If I had immune checkpoint inhibitor available, I think it'd be a very small subset of patients that would ultimately receive it in my practice up front.

Petros Grivas: I agree with you, Kala. I think, my practice, I agree with you. Gem-Cis is my preferred, followed by avelumab maintenance. If I cannot give Gem-Cis, I always give a Gem-Carbo followed by avelumab maintenance. The data with Gem-Carbo in the modern phase III trials do not look as bad as we thought maybe 10, 20 years ago, maybe because of patient selection, best supportive care. So, in cisplatin-unfit patients, I use Carbo-Gem and called avelumab. And as you alluded to, I reserve checkpoint inhibitor alone, monotherapy, in platinum-ineligible patients, about 10% of patients in my practice, that are not fit for any platinum chemo.

At ASCO 2022, we had this poster with Dr. [inaudible 00:12:14] (SilvyGoopta?) about 60 medical oncologists that were surveyed to define together or help inform which criteria we use for this platinum-ineligible population, which patients we think are not a fit for platinum, Cis, and Carbo. This poster hopefully will be a manuscript in the near future to help us define this population, which I agree with you, it's very small.

Time goes very fast when we have fun and I always learn from you, Kala. You're doing a great job. Thank you so much for your time today and looking forward to interacting and collaborating with you and learning from you in the future.

Srikala Sridhar: For sure. Thank you so much for having me always a pleasure to chat with you as well, Petros, and I look forward to seeing you again in a meeting sometime soon in person.

Petros Grivas: Thank you so much. Stay well and see you very soon. Thanks to the audience as well for the attention.