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Pat Hensley: Good morning and welcome to today's UroToday session on first-line systemic therapy agent selection for locally advanced and metastatic urothelial carcinoma. My name's Pat Hensley, and I'm a Urologic Oncologist at the University of Kentucky College of Medicine. I'd like to welcome two esteemed guests with us today. First, Dr. Karima Oualla, who is an Associate Professor of Medical Oncology at the Faculty of Medicine and Pharmacy in Fez, Morocco, and Dr. Shilpa Gupta, who is a Director of Genitourinary Medical Oncology at the Cleveland Clinic. Dr. Oualla and Dr. Gupta are both members of the International Bladder Cancer Group and thought leaders in advanced bladder cancer, so thank you very much for joining us today and welcome.

The topic of discussion is agent selection, systemic therapy agent selection in the first line for locally advanced and metastatic urothelial carcinoma of the upper tract and bladder. I'll start with you, Dr. Gupta. For decades, cisplatin-based multi-agent chemotherapeutic approaches have been the first line and really the mainstay treatment for metastatic bladder cancer. If you don't mind, walk us through the rationale for that and the data to support that approach.

Shilpa Gupta: Yeah. Since the early 1970s, cisplatin-based therapy has been the mainstay of treatment, for the most part, for the last four decades. Even though different agents have been tried to add to cisplatin-based chemotherapy, like taxanes and bevacizumab, nothing really beat the backbone of gemcitabine and cisplatin or dose-dense MVAC. That's been our historical standard, only because there was really nothing effective at the time. Even after the advent of immunotherapy, there were huge efforts to combine immunotherapy with cisplatin-based chemotherapy in the frontline setting versus just only chemotherapy, and those studies were all negative. Cisplatin is a very effective agent and has been the backbone for ages.

Pat Hensley: As we're all well aware, the EV-302 trial results have been published. The results have been incorporated into guidelines. EV-302 was a prospective, randomized trial looking at the combination of enfortumab vedotin and pembrolizumab versus platinum-based chemotherapy for first-line metastatic and locally advanced bladder cancer. Dr. Oualla, if you don't mind, walk us through the rationale of the combination of enfortumab vedotin and pembrolizumab in terms of mechanistic action, and then also some take-home points from the EV-302 trial in terms of toxicity and efficacy.

Karima Oualla: Well, yeah, first of all, it was interesting to test this combination of pembrolizumab plus enfortumab vedotin since we already had data for each one separately in monotherapy for previously treated patients with urothelial cancer in an advanced metastatic setting, and they were already approved in second line and later lines. The concept of this combination is very smart to evaluate. We have the enfortumab vedotin, which is an ADC, an antibody-drug conjugate, meaning it's a combination of a monoclonal antibody that is covalently matched with a cytotoxic drug. In the case of enfortumab vedotin, it's linked to a microtubule-disrupting agent, the MMAE, and they will fix and target the NECTIN4 that is expressed on the cell surface and then get into the internalization of this NECTIN4 and then the release of MMAE. It's a fully human monoclonal antibody with this anti-microtubule, so it's very interesting to have the advantages of both mechanisms of the monoclonal antibody and the cytotoxic drug.

Pembrolizumab, while we are very familiar now with the immune checkpoint inhibitor, has the role to block those receptors for the ligands PD-L1 and PD-L2, aiming to restore the T-cell response and enhance the immune response. This combination was, as you say, tested in the phase three trial 302. Already we had the results from the cohort before for patients who are cisplatin ineligible, and it was approved for those patients with a very high rate of response, so that's why it was very exciting to test it among the general population, fit or unfit to cisplatin. It's a phase three trial enrolling around 886 patients. They were randomized one-to-one to receive either the experimental arm for the combination of enfortumab vedotin and pembrolizumab, pembrolizumab for the non-flat dose of 200 milligrams every three weeks, and the enfortumab vedotin 1.25 mg per kilogram, on day one, day eight, and then had to repeat each three weeks versus chemotherapy based on platinum.

This trial had two primary endpoints, co-primary endpoints, the progression-free survival and the overall survival. There were also some stratification factors that added the level of expression of PDL-1, high versus low, the eligibility to cisplatin, and also the site of metastasis, like liver metastasis. The treatment was given until progression or toxicity. We know that for pembrolizumab you go until around two years, 35 cycles, and the first primary endpoint, PFS, was just dramatically improved. We all remember the curves, how they were widely separated in favor of EV plus pembrolizumab. It was almost doubled. 12 months and a half versus six for chemotherapy, hazard ratio 0.45, so a reduction of 55% in the risk of death and progression for patients who received the combination.

Similarly, we were also very happy to see the curves of overall survival almost again doubled, so 31 months versus 16 for chemotherapy, hazard ratio 0.47. A huge risk reduction in terms of death for patients who received this combination. As I said, there were some stratification factors, and this is also something that gives more consistency to those results because regardless of any subgroups, regardless of eligibility to cisplatin, PDL-1 expression, and the site of metastasis, all subgroups got the benefit from the enfortumab-pembrolizumab combination.

Pat Hensley: I think we can all agree this is practice-changing data. Indeed, EV-pembro has moved as the preferred first-line agent for metastatic and advanced urothelial carcinoma. Dr. Gupta, do you mind commenting on maybe some of the adverse events in the trial, and some barriers to incorporating EV-pembro in your practice?

Shilpa Gupta: Yeah. I'll first add that definitely this is a practice-changing trial. Just want to highlight a couple of nuances that in the control arm, only 29% of patients got maintenance immunotherapy, which was based on JAVELIN Bladder-100, so we are not really comparing it to the standard, but only to platinums, which probably reflects real-world practice. Also, this study included patients who were cisplatin ineligible, and when we saw the subgroup analysis, those patients actually benefited much more than those who were cisplatin eligible. I think platinum eligibility, like Karima said, will become a moot point. Now, the toxicities are pretty unique for this agent. The MMAE causes severe neuropathy, not just peripheral, but also motor neuropathy. We see patients can sometimes have falls and gait problems, which if we are not acting in time, can become irreversible and debilitating, and this can cause... I think over 55% of patients had neuropathy grade two or higher, which is really bad.

With cisplatin, you can get neuropathy, but it's not that bad where people are having motor neuropathy resulting in falls. Rash is another key side effect, which can be life-threatening and fatal. In the EV-103 study, there was a toxic death, but thankfully in the EV-302, there were no toxic deaths, but there were severe incidences of rashes. It can cause catastrophic diabetes even in patients who have no history of diabetes, so it's very important to check the blood glucose level each time we are giving it. I think in a nutshell, there's a lot of education that needs to be out there because this is the only indication for EV and people have been using platinums for decades, but these certain things can get missed. On top of that, of course, there's the typical chemo-like effects like alopecia, taste changes, and some diarrhea. I won't say that this is a chemo-free regimen because there are chemo-like side effects.

Pat Hensley: Absolutely. In your practice, are there any patients that you're still prioritizing platinum in the first line?

Shilpa Gupta: There are patients who, let's say, have uncontrolled diabetes; that despite best management, their glycosylated hemoglobin is above eight. I would be hesitant to give EV-pembro, and that was actually the eligibility criteria too. We have to remember that in the eligibility criteria, even though they included ECOG performance status two, but they were really very fit ECOG PS2, with hemoglobin above a certain cutoff and creatinine clearance above 50. Our bladder cancer patients...

Karima Oualla: ... aren't always fit.

Shilpa Gupta: Yeah. The ECOG twos, we usually avoid cisplatin, but I would be hesitant to give it to the frail kind of ECOG one patients. Somebody with bad neuropathy, of course, cisplatin we like to avoid anyway, but I think for the most part, people who have uncontrolled diabetes, I'll avoid, or somebody who's known to have falls and just...

Pat Hensley: Frailty.

Shilpa Gupta: Yeah, frailty.

Karima Oualla: Yeah. We have to, as should I say, take into consideration the profile of each patient. It's always case by case, but overall, the overall side effects were not worse in the enfortumab, pembrolizumab arm, and even when we look at the grade three and higher side effects, there were fewer in the enfortumab, pembrolizumab arm than the chemotherapy arm.

Shilpa Gupta: Yeah. I think to that point, that was mainly myelosuppression in the chemotherapy arm, which we can prevent with growth factors, we can treat. I know numerically it was a little less, but the profile of this, because we don't know which patient will get rash, which patient will get severe neuropathy, but we know most patients will get myelosuppression. Totally preventable, so I think that is something I would highlight that with cisplatin, all the toxicities we know that can happen, we know how to prevent them, and that's not the case with EV, pembro.

Pat Hensley: I want to shift gears and talk about patients who are treated with EV, pembro in the first line and achieve a radiographic complete response. How do you manage those patients? How do you de-escalate and de-intensify some of the toxic therapeutic regimens that they're on? I'll start with you, Dr. Oualla.

Karima Oualla: Yeah. Well, we have a good proportion of patients who achieved complete response. Even in the trial, it was around 29% of complete response in the arm of EV, pembrolizumab, which is very good for our patients to announce as news, but also it's challenging for us as physicians, as practitioners. How to deal with the strategy now. Should we start? Should we continue? Should we de-escalate the doses specifically? I think for enfortumab vedotin, it's more discussable for the EV because, well, for pembrolizumab, we know that we go until 35 cycles. If it happens, any tolerance problems, we can keep pembrolizumab if we are still not finishing the 35 cycles and skip some doses or lower the doses of EV. I think the main point is the tolerability of those treatments even if we achieve the complete response because the patient is free of disease, but he should maintain a good quality of life, and I think Shilpa must have more experience with dealing with those escalations for EV.

Shilpa Gupta: Yeah, I totally agree with you. If patients have a complete response, which is sustained, we can certainly think of de-escalation. Think of it like the chemotherapy induction followed by maintenance. EV is really doing that part upfront, so I don't really think that moving forward this will be thought of as an indefinite number of cycles. I think we need to do these trials for de-escalation because the toxicities, financial toxicities, are really bad. In my experience, even when you hold the EV, patients keep having responses, so you can almost go on if they start developing recurrence, you can reintroduce at a lower dose, but you don't need to keep going.

Pat Hensley: What are you turning to after EV, pembro in the first line, therapeutic failure of EV, pembro? What are you turning to? What did the patients turn to in the EV-302 trial? I'll start with you, Dr. Gupta.

Shilpa Gupta: In the trial, about 30% of patients got platinums actually in the second line, and they had responses to that. I think platinums will certainly have a place in the treatment journey of a patient who progresses on EV, pembro, and we need more prospective data. Now, we have other antibody-drug conjugates, such as sacituzumab govitecan, which currently has a temporary approval for patients who had prior platinum and prior immunotherapy. Post-EV, pembro, there is really no data or approval for that, but I think comparing these two regimens is something we should look at doing.

Pat Hensley: How are you managing EV, pembro failures?

Karima Oualla: Yeah. I completely agree. I think chemotherapy still has a good place in the second line for those patients who are fit to receive chemotherapy by platinum-based regimens, either cisplatin or carboplatin. Also, we should not forget to test our patients with advanced bladder cancer for the EGFR alterations, because in case of mutations or fusions on EGFR, it makes them eligible for erdafitinib. I think we have chemotherapy. As we mentioned, we have sacituzumab govitecan. This part, we don't have really data about the sequence after enfortumab, and also we have erdafitinib for those patients who are EGFR-altered.

Pat Hensley: Wonderful. I'd like to conclude by just getting some closing thoughts from each of you and maybe some next steps or unanswered questions in this disease space. Let's start with you, Dr. Gupta.

Shilpa Gupta: I'll say that this is landmark progress after decades of no progress in the front line and really unprecedented results, but the big question is, what will the rest of the world have? Will they ever see EV, pembro because most countries don't even have EV right now. What can the authorities and the sponsors do to make these drugs accessible and affordable and not just in select countries? I think the second question is the de-escalation of therapy and minimizing the excessive use of the EV.

Pat Hensley: Dr. Oualla?

Karima Oualla: Yeah. Well, I also want to underline this problem of access and availability of treatments in many parts of the world. Those drugs are very efficient, yes, but also they are very costly, and we really hope to have some democracy in terms of access to those drugs for all patients with advanced urothelial cancer. I think, yeah, we still have some open questions or debatable situations specifically now moving the CPI, the immunotherapy in the adjuvant setting previously with nivolumab and more recently with pembrolizumab. Many questions are still unanswered about the re-challenge of immunotherapy in case of progression and/or relapse in metastatic urothelial cancer. Should we take the interval, the non-interval that we use in many other solid tumors as a criterion to re-challenge or not immunotherapy, and also I think the field of biomarkers still needs to be explored in bladder cancer.

Pat Hensley: Absolutely.

Shilpa Gupta: I think... one more closing thought. What if the EV, pembro moves in the perioperative setting, and then what are we left with in the front line? I think it'll be platinum.

Pat Hensley: Absolutely. Well, excellent thoughts. Thank you for the discussion. Karima Oualla, Dr. Shilpa Gupta. Thank you very much for joining us, and thank you for joining us for this UroToday session live at AUA 2024 in San Antonio.