Advancements in Treatments for Metastatic Urothelial Carcinoma (mUC) - Petros Grivas

June 29, 2020

Alicia Morgans, MD, MPH, and Petros Grivas, MD, PhD, discuss the recent updates in the metastatic urothelial carcinoma (mUC) disease space. Together they discuss multiple presentations given during the virtual ASCO 2020 including the IMvigor010 trial. They discuss other adjuvant immunotherapy trials for mUC, as well as new results from IMvigor130 assessing biomarkers. Dr. Morgans and Dr. Grivas also emphasize the importance of the JAVELIN trial which showed practice-changing results with an overall survival benefit for mUC patients.


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

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's Alicia Morgans, and I'm an Associate Professor of Medicine and a GU medical oncologist at Northwestern University.

I am so excited to have here with me today a good friend and a colleague, Dr. Petros Grivas, who's an Associate Professor of Medicine at the University of Washington, as well as being a GU medical oncologist at the Fred Hutchinson Cancer Research Center, and a member of the Seattle Cancer Care Alliance, where he is also the Clinical Director of the GU Oncology Program. Thank you so much for being here with me today, Dr. Grivas.

Petros Grivas: Thank you so much, Alicia. It's always a pleasure to interact with you. And thanks for inviting me to this exciting discussion.

Alicia Morgans: Wonderful. And it is always a pleasure for me to speak with you, too. And since we weren't together in person this year at ASCO, ASCO was virtual as we all know, I thought it would be a really great idea for us to go through some of the highlights of the urothelial cancer program. And there were multiple really exciting advances this year. But we're just going to really focus on three. So, let's talk first about the IMvigor program that was presented by Maha Hussain. Can you tell us a little bit about this? This was in the adjuvant setting, the use of atezolizumab.

Petros Grivas: Sure. This was a very important trial that Dr. Hussain presented at the virtual ASCO, and captured significant attention. As you pointed out, Alicia, this was an adjuvant trial after radical surgery, after radical cystectomy and lymph node dissection, or radical nephroureterectomy. And these patients may have received, or not, neoadjuvant chemotherapy. In other words, neoadjuvant chemotherapy was allowed, but not mandatory in this trial. The patients had a high risk of recurrence, meaning a significant risk of progression after the surgery, based on the pathologic state.

So if someone had received neoadjuvant chemotherapy, if the patient had a pathologic T2 or higher stage, T3, T4 or node-positive disease, could be eligible. Or if someone did not have neoadjuvant chemotherapy, they had to have pathologic T3 or higher stage to be eligible for the study.

And the randomization, as you pointed out before, was atezolizumab and best supportive care observation, which is what we do outside of care now in patients who already received neoadjuvant chemotherapy, or could not receive it because of medical conditions, or refuse it.

So the prominent point was disease-free survival. And there was a significant, I would say, study because we have a paradigm in urothelial cancer. It was very hard to accrue adjuvant chemotherapy trials. However, the study was able to accrue well and met their accrual goal. The primary point was not met. Atezolizumab was not significantly different, compared to observation or surveillance, in terms of disease-free survival. And the overall survival was also not significant, but it was probably not mature enough.

So this came as important news, definitely at the ASCO virtual meeting, and raises many questions about whether immunotherapy is the right strategy in the adjuvant setting. What about the other, there are two other, adjuvant immunotherapy trials. And what about the perioperative trials with neoadjuvant immunotherapy? So many questions we can start if you want, but at least that particular study, the IMvigor010, despite being very significant, did not meet the primary point of disease-free survival in the adjuvant setting.

Alicia Morgans: Yeah, I think that this is something that is so important as a negative trial. Whether it was negative or positive, this information was going to be really important for us as a field to understand.

As you said, this is in the adjuvant setting. These patients may or may not have had neoadjuvant chemotherapy. The addition of atezolizumab right off the bat in the adjuvant setting, in the evidence of no residual disease that we could identify, was not beneficial in terms of prolonging disease-free survival.

As you said, there are ongoing trials. One of the ones that I'm actually participating in as an Alliance site at Northwestern, and you may be participating in studies as well. We're participating in the AMBASSADOR trial, which is using pembrolizumab in this setting, which has, at this point decided to continue on. This is a different drug.

And so, because there wasn't a clear safety signal to the negative with this IMvigor010 study, I think it's reasonable, absolutely, to proceed with the AMBASSADOR trial, which is again, putting in pembrolizumab in that adjuvant setting because there's no negative safety signal. What is your thought about that, and the continued investigation of this particular space?

Petros Grivas: I totally agree with you, Alicia. We have the AMBASSADOR trial open at our site and we accrue patients. Actually, we have a very significant accrual in that study, and we'll continue that. To your point, this is a different drug, different study. I think it's still important to answer the question. So we continue the accrual. There is a third trial with adjuvant nivolumab versus placebo, which has not reported yet. It will be interesting to see the results of that trial. And it is a little bit different mechanism of action.

There is an adjuvant trial called PROOF 302. Dr. Sumanta Pal and Sia Daneshmand are the PIs. And I'm also part of that study, in full disclosure. And this is a study evaluating the FGF receptor inhibitor, infigratinib, in patients who have similar criteria with the IMVigor010 trial. Either with or without neoadjuvant chemotherapy, depending on the pathologic states.

But the tumor tissue specifically has an FGFR inhibitor of 3, mutation or fusion. And, if that mutation or fusion is present, the patients could be eligible if they meet other criteria for the adjuvant infigratinib placebo. And that's another discussion about the placebo versus observation as a control group. But it's interesting to see the results of all those other trials.

Alicia Morgans: Absolutely. So I do think this is going to be an area of ongoing development, but it is very important and helpful for us as a field to have this negative trial, just to inform the use, at least of atezolizumab in this adjuvant setting. So there were multiple other things that were exciting at ASCO 2020, the virtual meeting. Where do you want to go next in terms of the studies that were presented?

Petros Grivas: I agree with you Alicia, very exciting data. I think it's noteworthy to discuss a little bit the updated results in the biomarker work that Dr. Galsky and colleagues did at the IMvigor130 trial.

And you know me well, every time we meet, I talk about biomarkers. So I was very excited to see this work and I got to congratulate Matt and other colleagues in this, and the sponsor who did this work in the IMvigor130. Very important work.

They look at different biomarkers that we thought are related, and we think are related to immunotherapy response. PD-L1 expression, tumor mutational burden, [inaudible] signature has to do with the mutational signature and the cancer tissue, as well as TGF beta in signature with RNA sequencing and RNA gene expression work. Overall, the data was very interesting in my opinion, suggesting that there are certain biomarkers specifically [inaudible] expression, tumor mutational burden, that could actually correlate, were associated with higher response to atezolizumab.

Either it combined with chemotherapy versus chemotherapy placebo, or atezolizumab single agent compared to chemotherapy placebo? And I think this is hypothesis-generating data. I do not think they informed clinical practice yet, but it's a very important step in the right direction. And again, I cannot emphasize how important these studies are.

The other interesting point is that we need to try our best to try to measure the similar biomarkers across different studies, so can validate the work of each other, and do a little bit more coordinated work in our clinical trials, because different sponsors that have different assets, Alicia, as we have discussed before. And this creates a challenge in how to validate a biomarker, and assays across different studies.

The last point I will make about this excellent data, is the TGF-beta signature. And our team and other teams have shown similar results. For example, the KEYNOTE-052 trial, we presented data last year, and Matt Galsky presented data from IMvigor130, as well as the nivolumab trial before that saw that a higher TGF-beta expression in the tumor microenvironment may be associated with less response to checkpoint inhibition.

So the TGF-beta signature may be a mechanism of resistance, and this is something we're working on designing trials now, Alicia, to combine targeting against PD-L1 and TGF-beta. And there are a couple of studies coming up in the near future looking at that.

Alicia Morgans: Yeah, I think that the importance of this work, and to just be very clear, this was an investigation that would need to be validated in other prospective studies, just as you mentioned. Ideally with the same assays and the same drugs. And that's challenging, given that all of the drugs have actually separate assays. But it was really encouraging and interesting to see that there may be some ways for us to understand who may do better with checkpoint inhibitor upfront approach, and potentially patients who may do more poorly with checkpoint inhibitor upfront approach.

So, really just to emphasize the patients who had higher expression of PD-L1, who had two to three, and also had higher tumor mutational burden, seemed to do better in terms of survival with atezolizumab upfront. And even the arm of treatment that included atezolizumab with chemotherapy, platinum-based chemotherapy, did not seem to experience a similar benefit. And then the chemotherapy alone also did not seem to experience that benefit.

And then as you said, that the TGF-beta group as well, seemed to have this poor response with atezolizumab, maybe could do better with chemotherapy. It's just a step in the right direction, to help us understand the heterogeneity of disease, and help us choose the right treatments. But like you said as well, this isn't ready for prime time in terms of treatment decision making, but really exciting as we think about where the field is going.

Petros Grivas: Absolutely. I totally agree, very exciting data. It would be nice to have similar data sets from other studies. Not ready for prime time, as you mentioned, but gives us useful mechanistic insights that can inform future trial designs. And upon further validation, hopefully we'll get the Holy Grail, which is personalized medicine in the future, and do a better job as a scientific community, to select the right patient for the right treatment down the road.

Alicia Morgans: Absolutely. And there is something though, that was presented at ASCO this year, that I think is probably ready for prime time. This was the first overall ASCO plenary that actually was focused on urothelial cancer in the history of ASCO. So it's very exciting that we have reached this milestone presented by Tom Powles, this was the JAVELIN study. Can you tell us a little bit about this?

Petros Grivas: Absolutely. And as you mentioned, Alicia, it's exciting to see all the studies. We talk about IMvigor130, that Matt Galsky presented, very exciting data. And again, I cannot emphasize how important the biomarker work is, and I congratulate them.

At the same time, we saw the results of the JAVELIN trial, which I agree with you, it's practice-changing, and it's really one of those moments in our careers where really it's so humbling. But we're able to hopefully contribute to longer a patient's life and better life in some of the patients. And to be more specific to your introduction here, JAVELIN trial was a randomized Phase III study, comparing avelumab and other anti-PD-L1 agents, plus best supportive care, versus best supportive care alone, in patients who have completed induction chemotherapy with some gemcitabine/cisplatin, or gemcitabine/carboplatin, for five or six cycles.

And they had a response of stable disease. And we know that this benefit doesn't stay forever. It's short-lived. The median PFS is about eight months. So, the goal of that study was to capitalize on this benefit that sits with chemo and maintain it with a switch to maintenance approach, using immunotherapy after chemotherapy, not concurrently.

And obviously these patients with progression moved onto the second-line therapy and were not part of the JAVELIN trial, but those who had residual response were randomized to avelumab best supportive care, or best supportive care alone.

Primary endpoint that was met was overall survival. And there was a significant difference as you implied Alicia, in all-comers, that regardless of PD-L1 expression, and also the subset of patients with high PD-L1 tumors, in terms of the overall survival benefit of a median survival difference of 7.1 months favoring the avelumab arm, with a hazard ratio of 0.69 in all-comers, and 0.56 in the PD-L1 high population with a very significant P-value. And this was corroborated by a significant difference in the PFS, progression-free survival, and also higher response rates in patients on the avelumab arm.

The overall survival benefit was shown to be significant, of course, in the primary endpoint in these populations. But it was also shown in a different subset of patients. If you break it down in a forest plot, you see that all the subsets that you can imagine had some degree of benefit, other bigger, other less benefit with avelumab.

And overall the toxicity profile was consistent with what we expect with avelumab, from platinum-refractory disease or other tumor types, no new signal here. Nothing different compared to what we know from checkpoint inhibitors.

The treatment-related adverse event, immunotherapy related adverse events, any grades were 29% approximately. And the grade 3 treatment-related adverse events was 7%, and there was no grade 4 or grade 5 adverse events. So, overall a well-tolerated treatment.

And I agree with you, Alicia, this is in my opinion, going to change practice right away, the manuscripts should follow up soon and we're waiting for the regulatory review.

Alicia Morgans:  I think that it's great and I'm excited to have an advance for our patients with urothelial cancer. One of the things that I think is so exciting and important about this is that we saw this approach actually seemed to benefit patients with Matt Galsky's work with pembrolizumab in a similar situation where patients were responding to chemotherapy, then receiving pembrolizumab.

We did see that in that Phase II, there was a longer progression-free survival for those patients. Importantly, those patients actually could crossover to pembrolizumab, if they were in the control arm and had progression.

And so whether we'll see a survival difference overall remains to be seen. But that's really not the goal of a Phase II. A Phase II is meant to find that signal, then we verify in a Phase III. But it is nice supportive evidence for the Phase III, this JAVELIN trial. Different drugs, but a similar, at least thought process, and a similar approach.

So, as you're implementing this data in your practice, do you find that you're implementing this maintenance strategy with avelumab? Do you find that you're using other checkpoint inhibitors, to do this maintenance strategy? How is this being actualized in your clinical practice?

Petros Grivas: Great point, Alicia, and I agree with you that Matt Galsky at Hoosier's switch maintenance pembro study, corroborated the idea, and made the primary endpoint of PFS. This was a smaller study with 108 patients and a crossover design. And to your point, it met PFS primary point suggesting that switch maintenance has met primary endpoints in two trials, but did not show an overall survival difference. It was very hard, just because it was a small study, 100 [inaudible] to show overall survival in that mode. So, we're left with a confirmed notion that switch maintenance is the right way to go.

However, when we have to make clinical decisions in clinic, to your point, we have to use Level I evidence. And we train our mentees and residents and fellows and students about evidence-based medicine. And my approach here would be to go with the Level I evidence and use avelumab, based on the overall survival benefits shown in a Phase III study like JAVELIN.

And in full disclosure, I'm the senior author in that study, but I would probably give you the same answer. I think, and I believe regardless of that because it's just the Phase III large Phase II study.

Now, exceptions can happen, right? I had a patient from India, literally. Who reached out, or patients from Greece, who may reach out, and other places where they may not have avelumab available in that country. And I think in those situations it's reasonable to go with another checkpoint inhibitor. Pembrolizumab has data, so I think it's reasonable in those situations with no access to avelumab.

At the same time, if you have access to avelumab, I would go with that, just based on the Level I evidence. Again, scenarios of course can happen. Someone who lives very far away cannot come every two weeks. We can think about scenarios if we're going to use pembro, but I think for the vast majority of patients would go with the larger trial and avelumab.

Alicia Morgans: I agree. And I think it'll be really interesting to see how this plays out. I am very dedicated to the data myself. And as I see these patients, avelumab, as long as it will be feasible for an individual patient, is probably going to be the way that we're going to go. Though of course, as you mentioned, there may be situations where we have to stray from that a little bit, with the hope that we'll still have the same benefit. But of course not ever quite knowing, because we just don't have that level on evidence, which we now have with JAVELIN.

So we do look forward to that publication. We look forward to seeing your name on it, and I so appreciate you taking the time to review the highlights of ASCO 2020 with me, as they regard to urothelial cancer. So if you had to sum up this year's ASCO in terms of urothelial cancer, what would your message be to take home to listeners?

Petros Grivas: I think number one, I would go with what the ASCO president said. Skip made a very good point: unite and conquer. We have to work together, and his message was very strong, and we have to work in teams. And I know you and me collaborate, Alicia, in projects. And I think nothing can come from one person. The approach should be a team. And many teams are larger teams. So, I think that's the spirit of oncology.

And on that note, I think exciting data overall at ASCO, we saw very interesting data across tumor types, we highlighted some data from urothelial cancer and biomarkers that practice-changing and avelumab, in the context of other studies we mentioned. And also, I think at another point, it was very interesting and exciting to see the work with a COVID-19 and cancer consortium, that you and I discussed in different podcasts.

Just another example of teamwork, how can one generate data for patients with cancer and COVID-19? And that it will be more data coming up. There is a publication now at Lancet, as of May 28th 2020, that the audience can look at this, across tumor types, of course.

But more data will come and hopefully more data specifically to GU cancers. So there was a nice overall presentation at ASCO about that. But overall, the field is moving forward. And despite COVID-19, I thought that ASCO virtual was a success. And at the end of the day, the data is the data.

Alicia Morgans: That's a great message. Of course, at the end of the day, the data is the data, but it does take an entire community to pull it all together. Our patients know this, they know that they're never in it alone. And I do think that it is so important and so special that the urothelial oncology community, the larger GU oncology community comes together every day, all the time, to get the data for the patients, to do what's right. So, thank you so much for sharing your expertise and reviewing ASCO 2020 for urothelial cancer with me.

Petros Grivas: Thank you so much, Alicia.