For Bladder Cancer Patients, New Hope From Immunotherapy Innovations from ESMO 2023 - Petros Grivas

November 14, 2023

Ashish Kamat and Petros Grivas discuss recent advancements in metastatic bladder cancer treatments from ESMO Congress 2023. Key highlights include the CheckMate-901 and EV-302 trials. Dr. Grivas highlights the CheckMate-901 trial's success with the combination of gemcitabine, cisplatin, and nivolumab, which shows notable improvements in overall survival and progression-free survival with a manageable toxicity profile. He emphasizes the EV-302 trial as particularly transformative, showcasing the effectiveness of enfortumab and pembrolizumab over chemotherapy in advanced urothelial carcinoma. Dr. Grivas asserts that this combination is now the preferred standard of care where accessible, potentially replacing other treatments like gemcitabine/cisplatin/nivolumab. They also discuss the role of erdafitinib for patients with specific FGFR2 or FGFR3 mutations, proving effective over standard chemotherapy. They conclude with an emphasis on the need for multidisciplinary approaches, patient-specific considerations in treatment choices, and continued research, particularly in locally advanced bladder cancer cases.


Petros Grivas, MD, PhD, Associate Professor, Department of Medicine Division of Oncology, Clinical Director, Genitourinary Cancers Program, University of Washington Medicine, Seattle, WA

Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX

Read the Full Video Transcript

Ashish Kamat: Hello, and welcome again to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, and I have the distinct pleasure of welcoming again, one of our dear friends, and guests, and experts, and everything to do with urothelial cancer, Dr. Petros Grivas. Petros, thank you so much for taking the time.

So much happened at ESMO this year, when it came to bladder cancer in general. Especially in the field of metastatic cancer, where a major breakthrough, and a huge win for our patients occurred. And you were there, right in the heart of things, participating, being part of all these trials. And it's really great that you could spend some time with us today, to sort of distill down what you think are some of the key takeaways in bladder cancer from the ESMO meeting. So Petros, the stage is yours.

Petros Grivas:
Thank you so much, Ashish. You are totally right. It was such an amazing experience to be there at the ESMO Congress 2023 in Madrid. So much happened, and really real transformative data sets in the field of metastatic urothelial carcinoma. I'll try to make it as brief as possible, because there's so much data to cover. So I will just focus on a couple of data sets that I think are really important, especially for metastatic urothelial cancer. And to your point, there's so much else going on in the field of non-muscle invasive disease. Maybe you and me will talk in another podcast or webinar about the other therapy settings in bladder cancer.

These are my disclosures.

And I will jump right in with the CheckMate-901. This is a first-line metastatic urothelial carcinoma. Front-line space patients did not have any prior therapy for metastatic disease. They were cisplatin-eligible, and you see that this includes ECOG P 0 to 1, and other eligibility criteria for cisplatin. Then they got randomized to gem/cis chemotherapy, up to six cycles on a 21 day cycle, versus gem/cis plus nivolumab. Nivolumab was given at the same time, concurrently with chemotherapy, and continued as continuation maintenance for up to two years, unless there was progression or toxicity happening in between. And this trial had the primary endpoint of overall survival and progression-free survival as per a blinded independent review committee. Patients were stratified based on liver metastasis, yes or no, and the PD-L1 expression.

Here, the slide with the primary endpoint. The trial met the primary endpoint of overall survival. This was statistically significant. You see that the curve starts, separating early on, maybe about the time that the chemotherapy completes, and there is some suppression of the curves continuing. You see that about 47% of patients remain alive at two years. And you see the hazard ratio 0.78 favors gem/cis/nivolumab over gem/cis. Now, progression-free survival was also statistically significant, favoring gem/cis/nivo over gem/cis. You see about a quarter of the patients are progression-free and alive in two years. And you see, again, the hazard ratio, statistically significant, 0.72, favoring the concurrent gem/cis/nivo combination over gem/cis.

Now, toxicity is important. Every time you add a treatment to something else, you may add more toxicity, you may add cost to the system. The combination is manageable, feasible. You see that the occurrence of treatment related adverse events in each group in this slide. And you see that obviously, nivolumab can cause immune related adverse events. There was no surprise in this study in terms of toxicity. There was no new safety signal. It's what we would expect with the addition of a checkpoint inhibitor to the backbone of chemotherapy. So I would say overall, the combination is feasible. And of course, we have to be cognizant of the side effect profile of chemotherapy and the checkpoint inhibitor.

This is a summary slide that Dr. Michiel van der Heijden showed at ESMO in his talk at the Presidential Symposium. There was a significant improvement in progression-free and overall survival with the addition of nivolumab concurrently, and then as continuation maintenance with the gem/cis backbone. Overall response rate I did not show, but it was higher with the gem/cis/nivo. I think it was about 57% or so with the combination, was 43% with gem/cis alone. And interestingly, 22% of patients with gem/cis/nivo had a clinical complete response. And the median duration of complete response was about three years. So there was durability of response in those complete responders. And again, the nivo continued for up to two years.

There was no surprise, in terms of toxicity, there was no new safety signal. And I think that combination is one of the standard of cares. And especially I would make the point, for patients with no access to pembrolizumab/enfortumab. We'll see the data of that combination in a second. And also, in very few patients where an enfortumab vedotin may not be a great option, for example, for greater higher neuropathy, or some other clinical reason, that the patient cannot tolerate or refuse enfortumab. In those cases, if someone is cisplatin eligible, gem/cis/nivo is one of the options.

And at this point, it's a great segue to talk about the EV-302 trial, that received a standing ovation that we experienced with thrilling moments at ESMO 2023 in Madrid. This is the same patient population in the front-line setting of advanced urothelial carcinoma. These are patients who were eligible for cisplatin or carboplatin, so it'll be the broader population. ECOG PS 0, 1, or 2. Patients received a combination of enfortumab plus pembrolizumab, an anti-Nectin-4 antibody drug conjugate plus an anti-PD-L1, and that combination was compared to chemotherapy. As I mentioned, gem/cis/carbo for up to six cycles.

There's a lot of discussion about maintenance avelumab in the study. Maintenance avelumab was allowed, it was not part of the study schema, it was allowed, and about one third of the patients received avelumab at some point. This is in the control arm. And there was an amendment, at some point later on, to clarify that avelumab palliative was allowed. As I mentioned, only about a third of the patients received avelumab maintenance in the chemotherapy control arm. And patients were stratified based on cisplatin eligibility, liver metastasis, and PD-L1 expression.

This is the progression-free survival data, significant. And I would say dramatic improvement favoring pembrolizumab/enfortumab. And you see a hazard ratio 0.45. And the doubling of the median PFS favoring pembro/enfortumab over chemotherapy. And you see that 44% of patients are progression-free and alive at 18 months with pembro/EV combination.

Overall survival, that's where we saw the standing ovation. You see a significant, phenomenal, I would say, improvement in overall survival. Hazard ratio 0.47 favoring pembro/EV. There was a doubling of median overall survival from the conventional numbers we have for decades. It was about 16 months, up to approximately 32 months, with the combination of pembro/EV. It's very interesting, in my opinion, to see the subsequent therapies in the manuscript that will come up in the future. I assume that there are very, very few patients who had access to EV in the chemotherapy control arm. And that part, along with only 30% that got maintenance avelumab, may have explained the magnitude of benefit, the degree of hazard ratio. But still, this is an impressive result, and I think it's transformative for the field, with almost doubling of median overall survival. And you see that about 70% of patients are alive at 18 months. And the benefit with pembro/EV applied to both cisplatin eligible and cisplatin ineligible patients in both categories. And you see, it's a very significant difference between pembro/EV and chemotherapy in both cisplatin eligible and ineligible patients.

The forest plot is also impressive. You see that across the board the significant benefit in favor of pembro/EV applies across different subsets of patients. And this difference, it's very significant. You see, there is no subset that crosses one. So very, very significant benefit across the board.

Toxicity is something very important to discuss. Obviously, we need to pay close attention in the clinic for our patients regarding toxicity. And 56% of patients, a little bit more than half, had grade 3 or higher treatment related adverse events with the combination. Peripheral neuropathy happened in about half of the patients, skin rash, pruritus, alopecia, fatigue, nausea, anorexia, dyspepsia, diarrhea, and cytopenias can be seen with enfortumab. And hyperglycemia can happen too. It requires very close attention. The treatment related adverse events that resulted in death was rare, it was 0.9% in each arm. And you'll see the details in the slide about toxicity.

To conclude, I borrowed a slide by the fantastic discussion by Dr. Apolo. You see that both studies, CheckMate-901 and EV-302 were positive. I think I agree with Dr. Apolo, that based on the totality of the data pembro/EV, anti PD-L1 plus the anti-Nectin-4 antibody drug conjugate is the standard of care, the preferred standard of care for patients who have access to it. And that's a whole other discussion about countries in the world that may not have access to this combination. Because of course, that's a whole separate discussion of global oncology, and of course, equity of care. But I think, if you have access to pembro, this standard of care, maybe for some rare patients, as I mentioned, who may not be able to tolerate EV, and those who have discussed other options.

And I think there are multiple unanswered questions that I put into that slide. What about second-line therapy? What about de-escalation? What about underlying biology? What about earlier therapy settings? As an expert in bladder cancer, we are thinking about all the spaces, non-muscle invasive bladder cancer, muscle-invasive. Can we cure more patients with these combinations early on? That's the open questions with ongoing trials.

We talk about the access to care. And what about prior checkpoint inhibition? What do you do in patients who had adjuvant nivolumab, for example. Or, potentially pembrolizumab for BCG unresponsive, high risk non-muscle-invasive disease. These are open questions we need to answer.

And before we go and conclude the presentation, I want to briefly point out that the third trial was very important, and I would say, a very interesting trial. These are patients who had prior immunotherapy, many of them had prior platinum-based chemotherapy as well, and they received either erdafitinib an oral FGFR inhibitor, or salvage chemotherapy, taxane, docetaxel in the US, or vinflunine in Europe.

And that trial is only for patients with an activating mutation or fusion in FGFR2 or FGFR3. A selected patient population. It's about 20% of patients with metastatic urothelial carcinoma who have this biomarker positive. It's very important to test our patients for metastatic urothelial carcinoma with this biomarker. We used to do genomic sequencing in the tumor tissue to evaluate, and sometimes we may also add, additionally, ctDNA in addition to tissue, to look for those genomic alterations. FGFR2, FGFR3 activated mutation or fusion. Erdafitinib prolonged overall survival, compared to docetaxel or vinflunine, in this particular patient population. Hazard ratio 0.64 favoring erdafitinib. Median overall survival, 12 versus about eight months. And this, I think, cemented the role of erdafitinib. The question is the optimal sequence of this agent. We'll come back to that in a second.

The forest plot saw that more or less, with different degrees of benefit and magnitude of benefit, erdafitinib was superior to taxane or vinflunine. And again, should be given before taxane or vinflunine. And you see here, the different forest plots analysis with different subsets in this slide.

And the last point is the cohort two of the third trial. This is a cohort that randomized patients to erdafitinib, the same oral FGFR inhibitor, compared to pembrolizumab, anti PD-L1. These are patients who are platinum refractory, had progression on platinum, did not get maintenance avelumab. Had an ECOG P of 0,1, or 2. If they had the biomarker positive FGFR2 or 3 mutation or fusion, they were selected, and they were randomized to erdafitinib or pembrolizumab. Primary endpoint was overall survival. Again, this is a kind of platinum refractory second-line setting for example.

And this is the overall survival curve. There was no significant difference between erda and pembro. The curves are close together and the median was about 11 months in both arms.

Also, PFS. There was no significant difference between erda and pembro in the PFS. You see, the curves are very close together. There was a numerical advantage of erda, but this did not reach statistical significance.

The response rate, however, was almost double with erda, 40% versus 22%. So my take on it is, patients who need a response right away, with visceral metastasis, liver mets, symptomatic disease, high cancer burden, you need a response. Erdafitinib is a very attractive option for those patients with FGFR2 or 3 mutation or fusion. However, if you get a response with pembro, that can be durable. So the overall response rate favored erda, the duration of response favored pembro. And I think overall, at the end there was no significant difference in survival.

Toxicity profile, there was, as expected, erdafitinib can cause nuanced toxicity, sometimes requiring consultation with an ophthalmologist at baseline and during treatment. An Amsler Grid to check for blurry vision. And a clinical and lab evaluation, hyperphosphatemia, stomatitis, nausea, diarrhea, dry mouth, nail changes, Heerfordt syndrome, hyponatremia, were noted. And with pembro, the classical immune related adverse events as we all know.

This was how I used to treat metastatic urothelial cancer before ESMO. Gem/cis followed by avelumab maintenance, or gem/carbo followed by avelumab maintenance was my preferred option in cisplatin eligible and ineligible patients, respectively. And subsequent therapies, of course, depended on first-line therapy, prior therapies, organ function, performance status, and comorbidities and toxicity profiles.

Clinical trials are very important. And now, this is the slide that shows how I treat urothelial cancer after ESMO. And I think pembro/enfortumab is the preferred option in patients who have access and can tolerate it. In countries where pembro/EV is not an option, I think in cisplatin eligible patients, gem/cis plus nivolumab is attractive.

We have, of course, a JAVELIN Bladder 100 paradigm, with gem/cis followed by maintenance avelumab. It's hard to compare those two trials in patients who are cisplatin ineligible. Carbo/gem followed by avelumab maintenance is a standard of care still in countries with no access to pembro/EV. And subsequent therapies, of course, depend on all these factors; prior therapies, organ function, performance status, comorbidities, toxicity profiles, level of evidence provided, familiarity, patient preference, and therapy burden. And of course, clinical trials are still the way to go.

Thank you so much, Ashish. There's so much data here to talk about. And I'm really, really happy that we had the chance to cover the key highlights.

Ashish Kamat:
Absolutely, Petros. So Petros, you covered everything so well, which you always do. And our audience can go back and listen and review. So let me ask you some practical questions that our audience, which, as you know, is a lot in North America, but many in Europe and across the world. Is the new standard of care EV/pembro for first-line?

Petros Grivas:
I think the short answer is, yes. I think the degree of benefit is really, really impressive. There are caveats, as I mentioned. The proportion of patients who get maintenance avelumab is only 30%. Although you may argue, it's not too different from some real world data with Flatiron. At the same time, the access to EV on the control arm was very, very small, if any. Having said that, I think the degree of benefit was so big that I think, even with those caveats, this is transformative. And I think pembro/EV is the preferred standard of care in patients who have access to it and can tolerate it. And I would say, I can envision very few patients, I have to think hard, who cannot tolerate EV. But maybe patients with very bad neuropathy or a higher rate. Maybe uncontrolled diabetes, or obesity with liver disease. You have to think through some scenarios. But I think across the board, pembro/EV is the preferred standard of care, and hopefully there will be access to it.

Ashish Kamat:
Great. And a few years ago, or even last year, if the CheckMate data had come out, we would've been all jumping up and down, because it was so exciting and positive. But compared to the EV data, it really didn't pan out. But you've raised a good point about access to EV. So if people don't have access to pembro/EV, then your standard of care would be gem/cis/nivo. Yes? Or would you still recommend dose dense MVAC over gem/cis?

Petros Grivas:
Great question, Ashish. It's always very difficult to compare across trials. I agree with you, that it was very hard what Dr. van der Heijden did to get to the stage, just after the standing ovation that Dr. Powles had. It was a very hard act, right? But I think he did a great job presenting the CheckMate-901 data in the plenary session. Both Tom and Michiel did a fantastic job. I think practically speaking, again, pembro is the preferred standard of care in my opinion, and should be given. In patients who have no access to pembro or cannot tolerate EV, now you can argue why? If it's neuropathy, grade two or higher, cisplatin may not be a good option either.

But let's say pembro/EV is not available. I think the question is, do you do gem/cis followed by avelumab? Do you do dose dense MVAC followed by avelumab? Do you do gem/cis/nivo? It's hard to answer this question, because it's apples and oranges. The attractive points that may make you choose gem/cis/nivo is the higher response rate. The higher durability of response, especially with a 20% of complete responders. The lower primary progression rate was less than 10%. Those who had progression as the best response, obviously, you have to maintain that no progression to get to maintenance. But I think that these points may make gem/cis/nivo attractive. But we don't know exactly the contribution of the concurrent nivolumab component, versus the maintenance, as we had in JAVELIN.

So it's a hard question. I think it's a discussion with the patient. I assume many patients might opt to get the IO upfront, to try to attempt to stay on therapy with less progression rate. But I think still, the discussion has to happen with the patient, with all those important and positive trials.

Ashish Kamat:
Great. Petros, I want to pick your brains for a few more points, if you have the time. One is from the perspective of your urology colleagues, right? Because both of these studies were predominantly in metastatic patients, but there were some lymph node only patients in both the trials. And for decades now, going on almost 30 years, the paradigm we've followed is that, if someone has node positive disease, and responds really well to systemic chemo, what do we do with the local disease, right? And before the JAVELIN study, it was radiation, surgery. We really didn't have much to offer the patient. After JAVELIN, we're like, okay, now we have to have a debate. Do we go on maintenance? Or is the patient having symptoms, and would they benefit from local consolidation? How does EV/pembro and the gem/cis/nivo... Or let's talk about EV/pembro, since that's the big elephant in the room. How does that data in the non-metastatic lymph node only positive patients or locally advanced patients, factor in your thinking as to, will these patients require consolidation? Can they go on forever? Clearly not, right, with EV. So how does that factor in?

Petros Grivas:
It's a great question, Ashish. And I remember we had a great debate with a good friend, Dr. Max Kates from Johns Hopkins, at the AUA in Chicago. It was April of this year. And we had a scenario of a clinical node positive and N2, I think, patient scenario. And we had patients had a wonderful complete clinical response to gem/cis. And again, the JAVELIN Bladder 100 still, it's a very important trial we think about. And that patient had a clinical complete response with N2 disease. The question is, what do you do? Do you do consolidation, or radical cystectomy, lymph node dissection? Do you do consolidation chemoradiation? Do you do maintenance avelumab in that N2 patient with no distant mets and complete response on imaging? And that was a great debate. I think this question will become again relevant in the context of pembro/EV, when you have more effective systemic therapies with a higher chance of complete response.

By the way, the complete response rate with pembro/EV was 29%. We have to see, of course, who are those patients? And I bet it's much higher chance to have a complete clinical response if you have lymph node only disease, to your point. Like localized bladder area and resectable lymph node disease. So we have to see in the manuscript, how many of the complete responders are those kind of locally advanced versus metastatic disease.

And in the locally advanced scenario, I think it begs the question, what is the role of consolidation in those patients? So I think this is the value and importance of the sometimes luxury of having multidisciplinary and interdisciplinary tumor boards, like the one you guys have, and we have at the University of Washington. We take the time, we have the urologist, rad-onc, med-onc, pathology, radiology. We look at the scans before and after treatment, pembro/EV for example. We see how the patient is doing clinically. What is their performance status? What tolerability? How the patient is doing, patient preference, location of the disease. And we make a very nuanced complex decision-making about potential consolidation.

I think your question is great, and ideally requires some degree of data, either real world data and/or clinical trial data. I think in the future, since we have two trials moving pembro/EV in the perioperative space, KEYNOTE-B15 in cisplatin eligible patients, pembro/EV versus gem/cis in cisplatin ineligible patients, the KEYNOTE-905. I may be wrong, but I think it's likely that pembro/EV might move to the earlier disease, perioperative disease space. And that may make this discussion even more practical and relevant.

And then the question, the separate discussion question is, what about bladder preservation? Can we potentially find a biomarker and cure patients with pembro/EV alone early on? Open questions, and I'm excited to keep working with you, my friend, and try to find the answers.

Ashish Kamat:
Yeah. No, there's so much to talk about, Petros. We're going to have to obviously bring you back on this forum, but stay tuned for the AUA. We're going to have another IBCG AUA forum next year. They've given us a platform. You are definitely going to be part of it, so come prepared. I'm going to have you debate some sticky points. I always look forward to it.

Petros Grivas:
I look forward to it. That's how we learn. And that's why we had this Uromigos podcast at the meeting this last weekend in Nashville, Tennessee, and one of the highlights were this educational value of having this kind of medical jeopardy setting of the Uromigos camp. And we all learned so much by doing this. And the debates that you're setting up in various meetings is an excellent way to convey the educational mission.

Ashish Kamat:
Great. Thank you so much, Petros. Take care.

Petros Grivas:
Thank you so much.