Platinum-based chemotherapy (CT) has been the preferred treatment for patients with unresectable locally advanced and/or metastatic (LA/m) urothelial cancer (UC) for several decades. With the evolving development of immunotherapy in the first-line (1L) setting, the standard management approach for LA/m UC consisted of cisplatin-based CT in cisplatin eligible patients or carboplatin-based CT in cisplatin ineligible patients followed by maintenance avelumab (an anti-PD-L1 inhibitor) in those who do not have disease progression with 1L platinum-based CT.
However, with the release of EV-302 and CheckMate-901 data during ESMO 2023, the landscape of 1L treatment becomes more competitive and complex. How can we access the new data? How can we strike a balance between efficacy and toxicity? How can we optimize decision-making regarding 1L treatment for both cisplatin-eligible and ineligible patients?
Let's watch the recorded video on 'Frequently Asked Questions (FAQs) for 1L Treatment Decision-making' to gain comprehensive insights from leading expert – Dr. Enrique Grande from MD Anderson Cancer Center Madrid.
Platinum-based chemotherapy (CT) has been the preferred treatment for patients with unresectable locally advanced and/or metastatic (LA/m) urothelial cancer (UC) for several decades. With the evolving development of immunotherapy in the first-line (1L) setting, the standard management approach for LA/m UC consisted of cisplatin-based CT in cisplatin eligible patients or carboplatin-based CT in cisplatin ineligible patients followed by maintenance avelumab (an anti-PD-L1 inhibitor) in those who do not have disease progression with 1L platinum-based CT.
However, with the release of EV-302 and CheckMate-901 data during ESMO 2023, the landscape of 1L treatment becomes more competitive and complex. How can we access the new data? How can we strike a balance between efficacy and toxicity? How can we optimize decision-making regarding 1L treatment for both cisplatin-eligible and ineligible patients?
Let's watch the recorded video on 'Frequently Asked Questions (FAQs) for 1L Treatment Decision-making' to gain comprehensive insights from leading expert – Dr. Enrique Grande from MD Anderson Cancer Center Madrid.
To treat our patients with cisplatin, or carboplatin in the first line metastatic urothelial carcinoma setting, we are using the traditional Galsky's criteria. These criteria include the creatinine clearance and the performance status. These are the two most frequent factors that are conditioning the eligibility to receive cisplatin in daily practice. And on top of these two factors, neurotoxicity or at least neuropathy that may condition for neurotoxicity and hearing loss is also important. Of course, those patients, because of the need of high doses of liquids, those patients cannot manage these doses, high doses of liquids because of the nephrotoxicity of cisplatin. So those patients with cardiomyopathy are not good candidates to receive cisplatin in daily practice. Taking into consideration the patient profile, the age at diagnosis of metastatic urothelial carcinoma is in the range of 73 years old. What does this means? It means that these guys, because most of them, three fourths of the patients with metastatic urothelial carcinoma will be male, probably will have associated comorbidities that can also influence the treatment of choice that we want to use in the daily practice. The JAVELIN Bladder 100 trial is a phase III pivotal trial that supports the approval for the first time of an immuno-oncology drugs, an anti- PD-L1 compound, avelumab. after induction chemotherapy, 4 to 6 cycles as an upfront treatment in the maintenance therapy. What does this mean? It means that an impact in the overall survival of the patients with a hazard ratio of 0.7 was found, a clear benefit in terms of preserving the quality of life of the patients. Avelumab is well tolerated. At least 10% of patients who responded to the maintenance or during the maintenance therapy, but above all, these data in terms of efficacy, this is for the first time something that it is adding on top of the backbone therapy of chemotherapy that is impacting in the overall survival. We should not forget that the overall survival has not move since the early 1990s, in which a phase III trial comparing cisplatin versus MVAC demonstrated for the first time to reach 12 months of survival. Since then, the data that we have barely improved these figures. In the JAVELIN bladder 100, in this pivotal registrational phase III trial with avelumab maintenance, the use of immunotherapy, avelumab after the induction chemotherapy, is impacting the overall survival and we are almost doubling what we have. From 12 months, we now have a median survival in the intention to treat population of 23.8 months. When we want to use avelumab after induction chemotherapy, 4-6 cycles, we have a direct benefit, the direct benefit is the overall survival. This is the primary outcome of the study. And this is the primary goal that we are looking for in our clinic. The thing is, the benefit is not only in terms of survival. I will try to go beyond, the benefit is psychological benefit. Before, when we didn't have anything to offer in the maintenance therapy, we got our patient exhausted of receiving chemotherapy, exhausted because of the toxicity. And we couldn't go up to six, maybe seven, in some patients eight, maximum nine cycles of platinum-based chemo. We tried to maximize, we tried to squeeze the activity of the first line. Because there were no active options in the past. Taxanes were not so active. Vinflunine was not the ideal drug to offer. So we needed to squeeze the options that we had. When we were using cisplatin or carboplatin in the first line, and we needed to stop because of the toxicity. Well, our patients got a little bit frustrated, frustrated because they were asking,'Okay, so doctor, what is now?' And now was just, 'Okay, let's do a CT scan after three months and let's see what happens. Let's see when the tumor is going to progress to grow up once again.' And that was something disappointing for the patient. With the use of avelumab, we are not only impacting the survival, which is extremely useful, but also this is something very useful from the psychology perspective to the patient. The patient is feeling he's not abandoned by the doctor, by the oncologists in this setting. So this is something that is contributing to the self-perception of the patient, that he is still cared for, he is still on treatment. At this ESMO 2023, there were two phase III trials presented at the Presidential session. One of them is completely a practice changing the EV-302. EV-302 is elevating the bar of the activity that we can see in our patients with metastatic urothelial carcinoma. The combination of enfortumab vedotin (EV) plus pembrolizumab (pembro) when compared with chemotherapy, and 30% of the patients also received avelumab maintenance, it clearly impacted the overall survival. Median overall survival for the combination of EV and pembro was 31.5 months that compared favorably with the median overall survival of only 16 months in the standard comparator arm. The hazard ratio for survival was 0.47. I think this is practice changing. On top of that, there was an improvement in the progression free survival, hazard ratio was 0.45. And also in terms of responses, 67% of the patients achieved an overall response rate, including 29% of the patients with a complete radiological response. These responses were durable. In fact, after a median follow up time of 17 months, the median duration of response was not achieved. What should we take into consideration coming to the daily practice or trying to translate this data into daily practice? The activities are awesome. I think we all were surprised about the activity of the combination of EV/pembro. However, I have two concerns. Firstly, about the toxicity, the safety profile, particularly neurotoxicity and skin toxicity were higher, or at least higher than we want. We need to, we will have to learn how to deal with the toxicity. We will need to learn how to educate our patients in order to try to prevent the appearance of these toxicities. But definitely toxicity profile should be balanced with the activity. The second thing that I think it should merit to take into consideration is the cost. The cost of the financial toxicity associated to the use of both enfortumab vedotin and pembro is very high. And I don't know about your countries, but at least in a country like Spain, it is going to be hard to negotiate the price of these two drugs. Well, let's see who can afford to pay for this novel combination. The second phase III trial that was presented at the Presidential session was the CheckMate-901. Particularly, this is a sub-study of the CheckMate-901 because we have two studies. The main study, nivolumab/ipilimumab versus platinum-based chemo, including both eligible and ineligible for cisplatin patient population. We know from a previous release that this is negative. So nivolumab/ipilimumab is not impacting the overall survival in the PD-L1 positive subgroups. These data were not presented at this ESMO. But a sub-study was presented. The sub-study was conducted in patients eligible to receive cisplatin. And they were randomized to receive cisplatin/gemcitabine as the standard of care or cisplatin/gemcitabine plus nivolumab followed by nivolumab maintenance, after up to six cycles of chemotherapy. The trial was positive for the primary outcome of survival, so the combination of cisplatin/gemcitabine and nivolumab impacted in overall survival. However, the hazard ratio was 0.78 and the median survival was in the range of 21 months. These data are impressive, they are very good. However, not as impressive as the EV-302 data in which the median survival, instead of 21 months, was up to 31 months, and the hazard ratio for survival was 0.78 in the CheckMate-901, versus 0.47 in the EV-302. So of course it is unfair to compare trials, but I think the general feeling, the overall feeling about that is that maybe EV/pembro will become the reference standard of care. And unfortunately, cisplatin/gemcitabine and, nivolumab will not reach the market or at least will not reach the same robustness to be considered in daily practice. Well the use of Galsky's criteria to define the eligibility to cisplatin or not is traditionally performed in this scenario for decades. However, now we have new drugs, new tools, and we don't need only to identify patients eligible for cisplatin. We need to identify patients eligible for any platinum, including carboplatin. And this is the place for what we call the Gupta's criteria. Gupta's criteria, we're still waiting for the final publication, but they are considering patients with a deteriorated performance status with a creatinine clearance function of less than 30 ml/minute, and also, of course, with hearing loss, neuropathy or factors that are affecting the function of the heart like myocardiopathy. So if you use the criteria from Gupta that is fine. However, in daily practice we are using common sense. Common sense in a way that, well, what the patient that I have in front of me in my office. Is it patient able to tolerate carboplatin? If the patient is able to tolerate carboplatin, I think the standard of care so far is carboplatin/gemcitabine followed by avelumab maintenance. However, there is also the option for those patients ineligible for cisplatin but eligible to receive at least carboplatin, particularly if they are expressing PD-L1, to go for single agent IO, single agent pembrolizumab, single agent atezolizumab in this setting. Of course, what can we give to our patients that are not eligible, even for carboplatin? They are platinum ineligible. No matter if you are following the Gupta's criteria or your common sense, as I mentioned before. Well, we have the approval of pembrolizumab by the FDA in which patients ineligible for any platinum, regardless of the expression of PD-L1 can receive this treatment. So this is how we in the daily practice are classifying patients - patients eligible for cisplatin, patients eligible at least for carboplatin, and patients ineligible for any platinum based chemotherapy. And we can adapt, we can make it match the options that we have. According to the current FDA approval, enfortumab vedotin/pembro is an option for patients ineligible to receive cisplatin. That's a good option to have. This is an active option. It was approved because of two phase I/II trials showing a good efficacy, at least in terms of responses. In between 63 and 77% of the patients responded in the first line, despite being ineligible to receive cisplatin. The thing is, what is the main reason? Because the patient is ineligible for cisplatin, because according to the Galsky's criteria, one of the criteria is to have medical records or medical history of neuropathy. Those patients with neuropathy, they are not good candidates to receive enfortumab vedotin, because of the potential toxicity based on the neurotoxicity induced by enfortumab vedotin . Otherwise, hyperglycemia, another toxicity related to enfortumab vedotin or a skin rash could be limiting factors. So patients with skin alterations or patients with uncontrolled diabetes, they are not good candidates to receive enfortumab vedotin those patients with these co-morbidities may receive carbo/gemcitabine if they are eligible or if we are considering, they are eligible for at least to receive carbo according to Gupta's criteria. So this is what we can use in daily practice. Of course, there is one elephant in the room and the elephant in the room is the cost of the medication, carboplatin and gemcitabine, they are both agents with generics, so they are relatively cheap. So nothing to compare with the expensive cost of the combination of enfortumab vedotin plus pembrolizumab in this setting. Well, after the results of the ESMO 2023 data, we probably have a new standard of care, enfortumab vedotin plus pembrolizumab. However, because of the cost, because of the access, it will take long to replace the current standard of care, chemotherapy as induction followed by avelumab maintenance. On top of the cost issues, I would say that there are some patients, those patients with neuropathy, those patients with uncontrolled diabetes, and those patients with other comorbidities involving the skin, in which, you may think that probably the use of enfortumab vedotin could be very toxic. I think there is still room for the use of chemotherapy upfront followed by avelumab maintenance in this scenario. But definitely, the standard of care has changed and guidelines will be updated accordingly. And we are entering into a new era in the field of the treatment of metastatic urothelial carcinoma.