The therapeutic landscape of advanced urothelial cancer has undergone a significant transformation in recent years with the addition of PD-1/PD-L1 targeting immune checkpoint inhibitors and novel antibody-drug conjugates to the treatment armamentarium. In this Clinical Insights on the Treatment Algorithm in Unresectable Locally Advanced or Metastatic Urothelial Cancer, experts in the field will discuss the latest evidence supporting the use of these therapies in clinical practice, including patient selection for cisplatin/carboplatin eligible and platinum ineligible and optimal treatment strategy in the first-line setting, sequencing of treatments and the management of treatment-related adverse events. An improved understanding of the role and application of immunotherapy, chemotherapy, antibody-drug conjugates (ADC) and targeted treatments to routine patient care will facilitate optimal management of patients with urothelial cancer.
During this Expert Interview, we will be discussing the first-line treatment decision-making: How to define the patients of cisplatin eligible, carboplatin eligible and platinum ineligible? We are joined today by a leading expert in urothelial cancer, Dr Shilpa Gupta from the Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, USA.
The therapeutic landscape of advanced urothelial cancer has undergone a significant transformation in recent years with the addition of PD-1/PD-L1 targeting immune checkpoint inhibitors and novel antibody-drug conjugates to the treatment armamentarium. In this Clinical Insights on the Treatment Algorithm in Unresectable Locally Advanced or Metastatic Urothelial Cancer, experts in the field will discuss the latest evidence supporting the use of these therapies in clinical practice, including patient selection for cisplatin/carboplatin eligible and platinum ineligible and optimal treatment strategy in the first-line setting, sequencing of treatments and the management of treatment-related adverse events. An improved understanding of the role and application of immunotherapy, chemotherapy, antibody-drug conjugates (ADC) and targeted treatments to routine patient care will facilitate optimal management of patients with urothelial cancer.
During this Expert Interview, we will be discussing the first-line treatment decision-making: How to define the patients of cisplatin eligible, carboplatin eligible and platinum ineligible? We are joined today by a leading expert in urothelial cancer, Dr Shilpa Gupta from the Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, USA.
Hello and welcome to this Expert Interview entitled"Clinical Insights on the Treatment Algorithm in Unresectable Locally Advanced or Metastatic Urothelial Cancer." My name is Delyth Eickermann. I am delighted to be joined today by a leading expert in urothelial cancer, Dr. Shilpa Gupta from the Taussig Cancer Institute, Cleveland Clinic Foundation, Cleaveland in the United States. Welcome and thank you for joining me today, Dr. Gupta. Thank you for having me. During this Expert Interview, we will be discussing the first-line treatment decision-making and how to define patients who are cisplatin eligible, carboplatin eligible and platinum ineligible Dr. Gupta, following ESMO 2023, the treatment landscape has rapidly evolved with an increasing number of available first-line treatment options. Firstly, could you please share with us the criteria for defining patients who are eligible for cisplatin, carboplatin, and those who are ineligible for platinum therapy The criteria to define patients eligible for cisplatin were based on what Dr. Galsky proposed many years ago, called the Galsky criteria. In these patients who have creatinine clearance less than 60 milliliters per minute or have peripheral neuropathy Grade 2 or higher, or hearing loss Grade 2 or higher, or NYHA heart failure Grade 2, or ECOG performance status 2 or higher, these patients were considered ineligible for receiving cisplatin, which had been the standard therapy for urothelial cancer patients. And these are the patients who were considered eligible for carboplatin, because if they can't get cisplatin, carboplatin was the treatment available. Now, as you recall, back in 2018, the FDA restricted the label for single agent immunotherapies to, first, only patients who were cisplatin ineligible with tumors harboring high PD-L1 expression, and then later, further restricted the use to only platinum-ineligible patients, that is, patients who could not even get carboplatin. However, the definition was not provided. And so we did a consensus survey for defining platinum ineligibility in urothelial cancer. And we surveyed around sixty US medical oncologists who treat urothelial cancer and asked a variety of questions based on age, hearing loss, comorbidities, creatinine clearance, heart failure, neuropathy, etc. And we came up with a criteria back in 2019, where we did not find age to be a deciding factor, where the criteria defined ECOG performance status 3 or higher, peripheral neuropathy Grade 3 or higher, heart failure Class 3 or higher, creatinine clearance less than 30, and in patients who have ECOG performance status 2, creatinine clearance less than 30 also. And then, we later refined this criteria in 2022 based on the new treatment landscape with the maintenance avelumab, etc. And again, the consensus was based on these factors. ECOG performance status 3 or higher, peripheral neuropathy Grade 2 or higher. It scored a little bit different this time. And there was no criteria for hearing loss. There's creatinine clearance less than 30. And in patients who had ECOG performance status 2, creatinine clearance less than 30. So basically, these are the patients we wanted to highlight that cannot get even carboplatin. And these are the true platinum-ineligible patients. And the purpose of this was to avoid overcalling of platinum ineligibility because we know that carboplatin-based therapies followed by avelumab maintenance can improve survival. And carboplatin-based therapy was better than immunotherapy alone in terms of response rates. So this is where we come up with the platinum ineligibility. Thank you. Currently, enfortumab vedotin (EV) plus pembrolizumab has been approved by the FDA for patients eligible for platinum and also ineligible for cisplatin. Is it still crucial for clinicians to identify patients who are eligible for cisplatin and carboplatin, as well as those who are ineligible for platinum before initiating first-line treatment in daily practice? And do you anticipate the potential replacement of the eligibility definition for cisplatin and platinum with eligibility for EV/Pembro prior to initiating first-line treatment? This is a great question. I think given the results we saw from the EV-302, where it was superior to platinum-based chemotherapy, both for platinum eligible and cisplatin ineligible patients, I think that criteria for cisplatin ineligibility may not be very relevant moving forward. However, criteria for platinum eligibility, that is, patients who cannot get even carboplatin, they are relevant because in the EV-302 study, only platinum-eligible patients were allowed. That is, patients who cannot get even carboplatin were not enrolled in this study. Those are really frail patients as we just discussed. So I would say that the guidance would be, if somebody's platinum eligible, then EV/Pembro is the option compared with platinum. If somebody's platinum ineligible, then there's the option of single agent pembrolizumab and there's also a trial going on now where atezolizumab is being combined with the anti-LAG-3 and anti-TIGIT antibodies. And we've defined those patients based on the platinum ineligibility criteria. And these patients who are fully platinum ineligible, actually are only about 10 to 12% in our practice. So it is really important to make sure that, you know, for fully platinum-ineligible patients, EV/Pembro has not been tested in that patient population and the toxicities might be an issue. But we turn now to the decision-making process for first-line treatment in cisplatin-eligible patients. There are three regimens to choose from. Induction chemotherapy followed by avelumab, cisplatin-based chemotherapy combined with nivolumab and enfortumab vedotin plus pembrolizumab. How do you identify the potential impact factors for decision-making? These are great questions. It's great progress in the field to see so many options. And I would say that in terms of EV/Pembrolizumab data, you know, the response rates and the overall survival, progression-free survival, it really trumps anything else we have seen before. To put it into perspective, though, the control arm of around 30% of patients got maintenance avelumab. So, not everybody got the standard maintenance immunotherapy. And for the control arm in the CheckMate-901, even fewer patients got maintenance immunotherapy. So I would say when we look at the cisplatin-based chemotherapy and nivolumab versus EV and pembrolizumab, and versus platinum followed by maintenance avelumab, I think one has to really say, first of all, what is available and accessible? Because you know globally, that's going to be a challenge if these drugs are going to be available everywhere. But if accessibility is not an issue, we have to see what are the comorbidities for the patients. You know, for EV/Pembro, we want to see if the patients don't have bad neuropathy at baseline. That can get even worse with EV/Pembro. If those factors are not an issue, EV/Pembro would be the frontline preferred regimen. Regarding Gem/Cis and nivolumab, yes, it did result in encouraging complete responses. However, I think when you look at the overall data, EV/Pembro still trumps that. And only in patients where we cannot give EV for some reason, one could give Gem/Cis/Nivo. In a patient who has metastatic disease, but not bad visceral metastases or lymph-node-only metastases, I think platinum followed by avelumab is still a very good option because we see that these patients have very nicely maintained durable response rates and overall survival. So I think, based on what place we are practicing in, patient characteristics and the availability of future therapies, for example, if in a place where the single-agent enfortumab vedotin is available in second-line and subsequent therapies, then starting somebody on chemotherapy followed by maintenance avelumab in the first-line setting if they don't have high volume disease, is a reasonable option. If they can't take EV/Pembro for whatever reason, then doing that is an option. If somebody has bad disease and we really need to control it upfront, and we don't have access to EV/Pembro, then Gem/Cis/Nivo is a reasonable option. So I think depending on the patient scenario, one can really pick and choose. But for the most part, I think EV/Pembro really will find a place for majority of patients. Thank you for your insightful comments. Now, let's proceed to the treatment options for carboplatin-eligible patients. There are two options, induction chemotherapy followed by avelumab or enfortumab vedotin plus pembrolizumab. How would you determine the initial treatment for carboplatin-eligible patients? I think, again, it depends on the accessibility, availability and affordability of the new EV/Pembro regimen. But if we can give EV/Pembro, that would be the preferred option. We've really not seen such remarkable data for cisplatin-ineligible patients, and we presented the four-year follow-up results from EV-103 in cisplatin-ineligible patients, and the response rates, the PFS and OS were very well-maintained, and it was replicated in the EV-302 study. So that would be the preferred option. And if this is not available, then Gem/Carbo followed by maintenance avelumab. Thank you. The final question is for patients who are not eligible for platinum-based treatment. Should we consider immune checkpoint inhibitor monotherapy or combination therapy with enfortumab vedotin? Due to the lack of data in fully platinum-ineligible patients, I would say we should consider single agent immunotherapy, with pembrolizumab, or atezolizumab, whatever is available, and consider clinical trials. Now, we do have this trial where atezolizumab is being added to other novel immunotherapies. But without any data, I would be hesitant to use EV/Pembro in fully platinum-ineligible patients. It also depends on why they are fully platinum ineligible. If it is bad neuropathy, then obviously EV/Pembro would not be the best choice. If it's really poor performance status, you know, in the EV-302, patients with ECOG performance status 2 were allowed if they met some other criteria. So these were all robust patients. And the platinum-ineligible patients are not robust and the toxicities can become a challenge. So I would not push for EV/Pembro in this patient population, unless there is somebody who has developed some symptoms or worsening performance status is due to the disease itself, rapidly. It has to be a very cautiously made decision. Considering the different toxicity profiles of platinum-based chemotherapy and EV/Pembro, would it be advisable to establish guidelines for patient selection prior to initiating first-line therapy? Yes. I think this would be a great idea and we are working on developing criteria for this. I think patients with bad peripheral neuropathy at baseline, in any case, you know we avoid cisplatin in them, right? So I think it depends on if they are cisplatin ineligible. Then, they could get either Gem/Carbo or EV/Pembro. However, EV does have more potential to cause bad neuropathy and worsening of neuropathy. So I would be very cautious. In patients with uncontrolled diabetes, I think we have to be very cautious with EV/Pembro because even on this study, they needed an HbA1c level of less than eight, which means well-controlled diabetes. So, either we control the diabetes first and then consider this, or do the platinum, if they can get cisplatin otherwise. So I think some of these criteria, you know, which really stand out are based on how frail the patient is and their other comorbidities. And in our experience, for example, very obese patients really get more toxicities with EV, and that can become a challenge. So overall, depending on all the data we see in the trials, as to the toxicity data, if we can tease out which are the patients who got more toxicities, it would really help us choose this regimen for the right patient. Thank you, Dr. Gupta, for your valuable insights. We greatly appreciate the knowledge gained from your experience. Thank you. In our next session, we will delve into the topic of first-line maintenance therapy.