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 second-line treatment decision-making: How to identify the sequential treatment strategy? We are joined today by a leading expert in urothelial cancer, Dr Yohann Loriot from the Université Paris-Saclay and Gustave Roussy, Villejuif, France.
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 second-line treatment decision-making: How to identify the sequential treatment strategy? We are joined today by a leading expert in urothelial cancer, Dr Yohann Loriot from the Université Paris-Saclay and Gustave Roussy, Villejuif, France.
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 and I am delighted to be joined today by a leading expert in urothelial cancer, Dr. Yohann Loriot from the Université Paris-Saclay and Gustave Roussy in Villejuif, France. Welcome. Thank you for joining me today. During this Expert Interview, we will be discussing second-line treatment decision making. How to identify the sequential treatment strategy? Dr. Loriot, the treatment landscape is rapidly evolving, with an increasing range of available first-line therapeutic options by the end of 2023. This paradigm shift has significantly increased the complexity of subsequent patient care. Could you provide an overview of the different clinical scenarios that may occur during disease progression following first-line treatment? Hello, everyone. First of all, thank you for inviting me to this important discussion. So, coming back to your question, indeed, the landscape is moving very fast with a lot of data released recently. And basically, there is a different way to treat patients in first-line treatment. And there are different scenarios that can occur during the management of patients. So the standard of care in early 2024 is mainly, in first-line metastatic setting, of course, it's chemotherapy, platinum-based chemotherapy, usually followed by maintenance and treatment with immunotherapy like avelumab. Another standard of care could be the combination of enfortumab vedotin (EV) and pembrolizumab, because this combination is already approved in the US in cisplatin-ineligible patients. And rarely, some patients could be treated with chemotherapy only. And why chemotherapy only? Because there is disease progression during chemotherapy or upon completion of chemotherapy. So basically, there are three different clinical scenarios that may occur during the disease progression following first-line treatment. The number one is a progression after first-line treatment or within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy. So it means that the patients have disease progression during the chemotherapy. The second scenario is a disease progression during the treatment, maintenance with immunotherapy like avelumab and the number three could be a disease progression during or after first-line treatment with EV/Pembro. So basically, the three different scenarios that we can have in first-line, dependent on the local approval, of course. So it's quite different between Europe and the US currently. But with the recent data that we have from the CheckMate-901 and the EV-302 trial, probably the standard of care will be pretty the same between the US and Europe in the coming months. And what are the optimal treatment options for different clinical scenarios in subsequent management? Regarding the most frequent scenario, I mean, patients who have been treated with platinum-based chemotherapy followed by avelumab maintenance. If so, the standard of care, I would say, for these patients, is to give an antibody-drug conjugate, enfortumab vedotin, and why? Because we have a positive Phase III trial, EV-301 that showed that EV improves survival compared to a conventional chemotherapy like docetaxel, paclitaxel or vinflunine. So the drug is approved in many countries worldwide. And we can use this drug in so-called third-line treatment. In the US, there is also an option in terms of antibody-drug conjugates. Sacituzumab govitecan (SG), which is another antibody-drug conjugate that targets the Trop-2, is already approved based on a Phase II trial that showed that sacituzumab govitecan provides an objective response rate of around 30%, a median PFS more than five months, and a median overall survival of around one year. It's not approved in Europe, but probably this year, we will have the data from a Phase III trial called TROPiCS-04. And if positive, of course, the drug might be approved in many countries. It could be also another option on top of enfortumab vedotin. There's also another option which is not an antibody-drug conjugate. It is a targeted therapy. Erdafitinib, which is a pan-FGFR inhibitor, and the drug is already approved in the US and in many other countries worldwide. And very recently, we have data from a Phase III trial called THOR, which compares erdafitinib to conventional chemotherapy for patients previously treated with immunotherapy and also chemotherapy. Of course, we can give this treatment, erdafitinib, only if there is a mutation, a FGFR3 mutation or a fusion, a FGFR2/3 fusion in the tumors. But the drug has a level of evidence of one in this clinical scenario. So it could be, of course, a third option. If the patient had disease progression during the first-line chemotherapy, so the patient has not received immunotherapy, so the patient has disease progression during chemotherapy or upon completion of chemotherapy. Here, the standard of care is still immunotherapy, but it's not avelumab. It's pembrolizumab. Why? Because again, we have data from a Phase III trial. The KEYNOTE-045 that showed that in second-line or third-line, pembrolizumab improves overall survival compared to conventional chemotherapy that include docetaxel, paclitaxel and vinflunine. It improves overall survival and the objective response rate is a bit higher, 21% versus around 12% of patients treated with chemotherapy. So it has been a standard of care in many countries for a while now. And the last scenario, the patient has disease progression after first-line treatment of EV/Pembro. And here, it's more challenging because, of course, we don't have much data here to provide very strong recommendations because there is no Phase III trial that includes patients previously treated with EV/Pembro. So there are different options that you can discuss. The number one could be platinum-based chemotherapy. It's easy to give. We know, of course, chemotherapy and platinum-based chemotherapy for a while. But we don't know exactly if in second-line, after EV/Pembro, platinum-based chemotherapy is effective and safe. So, a lot of registries will be implemented to get this data. Another option could be, again, for patients with FGFR3 mutations or fusions, could be erdafitinib. In the Phase III trial that I discussed a few minutes ago, none of the patients had been previously treated with EV/Pembro. So again, the level of evidence is quite low. It's mainly three or four. But it's still an option, of course, because sometimes, patients prefer to receive an oral drug. Because erdafitinib is an oral drug. Then, an IV drug like chemotherapy after a long treatment with EV/Pembro. How can we provide some recommendations between erdafitinib or chemotherapy? I think it's a case-by-case discussion with the patients. You have to take into account for the comorbidities, the patient preference, and, of course, maybe the physician preference, of course. about erdafitinib. But erdafitinib here, is also another option that you can provide to patients. I have to remind that only 15 to 20% of patients have a FGFR3 mutation and fusion. So it's a minority of patients. But if you identify such a genetic alteration in the tumors in the patient, you have to discuss this option, of course, along with the chemotherapy. Thank you. And the topic of immunotherapy re-challenge is very interesting. Is there a role for re-challenge with immunotherapy? I would say it's a difficult question here because we don't have so many data. The available data are limited, of course. But that is something we have to address in clinical trial. There are some data in kidney cancer, for example, it showed that re-challenge with immunotherapy is not very effective. So if the patient has been treated with chemotherapy followed by maintenance avelumab and has a very mild disease progression, it probably doesn't make sense to give pembrolizumab in case of disease progression after avelumab or during treatment with avelumab. It's not the preferred option. If the patient has been treated with EV/Pembro in first-line and stop pembrolizumab for any reason, for toxicity, or because the patient has been treated for at least two years, for example, and the patient has disease progression one year later, as I said before, we don't have data here to strongly recommend re-challenge with pembrolizumab. But to me, again, it doesn't make sense to give pembrolizumab if the treatment-free interval is very short, probably around six to twelve months. So in this case, I would prefer to give platinum-based chemotherapy to this patient. And the next difficult question that we have to address is if the patient has this progression on EV/Pembro, and then, you use platinum-based chemotherapy in second-line, should we provide the patient with immunotherapy as maintenance avelumab? Here we don't know. We don't have data. Again, we need this data and prospective registry or data that can provide very useful insights for daily practice. Thank you for your insightful comments. It appears that we can now offer a wider range of treatment options to locally advanced or metastatic urothelial cancer patients, going beyond third-line therapies. Could you kindly share your insights on optimizing the continuum of care for locally advanced or metastatic urothelial cancer patients in order to maximize their survival benefit? I think the take-home message is the anticipation. So I give you an example. If the patient is treated with EV/Pembro in first-line and the patient has disease progression, you will try to identify if the patient has a FGFR3 mutation in the tumors. So there is a different way to test the tumor itself. Or the alternative could be ctDNA, but it takes days and weeks to get the results. And meanwhile, the patient could have a very rapid disease progression, and maybe you would lose the opportunity to provide the patient with erdafitinib because of a rapid disease progression, and the patient could be unfit to receive any subsequent treatment. So here, the anticipation is to test the tumor as soon as possible, as soon as you diagnose metastasis in a patient. So, during the first-line setting, it's very easy during the treatment with EV/Pembro or platinum-based therapy in first-line to request for a test to look for FGFR3 mutations and fusions, in tumors, or ctDNA. So you have the information. And if you know that the patient has FGFR3 mutations, it's more convenient, of course, to discuss the different options for the second-line therapy, and to discuss the option of erdafitinib. It's just an example. So, anticipation is the key. And, again, I think you have to monitor the patient very strongly because you have to avoid losing the opportunity to give a second-line or a third-line therapy to this patient. I mean you have to follow the patient very closely, to do CT scan every eight or twelve weeks to track and detect disease progression as soon as possible. Thank you, Dr. Loriot, for the insightful discussion. We greatly appreciate your valuable guidance regarding second and later-line treatment strategies. In our upcoming session, we will learn about the novel drugs currently under development. Thank you.