SECTION 1: Localized UC: VESPER & adjuvant therapy

Laurence Albiges:
Good morning, and welcome to Paris for this hybrid ESMO 2021. My name is Laurence Albiges, and I’m pleased to welcome you. I have the pleasure to welcome my friend and colleague, Dr. Enrique Grande. Welcome.

Enrique Grande:
How are you, Laurence?

Laurence Albiges:
Very good, thank you. Thank you for being here in Paris.

Enrique Grande:
It’s a pleasure.

Laurence Albiges:
So we have this hybrid meeting, few faculties onsite, and so we’re very fortunate to have the opportunity to discuss with you what are the updates in urothelial carcinoma. Over the course of the few past years, there has been tremendous changes in the way we treat patients with bladder cancer, and what we would like to do now is during this ESMO, understand what are the news, what are the discussions around patient management. So if you’re fine, we can start with localized disease.

Enrique Grande:
Perfect.

Laurence Albiges:
Patients with organ-confined urothelial carcinoma, bladder cancer, eligible for surgery. We have randomized data now to help to understand what is the optimal chemotherapy. Can you let us know more about the VESPER trial?

Enrique Grande:
Well, the VESPER trial, probably you know more than me about the trial because it was conducted here in France. I think a total of 28 sites spread all across the country participated in the VESPER trial. This is a cooperative group trial in between an association of the GETUG group and the Association of the French Urology. So I think there is a tremendous effort behind. Well, I congratulate Dr. Pfister, the lead of the trial, together with the Doctor, Professor Stephane Culine because they have a lot of merit to put that much effort to do such kind of a huge effort in coordinating all of these sites, recruiting patients in a very challenging setting of the disease, the perioperative setting. And this is one of the key things because they included 500 patients, were randomized in the perioperative setting, including patients in the adjuvant and in the neoadjuvant setting.

Laurence Albiges:
So when you say either neoadjuvant or adjuvant, can you explain what was the decision process?

Enrique Grande:
That’s one of the key things from this VESPER trial, and it is important to understand the selection of the patients recruited in the trial to understand the global environment, the global data. Well, it was dependent on the site if they were recruiting the patient for the neoadjuvant approach or the adjuvant approach after the cystectomy. And 88% of the patients recruited in the VESPER trial, they received neoadjuvant chemotherapy before the radical cystectomy as the guidelines are recommending. 12% were receiving cisplatin-gemcitabine, or dose-dense MVAC after the radical cystectomy. This is one of the key conclusions of the VESPER trial. We should perform neoadjuvant, preferably ahead of the adjuvant treatment of these patients.

Laurence Albiges:
So at least it’s feasible. What it tells us it’s feasible to do neoadjuvant-

Enrique Grande:
Absolutely.

Laurence Albiges:
The randomization, and we’re coming to that, was about the chemotherapy itself, but the physician could choose if it was offered in neoadjuvant or adjuvant. And we now know over 430 patients treated in the neoadjuvant space.

Enrique Grande:
Exactly.

Laurence Albiges:
So now, let’s get to the randomization. What was the comparison?

Enrique Grande:
The standard arm were four cycles of cisplatin-gemcitabine, four cycles. And the comparitor arm, the experimental arm, was the use of dose-dense MVAC, but instead of the four cycles, six cycles of treatment.

Laurence Albiges:
So it would be the same treatment duration?

Enrique Grande:
Absolutely. Probably, this is the same treatment duration, but maybe a different approach than the normal use of dose-dense MVAC we were used to deal with that. Does it matter the number of cycles? This is just a matter of intensity of the treatment we are giving. This is one of the key challenges. Another key point here is the primary endpoint. Progression-free survival rate at three years’ time. Is that endpoint better than the pathological complete responses? Because normally, we were selecting the treatment according to the pathological complete responses we obtained with the chemotherapy. I think clinically-

Laurence Albiges:
Yeah. It’s a very clinical, relevant endpoint.

Enrique Grande:
Absolutely.

Laurence Albiges:
And it was also matching neoadjuvant and adjuvant because at the time we wouldn’t know what would be the pickup for the adjuvant. Okay. So we do have results of pathological response. What are the key results on this?

Enrique Grande:
For those patients randomized to the standard arm, four cycles of CISGEM, 36% of patients achieved the pathological complete response, while 42% of patients achieved pathological complete responses with the dose-dense MVAC.

Laurence Albiges:
So numerically higher in terms of pathological response? Now-

Enrique Grande:
One good thing, 90% of each arm of the patients underwent the radical cystectomy. So dose-dense MVAC, the more dense regimen, it is not conditioned the radical cystectomy.

Laurence Albiges:
Excellent. Primary endpoint was progression-free survival at three years. What are the results with regard to PFS?

Enrique Grande:
10% difference, 66% of the patients treated with dose-dense MVAC before the surgery were free of progression after three years versus 56%. I think this is clinically meaningful, these results.

Laurence Albiges:
And so, the author looked at both the ITT, meaning the 500 ish patients, but also the neoadjuvant study subpopulation. Your feeling is that we should focus on this subset of patients?

Enrique Grande:
I think we should do that because this is a very robust subgroup. This is 88% of the patients recruited there. So this is a very robust subgroup. Statistically speaking, the VESPER trial, taking in the intention to treat in the global concept, it’s not positive, but I’m always saying the same. We are not statisticians. We are doctors. We are dealing with patients, not with numbers. And for me, the clinical data are relevant.

Laurence Albiges:
And so overall survival analysis, we have 14 months follow-up, so quite nice. The author planned to perform the full overall survival analysis after five years, but we already see a trend favoring dose-dense, right?

Enrique Grande:
Hazard ratio of 0.66 for OS, I think, is a very, very good trend. Of course, we cannot say this is statistically significant yet, but I think we are in the right direction.

Laurence Albiges:
So does that mean you’re going to change your practice and use six cycle of dose-dense MVAC?

Enrique Grande:
For me, the VESPER trail is confirming that six cycles of dose-dense MVAC is better in terms of activity than four cycles of CISGEM. For me, this is the main conclusion. The thing is, in the clinic, all your patients, Laurence, in your clinic are meeting, not only the Galsky criteria for eligibility to cisplatin but are meeting the criteria-

Laurence Albiges:
No, they are not.

Enrique Grande:
For dose-dense MVAC. This is the key thing here.

Laurence Albiges:
So now I want us to take a step back and think about what other data we have in the neoadjuvant space because we’ve been discussing chemotherapy, but we now have immune checkpoints that are coming in the neoadjuvant space. We have new drugs that are with high response rates that we want to see in this neoadjuvant space. So can you just put VESPER in the context of other neoadjuvant cohorts?

Enrique Grande:
Well, for those patients eligible for cisplatin, well, the current up and running Phase III trials are combining chemotherapy, CISGEM, plus immuno-oncology drugs. The thing is, when you see a small Phase II non-randomized data pathological complete responses, you can see are ranging between 37%, 39% versus 47, something like that. So 42% of pathological complete responses with dose-dense MVAC at VESPER is not doing that much different than the combination of chemo plus IO. In addition to that, chemo plus IO in the metastatic setting, IMvigor130, KEYNOTE-361 unfortunately is not showing synergistic activity. So I’m not really convinced about the data of these Phase III trials. And I’m not convinced about this comparator arm this trial had, cisplatin-gemcitabine. So let’s see.

Laurence Albiges:
Yeah. So basically, VESPER is providing the new benchmark for what we anticipate in neoadjuvant-

Enrique Grande:
Mm-hmm (affirmative).

Laurence Albiges:
In terms of pathological CR?

Enrique Grande:
I’m afraid when these Phase III trials are releasing the results, I’m afraid we will need to do an indicted comparison with the VESPER data, not only with the comparator arm, but with the VESPER data.

Laurence Albiges:
Okay, great. So we’ve discussed neoadjuvant, and there has been a lot of data coming in the adjuvant space and a lot of debate as well. So any news at this ESMO with regard to adjuvant in urothelial carcinoma?

Enrique Grande:
Well, nivolumab has just been approved by the FDA for the treatment of high-risk muscle-invasive bladder cancer patients with using nivolumab as a single agent in the adjuvant setting based on disease-free survival improvement. Is that clinically relevant without improvement in overall survival? There is a huge debate in the social media around it. My personal opinion here is that I think this is something useful, at least something that merits to be discussed with the patient. Hey, I have one thing that is impacting in the disease-free, but we don’t know anything about the overall survival because nobody has seen the overall survival data so far. We are looking forward to seeing that hopefully next year. We will have some preliminary data about the overall survival. But there was a subgroup of patients treated in the CheckMate 274 trial, particularly those patients who received neoadjuvant chemotherapy that seemed to benefit more in terms of disease-free survival than the others. So probably you can do both. You can do VESPER in the neoadjuvant treatment followed by adjuvant avelumab. I don’t know if a country like France can afford it, but a country like Spain-

Laurence Albiges:
Yeah.

Enrique Grande:
Maybe not. So let’s see, let’s see. We can translate the CheckMate 274 data to our daily practice.

Laurence Albiges:
Very interesting, and we are looking forward to have the overall survival data indeed.

SECTION 2 – Metastatic UC: NORSE

Laurence Albiges:
So now let’s move to metastatic disease. And I want to start with the biomarker-driven strategy. So we know that FGFR alteration can be seen in up to 20% of patient with urothelial carcinoma. We know that erdafitinib has been developed in a previously exposed patient population to cisplatin. And now, we have data in the first-line setting for those patients that are cisplatin non-eligible, that’s the NORSE trial. So maybe put that into the context, we had BISCAY in the past, which was in patients heavily pretreated. We had, at ASCO meeting, other FGFR inhibition that was tested. So let us know more about NORSE endpoint, NORSE strategy. What was this trial about?

Enrique Grande:
Well, this trial is combining erdafitinib, the first but not the last FGFR inhibitor developed in the field of urothelial tumors. Erdafitinib, don’t forget that it is already approved by the FDA. So our colleagues in the US, they have the opportunity to select patients and treat patients accordingly. Unfortunately, in Europe, we don’t have that data. We don’t have that approval, we are waiting for the Phase III trial in the salvage setting. In those patients, platinum refractory, IO refractory setting. This is the newest step in the precision medicine in urothelial tumors. This is bringing the precision medicine to the first line. We are pushing the precision medicine to the first line. So one of the key questions, when we should do the next generation sequencing to our patients? And we said, “Okay, after platinum or after immunotherapy.” Now, it seems that maybe, we can select patients upfront. I think this is too early to…Not too early, too soon to say that. But I think we are on the way to select patients. The sooner, the better. In the NORSE trial, this was a Phase II trial in which patients were receiving erdafitinib alone or in combination with a PD-1 inhibitor.

Laurence Albiges:
So if you think about the design, that is a bit puzzling, right? ‘Cause they went for a cisplatin non-eligible so standard would be carboplatin, the patient can receive carboplatin-based chemotherapy, or it could be PD-1 inhibition in this setting, right? In patient biomarker positive.

Enrique Grande:
Or carbo followed by avelumab.

Laurence Albiges:
Yes. So-

Enrique Grande:
Do you know-

Laurence Albiges:
That means that the control arm in NORSE, is that the one you wanted to see?

Enrique Grande:
Probably not. Probably not. But you know, we like to play to precision medicine or not. If you like to play to precision medicine, you believe that the FGFR is a driver at the urothelium tumors, and I don’t think we are at that point. In the salvage setting, the New England publication by your colleague and friend, our colleague and friend, Yohann Loriot, it is showing a great response rate, 44%. This is amazing, in a hundred patients in the salvage setting. Amazing! However, take a look at the median PFS, only five months. Take a look at the median duration of response, six months. This is not a driver, at least for me. I want to believe this is a driver. Maybe when you are using these kind of drugs before, when the patient has a better performance status before chemotherapy, maybe the responses are better. Maybe the duration of responses, the quality of the responses are better, but today-

Laurence Albiges:
You’re touching on the keynote lecture that we just had from Bill Kaelin. And I think it’s great to have the opportunity to see this lecture where he clearly was highlighting the idea that we’re developing targeted therapy in later lines where they may actually play a stronger role in earlier lines. So here in NORSE, a strong activity, right? It’s a preliminary data because the study is still ongoing, but strong activity of both erdafitinib alone and erda plus PD-1 inhibition, right?

Enrique Grande:
62% of respondents. 62% I think is a high bar. It’s a high bar in comparison with chemotherapy, with former chemotherapy. But the thing is, what about the median progression-free survival? What about the median overall survival? We don’t have this data. The NORSE trial is a very small trial. So far, 27 patients per arm, something like that. So I think we need more data, more robust data, longer follow-up to put these data into context.

Laurence Albiges:
And in the BISCAY study, which was presented at ESMO two years ago now-

Enrique Grande:
Physically.

Laurence Albiges:
Physically, at the time. We had a strategy of FGFR inhibition plus PD-1, PD-L1 access inhibition. And at that time there was no added value. Do you think because it’s not maybe not the same PD-1 inhibitor because it’s later in the disease? How do you see things?

Enrique Grande:
I love the BISCAY trial because they’ve recruited patients and selected molecularly patients, not only for FGFR alteration, but also for PI3K/AKT/mTOR, and also for DNA repairing genes alterations in combination with durvalumab. Nothing was succeeding, nothing was succeeding. So I don’t know, maybe it’s because of the IO that we’re choosing or the IO are behaving the same in this setting. Durvalumab is the same than atezo, or atezo is the same that cemiplimab. Let’s see, let’s see. We can’t compare small Phase II trials. Even if the patients are molecularly selected, I think this is a mistake that we all-

Laurence Albiges:
We all do, yeah.

SECTION 3 – Targeting EphrinB2

Laurence Albiges:
Okay. And so now we’re gonna move again a bit further into disease with very innovative data. So it’s a Phase II non-randomized with a new target, Ephrin-B2. And so this Ephrin-B2 seems to be expressed in more than half of the patients with urothelial carcinoma and seems to be associated with the ability to recruit immune cells and, therefore, enhance immune response. So what we’ve seen here is a non-randomized Phase II in patient pretreated with chemotherapy, but never treated with IO and who received this Ephrin-B2 inhibitor, it’s the B4 compound, a very sophisticated name. So we’re gonna say Ephrin-B2 inhibitor plus pembrolizumab. So what is your take on this study?

Enrique Grande:
I have a lot of challenges. I can see a lot of challenges on this trial. First, patient population recruited. After the approval of the JAVELIN maintenance strategy, we are all convinced that chemo followed by avelumab is the current standard of care. Even in those patients that are progressing to chemotherapy, immuno-oncological drugs is the standard of care because pembro has improved the overall survival. So the thing is, do we have now in our clinic patients refractory to platinum, but they are naive to IO?

Laurence Albiges:
The answer is no.

Enrique Grande:
I don’t. And the thing is that ethic? Because well, I think, I want to my patients, to provide things that are impacting on overall survival and immuno-oncology drugs are impacting on overall survival, either in the maintenance setting or in the second-line setting. So yeah, for me, it’s not easy to see this patient population with the data we have today. This is the first challenge. Second challenge. Well, Ephrin-B2 positive patients. That means expression of above 1% in the immunohistochemistry. You know that this is… I don’t know if we can consider positive patients as someone that is just 1% of immunohistochemistry expression. Probably elevating the bar of the expression, probably we would see more responses or not, or maybe not. A second thing. The Ephrin pathway is correlated with the expression of PD-L1 because… Dr. Sadeghi did a great job. And when you read the list of authors behind, they are David Quinn, Primo Lara. So there are a lot of authors that, they have a lot of experience here. So I didn’t see any data about the PD-L1 expression activity. So maybe, why not? I don’t know. Maybe we have a correlation in between the expression of B2 and the expression of PD-L1 and we are measuring exactly the same thing, but with different markers. I don’t know about it. Because the Ephrin pathway is involved in the traffic regulation of the immune cells. So maybe there is a correlation in between expression of B2 and PD-L1 and this is what we are seeing.

Laurence Albiges:
That would make our life easier actually ’cause it’s easier to get the expression of PD-L1 than Ephrin-B2, at least from a SOP standpoint. So that would maybe make our life easier. So you question the biomarker and its relation with PD-L1.

Enrique Grande:
I do, I do. Because don’t forget that Ephrin-B2 is particularly expressed on endothelial cells and the drug is given for hypertension. So maybe this fusion protein of EphB4 plus the human serum albumin, it’s just an anti-angiogenic agent. Maybe, why not? And when we have the data of carbo-atezo in this setting, well, 37% of responders in non-selected patient population-

Laurence Albiges:
While here in Ephrin-B2 we’re going above the 50%.

Enrique Grande:
Above, yeah. 52, but in the intention to treat population 37, exactly the same responders than with carbo-atezo.

Laurence Albiges:
Okay. So what you wanna see is more data-

Enrique Grande:
Absolutely.

Laurence Albiges:
More granularity with regard to… Yeah

Enrique Grande:
Randomized data.

Laurence Albiges:
And randomized data with an IO or at least a PD-1 inhibition in patients that are matching our routine practice, either maintenance or in maybe earlier stage.

Enrique Grande:
Or even with antibody-drug conjugates.

Laurence Albiges:
Okay.

Enrique Grande:
We will have enfortumab approved in Europe or available in Europe soon. So I want to see the data of enfortumab in Ephrin-B2 positive patients, and I want to see the randomization of these patients.

Laurence Albiges:
Excellent. Well Enrique, thank you a lot for all these insights on these important data. What is the next really hot topic for you in urothelial carcinoma for future meetings?

Enrique Grande:
The one that is coming shortly and I think it is coming sooner than expected is the results of the CheckMate 901. In PD-L1 positive population. I’m really looking forward to seeing this data.

Laurence Albiges:
So hopefully, we’ll have the chance to discuss that together in the future.

Enrique Grande:
Physically.

Laurence Albiges:
We’ll see.

Enrique Grande:
Hopefully.

Laurence Albiges:
And physically, I hope we’ll have the pleasure to welcome you again in Paris next year for our ESMO 2022 that will be hopefully, physically. Thank you very much Enrique.

Enrique Grande:
Thank you Laurence.

Laurence Albiges:
Thank you for your attention.

Recording date: 18-Sept-2021; Webinar broadcast date: 30-Sept-2021; Feature publication date: 01-Oct-2021.

Laurence Albiges

Financial Interests

Invited Speaker: Astellas, AstraZeneca, Bellerophon, BMS, Corvus Pharmaceuticals, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer & Springer Healthcare.

Non-Financial Interests

Principal Investigator: Pfizer, BMS, Ipsen

Clinical trial Steering Committee: Roche, Exelixis

Medical Steering Committee: Kidney Cancer Association

Scientific Committee: BMS France

Other: European Association of Urology (EAU): Member of the Renal Cell Carcinoma Guidelines Panel

Other: Kidney Can: Member of the Kidney Cancer Research Summit scientific committee 2021

Enrique Grande

Honoraria for speaker engagements, advisory roles or funding of continuous medical education:

Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Esteve, Eusa Pharma, Genetracer, GSK, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho & Thermo Fisher Scientific

Research Grants:

Astellas, Astra Zeneca, IPSEN, Lexicon, Merck KGaA, MTEM/Threshold, Nanostring Technologies, Pfizer & Roche