The Future of Immune Checkpoint Inhibitors in the First-Line Treatment of Metastatic Urothelial Carcinoma - Andrea Apolo

February 23, 2023

Andrea Apolo, head of the bladder cancer section of the genitourinary malignancy branch within the NCI, joins Sam Chang to discuss first-line therapies for patients with advanced and metastatic urothelial carcinoma. Dr. Apolo explains that several clinical trials have been developed to improve outcomes in patients in the first-line setting by combining chemotherapy with checkpoint inhibitors. One of these trials is the IMvigor130, which combined platinum-based chemotherapy with atezolizumab. However, the trial did not significantly improve overall survival compared to chemotherapy alone. Similarly, the KEYNOTE-361 study combining pembrolizumab and chemotherapy showed numerically higher overall survival but did not reach statistical significance. Ongoing trials may have different outcomes, and it is difficult to predict whether there will be a difference based on PD-1 and PD-L1, length, or combination of therapies. In closing, Drs. Apolo and Chang summarize more data is needed before we use PD-L testing because the results of these trials have not really identified the patients that respond the best using PD-L1. It is not yet a marker that we can utilize specifically in bladder cancer.


Andrea Apolo, MD, Medical Oncologist, Senior Investigator, Center for Cancer Research, National Cancer Institute, Head of Bladder Cancer Section, Genitourinary Malignancies Branch, Director of the Bladder Cancer and Genitourinary Tumors Multidisciplinary Clinic, Bethesda, MD

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, my name is Sam Chang. I'm a urologic surgeon at Vanderbilt University in Nashville, Tennessee, and we are very, very fortunate to have Dr. Andrea Apolo with us today. Dr. Apolo is the head of bladder cancer section of the genitourinary malignancy branch within the NCI. Dr. Apolo recently discussed at ASCO GU 2023 different first line therapies for patients with advanced and metastatic urothelial carcinoma. So thank you so much, Andrea, for being with us here today, and we look forward to your insights into different treatment options regarding bladder cancer. What's the background behind these studies?

Andrea Apolo: Thanks so much for having me here. I always love coming and chatting about bladder cancer updates. So let's talk about the first line treatment for patients with metastatic disease. Generally what we do is we divide the patients by cis-eligible and then cis-ineligible. The overall survival for these patients just with chemotherapy alone ranges from nine months with carboplatin based combination to 13 to 15 months with cisplatinum based combination.

But we do have checkpoint inhibitors that have been approved in the second line setting. So in order to improve the outcomes in patients in the first line setting, several clinical trials have been developed combining chemotherapy with checkpoint inhibitor in patients with metastatic urothelial carcinoma. And one of these is the IMvigor130 that combined platinum-based chemotherapy with atezolizumab as one arm and then it also had atezolizumab as a single arm versus chemotherapy and placebo.

So this was a pretty large trial, 1200 patients. And there have been other trials that have also done this, including the KEYNOTE 361 study that's combining pembrolizumab and chemotherapy. It also has a pembrolizumab monotherapy arm and a chemotherapy arm. There's been also the NILE study, which is combining durvalumab plus chemotherapy, and durvalumab plus tremelimumab, and chemotherapy versus chemotherapy, and then also the CheckMate 901 study, which is nivo ipi versus nivo plus cisplatin based chemotherapy versus chemotherapy.

So those are pretty large phase III trials that are asking this question about how do we improve outcomes in patients with metastatic disease by adding on checkpoint inhibitor to patients receiving platinum-based chemotherapy.

Sam Chang: So Dr. Apolo, let's focus on the IMvigor130 trial that was recently presented in terms of the examination of final overall survival. What were the key findings from that trial? And looking at the combination of etizo with platinum-based chemotherapy versus chemotherapy alone, what were the key findings?

Andrea Apolo: So that was arm one, and the study just for background was designed as hierarchal design. So first they tested the progression-free survival for the chemotherapy plus the atezolizumab, and then if they met that primary endpoint, which they did, that was actually reported at ESMO 2019, then they go on to assess the overall survival. So when they did an interim analysis of the overall survival at ESMO 2019, it looked promising, but it did not reach the statistical significance.

So we were really looking forward to the overall survival data for this trial for the combination of atezolizumab plus platinum chemotherapy. So the study results were presented and the median overall survival for patients receiving the chemotherapy was 13.4 months, and then for those receiving the combination of platinum-based chemotherapy plus atezolizumab was 16 months. So numerically a little bit higher, but statistically not significant.

Therefore, we concluded that clinically there was not a value for adding atezolizumab to platinum-based chemotherapy for the intend to treat population. And this was a little disappointing, but it's in line with what we had seen before for the KEYNOTE 361 study. We saw very similar results when we combined pembrolizumab, and this was presented at ESMO 2020 and it was a big shock to us.

But when pembrolizumab was added to platinum-based chemotherapy in the first line setting, again, the median overall survival for that was 17 months and the chemo arm was 14 months. So very similar, a little bit higher numerically, but statistically not significant. So that was very disappointing. Something that I did mention is that often these combination trials are compared to the JAVELIN bladder 100 study where the checkpoint was given after the platinum-based chemotherapy.

But what I want to emphasize is that it's not the same population because these are the responders to platinum-based chemotherapy. So it's a good population of patients versus in the IMvigor130 and in the KEYNOTE-361, this was all patients. So it's not really a fair comparison, although something to think about is that both the IMvigor130 and the KEYNOTE-361 did have a maintenance component to it.

So the patients received the chemotherapy plus the checkpoint, but then they could continue the checkpoint for the IMvigor130 until progression and the KEYNOTE 361 for a maximum of two years. Within all these studies, patients received about six to seven months of median of checkpoint inhibitor.

Sam Chang: Do you think with these results that it's somewhat, I think, discouraging for the other ongoing trials, or are we going to have a similar finding where perhaps some will be positive and some will be negative? I know it'll be difficult to predict, but could there be a difference between PD-1 and PD-L1? Could it be a difference in terms of the length? Could it be a difference in terms of combination? What do you think may be happening or may happen when these other phase III trials read out?

Andrea Apolo: Yeah, that's a great question. And one of the things that I think that we found interesting when reviewing this was that if you look at the subgroups, now this is all exploratory when you combined the atezolizumab with the cisplatinum based chemotherapy, the patients actually did better than when you combine it with carboplatin based therapy, and this was even more true in the patients that were PD-L1 high, using the Ventana SP142 assay, which is the assay that's used with atezolizumab.

And the reason that that is encouraging, although we didn't see that in the KEYNOTE-361 study, mind it didn't make a difference when you combine pembro with or carboplatin. But the reason that that was hopeful was because several of the trials, including the CheckMate901 study does have an arm that combined that combines nivolumab with cisplatinum based chemotherapy specifically.

I think it's even more important because we have several ongoing neoadjuvant trials combining checkpoint inhibitors with cisplatinum based chemotherapy for patients with muscle-invasive disease, including the NIAGARA study that has durvalumab plus gem/cis, the ENERGIZE study that has nivolumab plus placebo plus gem/cis, and the KEYNOTE- A66 study that has the pembrolizumab and gem/cis. So I think that's why it's important, but we don't know if it will make a difference depending on the chemotherapy that's used.

Sam Chang: And in looking at other possible combinations. Dr. Apolo, what do you think? Obviously there's been some excitement when we look at you differentiated between the cis-eligible versus the group that would normally get carboplatin. What about in those patients that are really at this point cisplatinum ineligible, that we look at a combination of carbo plus gemcitabine plus then maintenance therapy versus some perhaps more promising dialogue, at least from a urologic standpoint? We hear so much about enfortumab vedotin plus pembro. What is out there in terms of comparison for those patients that are cis-ineligible?

Andrea Apolo: So at ESMO 2022, last year, they presented the results of EV 103 cohort K, which is a study of enfortumab vedotin plus pembrolizumab. And the overall response rate was 65% for patients that were cisplatinum ineligible. So that was exciting. That was, I think, really good results in this patient population. 65% is in line with kind of what we see even better than what we see sometimes with gemcitabine and carboplatin followed by avelumab maintenance.

And then we're awaiting the results of the EV 302, which is a phase III trial in the first-line metastatic setting of EV plus pembro versus platinum-based chemotherapy. That study is fully accrued and we're waiting for the data. And there's also EV plus pembro in the neoadjuvant setting that's EV 304. That study is ongoing right now in patients with muscle-invasive disease of EV plus pembro versus chemotherapy.

So because of the cohort K results, the company actually in December submitted an FDA application for priority review and to receive accelerated approval for the combination of enfortumab vedotin plus pembrolizumab in the first line treatment specifically of cisplatinum ineligible patients. So we'll see how that goes.

Sam Chang: Yeah. That's very exciting news. So with that accelerated approval, should we hear something? Give me an estimate of when we think we would hear something.

Andrea Apolo: I would say by late spring, early summer probably.

Sam Chang: Okay. So we're not in Las Vegas. I'm in Nash Vegas. So let's say we play the gambling odds and let's say it gets approved. What do you think the uptake would be? And I don't want to put you in a difficult situation, but when you do the comparison of the EV plus pembro combination versus the carbo gemcitabine and maintenance with avelumab in terms of length of time and continued treatment, what do you think the uptake would be?

Andrea Apolo: I think that it will be used, it will become an option, and people want to be able to provide options for patients. I think chemotherapy will still be used. People feel very comfortable with carboplatin gemcitabine in the first line setting followed by avelumab, and I think that will probably continue to be the main combination used. But I think many people may adopt EV pembro as a first line option.

There's a lot of questions that we still have as to the combination of EV pembro. Can we dose reduce, can we de-escalate, can we just stop the EV and continue the pembro as maintenance? So I think those efforts are ongoing to develop trials where the therapies are stopped because as of right now, they're given continuously.

Sam Chang: So I've kind of put you on the spot regarding predicting which therapies would in fact perhaps win out in those patients who are cisplatinum ineligible. Tell me this, what do you think at this point would be the most exciting kind of therapy in the neoadjuvant setting? You mentioned looking at EV in the neoadjuvant setting. What else out there is exciting for you at this point?

Andrea Apolo: I think the antibody drug conjugates. So in addition to, there's several others that are currently being tested in the metastatic setting and some of them are being brought to the neoadjuvant setting. I think that's pretty exciting.

Sam Chang: How about the monotherapy arm when you consider those therapy options?

Andrea Apolo: Yeah, so the IMvigor130 study also had an atezolizumab monotherapy arm. And like I mentioned before, there's several phase III trials that also looked at monotherapy arms, including the KEYNOTE-361 with monotherapy pembrolizumab, the CheckMate901 with nivo ipi, although we did hear the press release that the arm for nivo ipi of the CheckMate901 did not meet its primary endpoint. And there's also the DANUBE study. So the DANUBE study was presented already at ESMO, and this is the study of in metastatic patients, durvalumab, durvalumab plus tremelimumab versus chemotherapy. And that has been reported.

So for the IMvigor130, the monotherapy arm was really technically exploratory because of the hierarchical design and not meeting the overall survival for the combination arm. But there was statistically no improvement for monotherapy atezolizumab versus platinum-based chemotherapy. And when we looked at the Kaplan-Meier curves, we saw very similar curves for the IMvigor130, the KEYNOTE-361 study and the DANUBE, where the chemotherapy patients do really well in the beginning and then the checkpoint monotherapy arm crosses over somewhere between nine to 12 months.

And that has to do a lot with the mechanism of action of the drugs. The chemotherapy work in a higher number of patients. It works faster, but the durability is not that long as opposed to the checkpoint inhibitors that work in a smaller number of patients, but it has a greater durability. So what was very interesting about the IMvigor, so I just want to mention the KEYNOTE-361 monotherapy pembrolizumab study was negative.

The DANUBE study with monotherapy durvalumab was negative. And the DANUBE study with the tremi and the durvalumab arm monotherapy versus chemotherapy was also negative, did not mean its primary endpoint. So that was unfortunate. However, in the exploratory analysis, looking at the PD-L1 high patients that received the durva/tremi, this is the DANUBE study, they did see that potentially the patients might have done better with the combination of durva/tremi versus chemotherapy. But this was all exploratory.

So going back to the IMvigor 130 study, when we looked at the biomarker, so again, this is the PD-L high patients, we saw that the patients that were PD-L1 high actually did better than the patients that were PD-L1 low for the monotherapy atezolizumab arm. And we specifically look at the patients that are cisplatinum ineligible. Those are the patients where this is indicated.

The atezolizumab is indicated in cisplatinum ineligible patients that are PD-L1 high. We actually saw that those patients did really well with monotherapy atezolizumab. So unfortunately, the label was voluntarily withdrawn by the company for monotherapy atezolizumab. But that's actually where, now this is exploratory because of the hierarchical design and statistically the way that the trial was designed, but that's really where we see activity for atezolizumab that's in the monotherapy arm in patients that were cisplatinum ineligible that were PD-L1 high. So I just kind of wanted to mention that.

Sam Chang: No, I think that's really important. But to be honest, it only adds to, from my standpoint, the confusion of what do we do with PD-1 and PD-L1 in terms of it being used consistently and effectively as a biomarker to really be truly predictive. Because there have been mixed signals, and I love the idea of being able to just, as you say, identify those patients that are most likely to benefit, but I think, do you agree then the next steps would be, again, larger studies based upon these cohorts that have some suggestion?

And are we going to be able to do that or are we going to get data from registry trial? What do you think is going to happen with our current PD-1, PD-L1 staining to help predict which treatments we should actually use?

Andrea Apolo: Yeah, that's a very complicated question because there's so many different tests. Every-

Sam Chang: Bingo.

Andrea Apolo: ... drug has a different test, looking at different cells. Some of them look at the tumors, some of them the immune cells.

Sam Chang: Inflammatory cells. Exactly.

Andrea Apolo: Different cutoffs.

Sam Chang: So what do we do?

Andrea Apolo: Well, I mean, I would say that if you're going to use an use a drug, you have to use the antibody for that drug-

Sam Chang: Yeah, okay, great.

Andrea Apolo:... those specific cells and using that cutoff. So it should be really restricted to that. And that's hard to do in the community. So it's not something, and I think that's what has been very complicated about using just PDL high, because it's not just PDL high, it's specifically the Ventana SP142, looking at the immune cells, using 5% as the cutoff. So that's where it becomes really complicated.

Sam Chang: So what do you think will ultimately, though, in all honesty, to help differentiate between these monotherapy or combination therapies or specific PD-1 versus PD-L? We're going to have to probably utilize in some way, some of these markers to help differentiate what's best for individual patient populations. Do you agree with that?

Andrea Apolo: I do as long as there's guidelines for everyone to know what to use for which specific drug, yes.

Sam Chang: So my next follow-up question is, are we going to get to that level of granularity where for each of these treatments, we're going to have to use the specific test prior to initiating that treatment to really determine if that's the best treatment. So in other words, our histopathologists, or are groups helping us determine are we going to have to do 10 or six, four, three different tests? Well, you think is going to ultimately happen, say a year or two from now I don't think much will change, but five years, 10 years from now, what do you think?

Andrea Apolo: Well, I think for now we don't use PD-L testing at all because of the results of these trials have not really identified the patients that respond the best using PD-L1. So it hasn't been a marker that we can yet utilize specifically in bladder cancer. So I would say it's not really a problem for us right now. What I do want to say is that when we looked at the IMvigor 130 monotherapy arm and we look at the patients that were PDL high in the cisplatin ineligible, they did benefit.

So maybe it's something that we can still do if you have a cisplatin ineligible patient and you specifically use the SP142 Ventana, they may still be a rationale for using atezolizumab, even though the label has been withdrawn. I don't know how that would work with FDA approval and with insurance coverage, but I think it's still an active drug. So that's something to consider.

Sam Chang: Thank you again so much, Andrea, for all your knowledge and for all your insight and for all your honesty in terms of, yeah, there's confusion. Yes, there are areas of uncertainty, but clearly there are areas of expertise focusing on certain subgroup populations that may actually really benefit different from the general population. And I think your insight is incredibly helpful for all of those who are treating patients who now have many more options, and hopefully many more soon as you discussed about hopefully accelerated approvals in the near future. So thanks again for your input and your insight, and we look forward to talking to you again.

Andrea Apolo: Thank you so much. It's my pleasure. Thanks for having me.