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 immunotherapy maintenance strategy: When and How to conduct the maintenance therapy? We are joined today by a leading expert in urothelial cancer, Dr Enrique Grande from the MD Anderson Cancer Center Madrid, Madrid, Spain.
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 immunotherapy maintenance strategy: When and How to conduct the maintenance therapy? We are joined today by a leading expert in urothelial cancer, Dr Enrique Grande from the MD Anderson Cancer Center Madrid, Madrid, Spain.
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. Enrique Grande from the MD Anderson Cancer Center Madrid in Spain. Welcome and thank you for joining me today. During this Expert Interview, we'll be discussing the first-line immunotherapy maintenance strategy. When and how to conduct maintenance therapy? Dr. Grande, historically, patients who did not have progressive disease after receiving four to six cycles of platinum-based chemotherapy were only offered a 'Watch & Wait' approach without any additional treatment options. However, in recent years, there has been a significant shift in the management of locally advanced or metastatic urothelial cancer, particularly with the introduction of maintenance avelumab following induction chemotherapy. Could you please share with us the concept and development of a maintenance treatment strategy? I'm delighted to be here with you. And I want to say hi to all of our attendees today. It was extremely frustrating for both the patients and the physicians in the past when we had only chemotherapy, platinum-based chemotherapy, to offer to our patients with metastatic urothelial carcinoma, because we were squeezing out the chemotherapy as much as we could. The patients were really exhausted with the toxicity of the cumulative dosing of platinum-based chemotherapy. So anemia, thrombocytopenia, particularly neutropenia, ECOG performance status deterioration, tiredness, nausea, vomiting, loss of weight were the cumulative toxicity of the chemotherapy we had. These toxicities in our clinical practice, and meant that in daily practice, we were only able to use in between four, five or six cycles for the majority of our patients. And then, we needed to stop. But not because of the lack of activity of the treatment, just because of the cumulative toxicity, because of the deterioration of the quality of life. Once we stopped at the chemotherapy because of the toxicity, because we reached the top bar of the maximum number of cycles, we just told the patients,"Okay, guys. You did a great job.""And now, we need to wait three months until you repeat the CT scan.""And let's see when the tumor is growing up again." It was really frustrating. The patient was disappointed. The physicians were extremely disappointed, and all the relatives surrounding the patients were extremely disappointed. We had nothing to offer. Just ‘Watch & Wait’. Just offer for repeating the CT scan three months later. This is why we needed something else. And this is why we are all very happy with the results of the JAVELIN Bladder 100, in which the possibility to use something, immuno-oncology drugs, immune checkpoint inhibitors like avelumab, fill out this field. Come fill out this period of time in which the patients who finished the chemotherapy are maintained for a longer period of time. The benefit of the response induced by the platinum-based chemotherapy. So this is why we think it is a very good news for patients to have this maintenance strategy in daily clinical practice. The expanding range of treatment options available in the first-line setting has resulted in a diverse array of approaches for maintenance therapy. Could you kindly begin by sharing the specific approach for maintenance treatment following first-line induction chemotherapy? The JAVELIN Bladder 100 was the pivotal registrational Phase III trial that gave the approval to avelumab as a maintenance strategy for our patients with metastatic urothelial carcinoma who did not progress during platinum-based chemotherapy. Both cisplatin and gemcitabine, and carboplatin plus gemcitabine regimens, were optimal regimens to be followed by maintenance strategy with avelumab. The main outcome of the JAVELIN Bladder 100 is an impact in overall survival without deterioration of the quality of life. Those patients who were not progressing during induction chemotherapy and who did receive avelumab as a maintenance strategy treatment, they had a greater overall survival, and the toxicity profile versus placebo was extremely good, since there were no differences in the quality of life of the patients, which how well avelumab is really tolerated in daily clinical practice. The impact in our consultations, in our daily life, is extremely important, because now, our patients have new options that are translating into a better survival, better progression-free survival. Additional 10% of patients that are responding. You have an additional tumor shrinkage in around 10% of the patients with the use of avelumab and also all of these things, without deteriorating the quality of life for the patients, which had already improved because of the response to the induction chemotherapy we have. So these are very good news for our patients in the practice. With the release of the data from the CheckMate-901 study at ESMO 2023, we now have an additional immunotherapy approach involving first-line chemotherapy and maintenance. Could you kindly provide further details regarding this new approach and share your insights on the distinctions among different strategies? Overall speaking, the CheckMate-901 trial is a... Let's say it's not easy to address the design of the trial because it has two parts. A main study, nivolumab plus ipilimumab versus chemotherapy in patients eligible and ineligible to receive cisplatin according to Galsky criteria which we know was not positive because of a press release in 2022. Unfortunately, we do not have any data about this main part of the CheckMate-901 trial and what was presented at the plenary session at the ESMO 2023 in Madrid, it was also published in The New England Journal of Medicine. The trial, led by my friend, Dr. Michiel van der Heijden, and colleagues who participated in the trial, well, now we know that in the subgroup of patients that are eligible to receive cisplatin, according to the Galsky criteria, when we added nivolumab to cisplatin and gemcitabine, there was a clear impact in overall survival versus those patients who received only cisplatin and gemcitabine. The impact in the overall survival was in the range of a hazard ratio of 0.78, which it is good and definitely better than with chemotherapy. However, there are many issues with this trial. The thing is, what was the proportion of patients who did receive in the control arm chemotherapy, Gem/Cis plus avelumab as a maintenance strategy. What would happen if that, instead of Gem/Cis only, the comparator arm would have been Gem/Cis plus avelumab. Were there differences in terms of overall survival? Probably not. Another important issue here. What about the progression-free survival differences? Because probably the long-term impact in survival is because of the maintenance part of nivolumab after the patient finished the chemotherapy. We know that the combination of platinum-based chemotherapy and nivolumab or pembrolizumab or atezolizumab, did not really result in significant differences overall in terms of responses and clinical significance differences in terms of progression-free survival. Now we need to understand better. What is the final position of the CheckMate-901 in patients eligible to receive cisplatin and gemcitabine? In the same plenary session, all the trials, the EV-302 trial with a combination of antibody-drug conjugates plus immuno-oncology drug, it seemed to have a better impact, much better than the combination of cisplatin, gemcitabine and nivolumab. The final position for this combination is still to be solved. Thank you. How could we optimize the maintenance strategy? Definitely. We have an issue with daily clinical practice to select patients that will get the maximum benefit from the maintenance strategy. We have a biomarker. The biomarker is the response to induction chemotherapy. Those patients that have a complete radiological response or a partial response, or at least a stable disease during maintenance for five or six cycles of Cis/Gem or Carbo/Gem could be good participants, to receive maintenance avelumab. Unfortunately, molecular biomarkers or immunohistochemistry biomarkers are not really helping us to identify in advance, which will be the patients that will benefit from this strategy. Unfortunately, we are not selecting patients according to this response to chemotherapy. And when we try to combine chemotherapy based on platinum plus immuno-oncology drugs without any patient selection, we have the data from the KEYNOTE-361 and the IMvigor-130 trials telling us that at least pembro and atezolizumab in combination with platinum-based chemotherapy are not really impacting, clinically speaking, the outcome of our patient. This is true. As we mentioned before, the data from the CheckMate-901, in patients eligible to receive cisplatin treated with gemcitabine, and cisplatin plus nivolumab are impacting in overall survival. The hazard ratio is modest at 0.78. And there was a small increase in the percentage of patients responding, particularly with a complete radiological response. But the question here is, are these complete radiological responders really long-lasting responders? We still need a longer follow-up on the CheckMate-901 trial to see if we can try to use this strategy, the combination of chemo plus immunotherapy strategy in daily practice. I think, honestly, that the benefit in the long-term overall survival from the CheckMate-901 is mainly coming from the maintenance part of nivolumab. Those patients who were treated in the CheckMate-901, started cisplatin and gemcitabine and nivolumab in a combination, and when they finished the chemotherapy after four, five, six cycles, depending on the toxicity, the patients were able to maintain nivolumab. Probably this maintenance immuno-oncology strategy is the one leading to the overall survival improvements. We can try to maximize. We can try to get a maximum benefit from the maintenance strategy by diminishing the number of cycles of chemotherapy as induction. Probably two or maybe three cycles are enough to get this initial response of the tumor, to get this initial control of the symptoms because of the size of the tumor. Probably in the first couple of cycles, maybe three cycles, no more than four cycles, you know who will be the patients that will be responding to platinum-based chemotherapy, and those are the ones that are benefiting longer from receiving avelumab. This is the scientific background behind the design of the DISCUS trial. The DISCUS trial is one of the most innovative trials, potentially practice-changing, if positive, in which patients with metastatic urothelial carcinoma who did not receive any prior chemotherapy in the metastatic stage, are randomized to receive chemotherapy based on platinum, cisplatin, carboplatin, according to the investigator, followed by avelumab. The thing is, how many cycles of chemotherapy are we giving? These patients are randomized to receive three versus six cycles, followed by avelumab maintenance in both arms of the treatment. What is the endpoint? The primary endpoint considering the DISCUS trial, is the quality of life. When the quality of life is assessed? The primary endpoint is the quality of life, three versus six cycles of chemo followed by avelumab maintenance on day one of the potential Cycle 6 What do we want to see at the DISCUS trial? We want to see no deterioration in the long-term overall survival of the patients, but an improvement in the quality of life of the patients because of the reduction of the number of cycles of chemotherapy as induction that are needed before the treatment with avelumab as a maintenance strategy. Other combinations, I'm talking about the JAVELIN Medley trial in which avelumab is combined with tyrosine kinase inhibitors or antibody-drug conjugates or other immuno-oncology drugs, are ongoing. Let's see what will happen. We still need to learn a lot about how to select the best treatment option for our patients with metastatic urothelial carcinoma. Currently there are many treatment options in first-line setting. How do you select the optimal strategy in clinical practice? This is a very nice question, and probably the most challenging one that we have today in the field of metastatic urothelial carcinoma. Now, with the new data from the EV-302 trial, in which the combination of enfortumab vedotin (EV) plus pembrolizumab is better than chemotherapy in terms of overall survival, response rate, progression-free survival. Well, it seems it is easy to address this question. Enfortumab vedotin plus pembrolizumab will probably become the standard of care. However, we have a lot of issues trying to translate this data into daily clinical practice. The first and probably the most important barrier that can limit the possibility of our patients to receive this combination, is related to the financial toxicity. Who can really afford this combination? Enfortumab vedotin plus pembrolizumab. Not only are we talking about the patients, but also about the stakeholders, the payers, governments, national health systems. This is really impacting in the budget of our societies. Second thing, toxicity. Enfortumab vedotin and pembrolizumab definitely have limitations in toxicity, including particularly neurotoxicity. And also hyperglycemia, neutropenia and dermatological skin toxicity. Those patients, regularly diabetic patients, in which they have neurotoxicity because of the diabetes. They have glucose elevated in the blood because of the diabetes. And they have also alterations in the skin because of the diabetes. They are probably not the best candidates to receive this new combination. I don't know in your countries, but in a country like Spain, around 20 to 30% of the patients above 70 to 75 years old, the median age in which metastatic urothelial carcinoma is diagnosed, they have diagnosed or underdiagnosed diabetes. So probably, we need to clinically select which of the patients that can benefit from new strategies, new combinations in this field. On top of that, do we have any biomarker that may help us to identify patients that will benefit more from these new combos? Unfortunately, we don't have any biomarker. At least with the data reported so far. But it seems that regardless of the PD-L1 expression, regardless... I don't know, NECTIN-4 expression. We still need to know more about what potential molecular biomarkers that may help us in the future to identify these patients. In absence of this biomarker, the best biomarker that we have today for a novel agent is the response to chemo. The response to platinum-based chemo. And only those patients responding to platinum-based chemo is the best biomarker to receive avelumab as a maintenance treatment. So we still need to know more about the patient profile that we can treat with in the next few years. What about the traditional Galsky criteria that we all were using to identify patients to be treated with cisplatin or carboplatin in daily practice? Are the Galsky criteria still valid to identify patients ineligible to receive enfortumab vedotin and pembrolizumab? Or do we need to create another criteria? To try to see the eligibility to receive enfortumab vedotin. A lot of debate is out there, and unfortunately, the follow-up of the EV-302 trial and all the trials in the first-line setting still need to mature. This is definitely a good challenge that we need to face shortly. Thank you, Dr. Grande, for your valuable insights. We greatly appreciate your expert guidance on the first-line immunotherapy maintenance strategy. In the next session, we will discuss decision-making for sequential treatment strategies. Thank you so much.