Long-Term Follow-up from the JAVELIN Bladder 100 Trial - Srikala Sridhar

March 24, 2023

Srikala Sridhar joins Sam Chang in discussing long-term follow-up from the JAVELIN Bladder 100 trial of avelumab first-line maintenance for advanced urothelial carcinoma. The JAVELIN-100 study was conducted on patients with metastatic urothelial carcinoma who had received frontline platinum-based chemotherapy and achieved a disease response. These patients were then randomized to receive either avelumab maintenance or best supportive care. The study showed a benefit to maintenance of avelumab, and this approach became the standard of care. The long-term results were presented according to subgroups defined by whether patients received gemcitabine cisplatin or gemcitabine and carboplatin. The benefits of maintenance were maintained regardless of whether patients received GemCis or GemCarbo. The tendency is that there is benefit across all subgroups, whether they are complete response, stable disease, or partial response. The long term results showed that avelumab maintenance provided similar overall survival and progression-free survival (PFS) benefit irrespective of 1L chemotherapy regimen received and that long-term safety was not compromised.


Srikala Sridhar, MD, MSc, FRCPC, Professor in the Department of Medicine at the University of Toronto and a Genitourinary Medical Oncologist at the Princess Margaret Cancer Center, Toronto, Ontario

Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center

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Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologic surgeon in Nashville, Tennessee, and I work at Vanderbilt. And we are quite fortunate to have Dr. Srikala Sridhar from Princess Margaret in Canada, our good colleagues up north, who is going to be presenting and talking about the abstract, looking at long-term results of adjuvant long-term maintenance, avelumab, I guess, for in the Javelin study. And so Kala, thank you so much for being here, and we look forward to hearing the long-term results.

Srikala Sridhar: Absolutely. So the Javelin Bladder 100 study, as you know, was a study looking at patients with metastatic urothelial carcinoma that had been treated with frontline platinum-based chemotherapy, either cisplatin based or carboplatin based. And then had achieved a disease response in the sense that they had a partial response, stable disease, complete response. And at that point they were then randomized one-to-one to receive either avelumab maintenance or best supportive care.

So there were about 700 patients randomized to this study, randomized one-to-one, as I mentioned, and the primary endpoint was overall survival. And this was looked at in all populations and in also those who were PD-L1 positive. So the results of this study we heard a few years ago, really showing a benefit to maintenance of avelumab. About 21 months or so was what we saw with the avelumab maintenance compared to about 14 for the best supportive care arm. So on the basis of that, this drug, this approach became fairly widely approved, FDA approved, and in other countries as well, and really became the standard of care.

Now since that time, we've collected data on long-term outcomes, as you mentioned. The data cutoff was June 4th, 2021 or so. About a year and a half ago. And the median duration of follow up was about 38 months in the avelumab arm and was about 39 months in the best supportive care arm. And the abstract that we are presenting here really is looking at long-term outcomes according to subgroups defined by whether patients received gemcitabine cisplatin, or gemcitabine and carboplatin. So that's really the first part of the abstract.

And what we essentially showed was that the benefits of maintenance were maintained regardless of whether patients received GemCis or GemCarbo. So that's the first point to keep in mind.

We did see that outcomes were probably a little bit better with GemCis compared to GemCarbo when this is consistent with what we know about these two treatment regimens.

Sam Chang: Sure.

Srikala Sridhar: Patients receiving GemCarbo tended to be a little bit older, tended to have a worse performance status, and their creatinine clearance was usually a little bit worse as well.

Sam Chang: Sure. Makes sense.

Srikala Sridhar: So that that's pretty standard, what we expect. In my practice, I do try to give cisplatin wherever possible, and we're probably a little bit more lenient on the GOSKY criteria in the sense that I will go to a bit of a lower creatinine clearance of down to about 50, ensure proper hydration, maybe get our onconephrologist involved just so I can get the cisplatin in if possible.

Sam Chang: Try to push to the cisplatin side if you can.

Srikala Sridhar: Exactly.

Sam Chang: But it definitely takes experts like yourself to do that because I think many of the practicing oncologists are a bit careful and at least in our area, tend to default to the gemcarboplatinum if there are concerns.

Srikala Sridhar: Right.

Sam Chang: But it's good to know that actually both arms, both groups of those patients that received the continued maintenance therapy did seem to get benefit.

Srikala Sridhar: Absolutely, absolutely.

Sam Chang: Was there differences in those patients that had a complete response, versus a partial response, versus stable disease? Or was there, again, benefit through the subgroups? You may not have analyzed that yet in this. But what's the tendency, at least that you can see?

Srikala Sridhar: Yeah, so the tendency is that there's benefit across all subgroups, whether they're CR, whether they're stable disease, partial response, as you say. Which actually makes it a little bit easier in giving this drug because you're not worried so much about the exact type of response.

Sam Chang: I see. Then, so when you look at tolerability data along with this long term, what was the median length of treatment of the avelumab? Was that basically continuous on throughout?

Srikala Sridhar: Absolutely. So this drug is continued basically until progression. So there's no stop time, which is maybe contrasted with some of the second line treatments, which we may give second line immune checkpoint inhibitors, which we may give for a period of two years and then stop. So that's an interesting distinction between the two immune checkpoint inhibitors in this setting.

Sam Chang: And then, so in your practice, do you do that or do you at times they're doing so well, perhaps I give him or her a break, a holiday. What do you do in your practice?

Srikala Sridhar: So my practice, I tend to continue as long as I can. If they do need breaks, I'm pretty liberal with breaks. I also use low-dose steroids. I find that can help sometimes deal with some of the little side effects that can happen with the drug. But in general, we feel that it's fairly well tolerated.

The one thing that we are running into now is we're using these drugs more in clinical practice, is that you may see patients with areas of oligo progression. So the big question for now is how do we address that? Do we go after that with, say, getting some radiation in there and then maintain the avelumab, or do we switch to another systemic treatment? Which now of course we have in this disease. But it's an open question right now.

Sam Chang: And these would be basically new small sites of disease. And then what you do with them. And again, I guess how you define progression then really is becoming more and more difficult because there's progression. And everybody knows when there's bad progression. But it's these areas of new small volume disease that I think is becoming definitely more problematic. I think that goes with all of our disease states that we're looking at. If you look at kidney cancer, look at prostate cancers, these same types of questions that we have.

In terms of now of standard of practice, avelumab now is basically standard of care, would you say?

Srikala Sridhar: Absolutely. So I think in all of my patients with metastatic urothelial cancer where we treat with upfront platinum-based chemotherapy, and as long as they don't have evidence of disease progression, we then go on to give them avelumab maintenance. And that's sometimes after four cycles or sometimes it's after five or six cycles as well. So they have to have a minimum in accordance with the Javelin study of four cycles of platinum-based chemotherapy.

Sam Chang: Chemotherapy first, I see.

Srikala Sridhar: Yeah, exactly.

Sam Chang: And then are there any patients at this point that you, I guess probably overall performance status or clinical situation in terms of where you don't necessarily use it? Or it's really, really ... if they're doing well enough, you tend to use it? That's what it seems like.

Srikala Sridhar: I think so. I think so. These are still new drugs, and so we have to make sure that we're educating ourselves and educating our patients and making sure that they're reporting toxicities that they may be experiencing. But I think it's relatively well tolerated across the board.

Sam Chang: Wow. Well, we very much appreciate it, Dr. Sridhar. The changes now with advanced metastatic urothelial carcinoma I think obviously continue to accelerate. We're seeing many of these treatments used earlier in the treatment paradigm. And so we're excited to see these long-term overall survival rates.

Srikala Sridhar: For sure, for sure. And I think the other thing that we did look at in this abstract was from the beginning of chemotherapy. So of course this is a subset of patients who came on study. So all of those patients who'd achieved a response on chemotherapy, we actually looked at survivals from that point in time, from the beginning of chemotherapy. Which again, a subset of patients. And now we're starting to see those numbers go up towards 30 months or so. And so if a patient were to respond to frontline chemotherapy, go on to receive avelumab, and possibly be exposed to some of the novel therapies that are coming along, we're seeing our survivals in this disease really go up significantly. And we think not that long ago, we were quoting survivals of about 14 months.

Sam Chang: Right, right.

Srikala Sridhar: So it's been a really incredible development in this disease. Lots of collaboration, lots of clinical trials. And I think really great engagement from industry, academia, everything. And so it's really been a great story I think.

Sam Chang: Yeah, it's been a sea change, no question over the past five years plus, the possibilities. And even more exciting is seeing these long-term results which impact on overall survival. So thank you again for spending some time with us.

Srikala Sridhar: Thanks for having me.