The Optimal Timing for Starting Avelumab Maintenance After Completing First-line Chemotherapy, JAVELIN Bladder 100 - Srikala Sridhar

June 4, 2021

The phase 3 JAVELIN Bladder 100 trial demonstrated that First-line maintenance therapy with avelumab + best supportive care (BSC) significantly prolonged overall survival (OS) compared with BSC alone, while the optimal timing for starting avelumab after completing first-line (1L) chemotherapy is still unknown. In a presentation at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Srikala Sridhar MD, MSc, FRCPC, presented this post hoc analysis reporting the efficacy by the duration of the treatment-free interval from completion of First-line chemotherapy. Dr. Sridhar joins Alicia Morgans, MD, MPH, to further detail this analysis supporting this new treatment strategy as a standard of care.


Srikala Sridhar MD, MSc, FRCPC, Associate Professor, Department of Medicine, Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today, Dr. Srikala Sridhar. She is currently an associate professor of medicine, but recommended to be full professor of medicine as of July 1st at the Princess Margaret Cancer Center in the University of Toronto. Thank you so much for being here with me today, Dr. Sridhar.

Srikala Sridhar: Thanks for having me, Alicia.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about the JAVELIN study and the work that you and your team did and presented at ASCO 2021. Can you tell us a little bit about the JAVELIN study first, and then we'll move into what your analysis was?

Srikala Sridhar: Yeah, for sure. I'm happy to do that. So the JAVELIN study is a phase three randomized trial that took patients with metastatic urothelial carcinoma who achieved disease control on frontline platinum-based chemotherapy. So these patients were randomized to receive avelumab, plus best supportive care, and I'm going to call that arm avelumab, versus best supportive care alone.
The median overall survival for the group who received maintenance avelumab was about 21 months or so compared to about 14 months for the group that received best supportive care. Hazard ratio there was about 0.69. So on the basis of this study, maintenance avelumab is now the standard of care, and this is for patients who achieved disease control on frontline platinum-based chemotherapy. And this is certainly very exciting, a very big step in the field.

So around the same time that this study, the JAVELIN study reported, we also heard about two other studies looking at combining chemotherapy and immunotherapy. So these were the KEYNOTE-361 and the IMvigor130 study. And perhaps the results of these studies were not as encouraging as we might've liked, keeping in mind as well that these studies also included a maintenance component of the immunotherapy. And so, I was curious to know, in the JAVELIN study, if there was any impact of the time from the end of chemotherapy to the beginning of immunotherapy, so what we call the treatment-free interval, on overall outcomes.

Alicia Morgans: Fantastic. And so, you and your team investigated this and what did you find?

Srikala Sridhar: Right. So we divided patients into three groups, so those who started between four and less than six weeks after ending chemotherapy, they started the avelumab or best supportive care, those who were in the six to eight weeks category, and those who were in the eight to 10 week category.

And what we first know is, within each category, the baseline characteristics were balanced between the arms that received either avelumab or best supportive care. For both groups combined, when we looked at the three subgroups, the four to six, six to eight, and eight to 10, we found that the group that started within four to six weeks of the end of chemotherapy did have a little bit more visceral disease. They did tend to respond more often to frontline chemotherapy and their performance status more often tended to be greater than one, so they tended to be a slightly sicker population. But essentially, we had these three groups that we were looking at, four to six, six to eight, and eight to 10.

What we found was that there was prolonged overall survival regardless of the treatment-free interval. So within the four to 10 weeks, all patients had a benefit of maintenance avelumab. Okay? When we look a little bit closer, perhaps there is a trend to greater benefit in patients who were in the six to eight or eight to 10 week period compared to the four to six week group. But again, we may be splitting hairs and we have to be cautious when making these assumptions. Essentially, all groups had benefit regardless of treatment-free interval in terms of overall survival.

Next, we looked at progression-free survival, and we saw a very similar trend in that patients who received the avelumab maintenance had a benefit regardless of the treatment-free interval. Again, perhaps there was a slight benefit in waiting beyond six weeks to start the avelumab maintenance. Okay? And then finally, we looked at the safety, and the safety across the board was maintained. So again, it didn't make a difference if you started four weeks or closer to 10 weeks. So that was also very encouraging.

So overall, what we can say is that the treatment-free interval did not impact significantly on the standard outcomes of progression-free survival or overall survival, or even safety, for that matter. So that's, that's good news. I think why this is important is because we all know when we treat patients with chemotherapy, when they are ready, the time when they are ready to start something else is quite variable. So some patients need time to get over the side effects of chemotherapy before embarking on immunotherapy. And I think what this study shows is that we can be responsive to our patients without having them to start right away on the immunotherapy. So I think that's a positive finding here. So really, I think that it just gives us a little bit more clarity. It is interesting that perhaps that early group maybe doesn't do as well as the other groups, but I think it doesn't make a huge difference overall.

Alicia Morgans: Yeah, and it's interesting too, that that early group seemed to have some risk factors of more aggressive disease perhaps, which might offset things. It's possible, certainly. But really reassuring, like you said, that if we have to wait because of recovery of the patient post-chemotherapy, or because they have something that they need to do or whatever life brings them, sometimes there are little longer durations, as long as we start within that window that was assessed within the trial, we are able to capture that benefit. And so that's, I think, like you said, very, very strongly encouraging, as is, of course, the similar safety across all of those subgroups. Again, even though the subgroup that seemed to start earliest might've had some higher risk features and may have had some poor prognostic signs associated with them.

Srikala Sridhar: Yeah, I think the applications are very practical in the sense that you can talk to the patient. I usually discuss the avelumab maintenance approach right when I'm starting the chemotherapy. And so, I think that manages the patient's expectations. They know what's coming next, instead of finishing chemotherapy and then turning around and going, okay, now I have something else. I think that's really difficult. So often what I'll do is I'll explain to them the maintenance approach. And then after, I'll say, "Well, we do have some flexibility within the four to 10 weeks after finishing chemotherapy to start on the avelumab." But I think that helps and then it gives them that comfort that if they do, like you say, have things that they need to do after the chemotherapy is all done, they can go forwards and do all those things and then be ready to start on the immunotherapy. So I think it's just really practical information, I think, for all of us on the ground.

Alicia Morgans: I would agree. And I think it's practical, similar to the previously presented work, that whether you get in four cycles or whether you get in six cycles of chemotherapy, as long as you have that stable disease or better, there seems to be a similar benefit to treatment with avelumab in the maintenance, as a maintenance strategy. So I agree. Both of these are very, very practical and really reassuring to clinicians and to patients that it's not that complicated. Just finish your chemo, you have stable disease or better, get yourself started on the avelumab maintenance, and we can get this actually pretty significantly dramatic, I think, survival benefit, which is phenomenal.

So any closing thoughts or summaries that you'd like to give for the audience as we wrap up?

Srikala Sridhar: So, absolutely. So I think that avelumab maintenance is definitely the new standard of care in this disease. I think it offers patients something in that time after chemotherapy is all done, where you and I have probably seen that it's actually somewhat of a difficult time for patients. They're used to coming in. They're used to the regimen. They're used to their friends that they see in chemo, and all of a sudden, it's all done. So I think to ensure that they're getting something in that period, they maintain their connection with us. I think it might actually help patients in more ways than just the pure survival benefit that we're seeing.

Alicia Morgans: I completely agree and really appreciate you, the co-investigators, of course, on this trial, and all of the patients who went through the process of finding this information. It certainly has transformed care in my practice and I think in many others. Thank you so much for your efforts and for your expertise today.

Srikala Sridhar: Absolutely. Thank you for having me.
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