There is a steadily widening range of second-line (2L) and subsequent treatment options for patients with advanced UC including chemotherapy, immune checkpoint inhibitors (ICIs) and novel therapies. In recent years, ICIs have predominantly replaced chemotherapy as the preferred 2L treatment. Furthermore, antibody-drug conjugates (ADC) and targeted agents have become available.
The selection of 2L and salvage treatments for advanced UC depends on many factors, including the initial treatment strategy used in the first-line setting. Molecular classifications appear to be promising in disease prognostication and prediction for UC.
Let's watch the recorded video on 'Frequently Asked Questions (FAQs) for 2L and Salvage Treatments' to gain comprehensive insights from leading experts – Dr. Francisco X. Real from National Cancer Research Center of Spain and Dr. Enrique Grande from MD Anderson Cancer Center Madrid.
There is a steadily widening range of second-line (2L) and subsequent treatment options for patients with advanced UC including chemotherapy, immune checkpoint inhibitors (ICIs) and novel therapies. In recent years, ICIs have predominantly replaced chemotherapy as the preferred 2L treatment. Furthermore, antibody-drug conjugates (ADC) and targeted agents have become available.
The selection of 2L and salvage treatments for advanced UC depends on many factors, including the initial treatment strategy used in the first-line setting. Molecular classifications appear to be promising in disease prognostication and prediction for UC.
Let's watch the recorded video on 'Frequently Asked Questions (FAQs) for 2L and Salvage Treatments' to gain comprehensive insights from leading experts – Dr. Francisco X. Real from National Cancer Research Center of Spain and Dr. Enrique Grande from MD Anderson Cancer Center Madrid.
The current standard of care is platinum based chemotherapy, followed by immunotherapy followed by avelumab maintenance. Depending on what the patients received in the first line, we can have different options, different alternatives in the second line setting. If the patients have received the standard of care, chemo followed by avelumab maintenance, the level 1a evidence is for enfortumab vedotin (EV) in this scenario. Enfortumab vedotin as a single agent, according to the data of the EV-301, it impacts the survival of the patients significantly. Hazard ratio 0.7, which is extremely good, I think, versus chemotherapy in this scenario. But I think at least in my opinion, the most important strength of enfortumab vedotin in this setting is the potency, is how many patients have responded. And 41% of the patients in the phase III trial responded, it's clinically significant. Because when you have a patient that is progressing to both chemotherapy and immunotherapy, you need something to really rescue these patients. In Europe, unfortunately, we don't have erdafitinib that is already approved by FDA. Erdafitinib is an oral FGFR inhibitor that in the third phase III trial demonstrated to be superior in terms of overall survival to standard chemotherapy. Precision medicine has arrived. Erdafitinib can be considered, I would say, should be considered in patients with FGFR 2 and FGFR 3 molecular alterations, including mutations and fusions. The toxicity of erdafitinib is something that could limit the activity and could limit the dose. Diarrhea, ocular alterations, mucositis can happen, and they can impact the quality of life of the patients, so careful selection of the patients from the molecular perspective is needed. What about those patients that are progressing during chemotherapy? These patients have the worst prognostic factor. Guidelines, at least the ESMO guidelines, are recommending as level 1 evidence, the use of pembrolizumab (pembro), which is extremely good, at least in terms of survival because of the data of the KEYNOTE-045. Pembrolizumab is well-tolerated. However, I have a concern and my concern is in regard to a patient that is progressing during chemotherapy, is it a good candidate or is it the ideal candidate to benefit from the use of immunotherapy single agent? Maybe not, because we know that immunotherapy needs time to respond, needs time to act on the tumor. And maybe this is not what we can expect from pembrolizumab. What am I suggesting? I am suggesting that maybe a potent drug like enfortumab vedotin can also rescue these patients who progressing on chemo. We need to go to the data of the EV-101, in which there were patients treated only with chemotherapy, without the use of immunotherapy in this field. And the responses we saw were independent of the use of chemo or the use of immunotherapy before for these patients. I think this is a good alternative that patients can receive. The third patient profile that we can have, we can find in the second line setting are those patients treated with single agent IO, single agent pembro, single agent atezolizumab (atezo). And maybe atezolizumab is becoming the standard of care. In fact, we have the data of the cohort 2 of the EV-201 trial, in which we can observe a response rate in the range of 80% when using enfortumab vedotin single agent after single agent pembrolizumab or atezolizumab It depends the sequencing strategy. It will be dependent on what we have in the first line and what it was, the response to the treatment we gave in the first line setting. Depending on how the progression has happened. I mean, if the patient has progressed during the induction chemotherapy or the patient has progressed after induction chemotherapy and immunotherapy, we can offer different alternatives to the patient. For those patients progressing during chemo. I would suggest to think if the patient needs a response, how rapid the progression was. Because depending on that question, we can go for the standard of care, pembrolizumab, according to the phase III trial KEYNOTE-045 impact on the overall survival versus former chemo taxanes or vinflunine. Or maybe you can go with, or you can consider the use of enfortumab vedotin single agent in this scenario. Because those patients progressing during chemo, the aggressiveness of the tumor, it is normally aggressive, to be really fast-growing tumors impact in the quality of life, impact with symptoms in the patients. So you need one potent drug that works fast, it's very important. So enfortumab vedotin could be that drug. For those patients receiving the standard of care chemo followed by avelumab maintenance, the use of enfortumab vedotin is considered the standard of care in this scenario, unless you have the opportunity to offer NGS testing and the opportunity to get erdafitinib for this treatment. If you need to choose in between enfortumab vedotin or erdafitinib, there are no head to head comparison, but I don't consider that one is better than the other. But I think you need to use common sense. And common sense says that if you perform the testing, if you have a positive result, please use the targeted agents ahead of enfortumab vedotin. Well, for those patients who receive in the first line, single agent pembro, single agent atezolizumab I think the most important strategy that we can use is enfortumab vedotin. Enfortumab vedotin in cohort 2 of the EV-201 trial has data that are showing 83% of responses according to RECIST criteria in patients not pretreated with chemotherapy, only treated with single agent immunotherapy. I think these data are amazing, are contributing not only to the tumor shrinkage, but also to controlling the symptoms of the patients. And definitely this amount of responses will impact the survival. I don't have any doubt about that. So enfortumab vedotin could be the alternative of choice for those patients progressing on atezo or pembro single agent. There is a lot of interest in implementing molecular analysis of bladder cancer and identifying the markers that could be predictive of response to therapy. For example, the luminal papillary subtype of bladder cancers that I mentioned earlier is highly enriched in point mutations and fusions in the FGFR3 gene. FGFR3 codes for a molecule which is a kinase that can be targeted by small molecules and antibodies. Therefore, the presence of mutations in FGFR3, as well as the presence of gene fusions, is highly predictive of response to drugs targeting FGFR3, most notably to the small molecules tyrosine kinase inhibitors. Regarding the classical therapy, such as cisplatin based therapy, chemotherapy, there have been several studies that have confirmed that ERCC2 mutations and ERCC2 low expression are associated with better response to therapy. Other genes have also been associated with response to cisplatin, however, they have not been corroborated in additional studies. Importantly, these predictive biomarkers have to be tested prospectively in new studies, and this is now challenged by the fact that obviously there is a plethora of new agents coming into play in muscle-invasive bladder cancer. In advanced disease, obviously, immuno-oncology and immune checkpoint blockade is becoming a very important drug being used in the treatment of these patients. However, unlike in, for example, lung cancer, in bladder cancer, the predictors of response to immuno-oncology drugs are much less robust. And I think that while they are being used somewhat extensively by the community and there can be companion diagnostics, their value is much more limited than in other tumor types. Regarding the new drugs that are emerging, such as the drugs targeting trop-2 or nectin-4, we still have too little information about which are the best predictors. But obviously we know that the presence, the expression of the target at the level of the tumor will be important. And this has already been shown for nectin-4 and there is less evidence on trop-2. So we have a new series of studies that need to be conducted in order to identify the predictive factors for these new therapies.