Several recent updates from clinical trials are transforming the treatment landscape for urothelial carcinoma across a variety of subtypes. The use of immunotherapy, in particular, provides patients who progress after standard platinum-based chemotherapy with new hope and a plethora of options. In the metastatic setting, there have been 5 immune checkpoint inhibitors approved by the FDA. If a patient is unfit to receive cisplatin therapy, atezolizumab (Tecentriq) and pembrolizumab (Keytruda) are approved for frontline use. Many clinical trials are looking at the combination of checkpoint inhibitors with other agents, but next steps include discovering more predictive biomarkers to help in selecting which patients would benefit most from immunotherapy. Checkpoint inhibition is also being investigated in nonmuscle-invasive disease and earlier disease settings in urothelial carcinoma. However, accrual in these clinical trials plays an important role in expanding this treatment landscape. “We definitely have to support clinical trial accrual,” Petros Grivas, MD, PhD, said. “That’s a message for across the board in academic and community sides.” In an interview with Targeted Oncologyduring the 36th Annual CFS, Grivas, director, genitourinary cancers program, associate professor, oncology, University of Washington, Seattle Cancer Care Alliance, discussed recent immunotherapy advancements in bladder cancer.Grivas: It’s really an exciting time in bladder cancer and urothelial cancer in general, specifically with the updates we have in immunotherapy for this disease that has transformed the way we treat urothelial cancer over the last few years. Specifically, in the metastatic urothelial cancer space, we have patients who get treatment with platinum-based chemotherapy and if these patients progress during or after this therapy, now we have 5 immune checkpoint inhibitors that are approved by the FDA in this platinum-refractory advanced urothelial cancer setting. One of them has a very promising point of overall survival compared to chemotherapy in a phase III trial with a high level of evidence in that space, and then 4 other checkpoint inhibitors are also approved as options. In the frontline setting, again in metastatic advanced urothelial cancer, if someone cannot get cisplatin because of medical comorbidities or performance status, we have 2 checkpoint inhibitors approved in that space, atezolizumab and pembrolizumab, based on single-arm phase II studies in the cisplatin-unfit frontline setting. More recently, we had this FDA alert that this particular use of those agents in patients with high PD-L1 status in the tumor tissue in this first-line cisplatin-unfit phenotype. However, if a patient cannot get any chemotherapy, either cisplatin or carboplatin, then there is no need to check PD-L1 in these first-line cisplatin-unfit patients. Definitely, [there are] FDA-approved options that have changed the way we treat urothelial cancer compared to prior years. I think the take-home point from my talk is that we now have emerging data with these checkpoint inhibitors earlier in the disease course in the nonmuscle-invasive disease setting [and] in neoadjuvant nonmuscle-invasive setting. In those settings, the data is not practice-changing yet but are very, very promising and definitely support further evaluation of checkpoint inhibitor therapy in earlier disease settings. Moreover, we have a lot of clinical trials with combinations looking at checkpoint inhibition plus other agents that are very important, and the take-home point is that we need to support and accrue rapidly in these clinical trials in order to identify new therapies and also potentially prognostic and predictive biomarkers, hopefully with clinically utility, that can help down the road to identify the right treatment for the right patient at the time.Grivas: That’s a great question. I usually start this answer just by quoting data that shows bladder cancer and even other types of urothelial cancer have many mutations. What do we see [as far as] tumor mutational burden (TMB)? In many patients, this is high. This high number of mutations create new proteins and new antigens. We call those neoantigens that could be potentially recognized by the immune system. Some of those neoantigens qualitatively can induce immunogenic responses. It’s hard to find the earlier, robust, strong neoantigens, [like] trying to find a needle in the haystack, but the more mutations you have, statistically, the higher the chances of you having this strong immunogenic neoantigen that could trigger the immune system. I think that is probably part of the reason why some patients may respond very well. [We] just have to find which of these neoantigens are, but higher TMB is probably 1 of the biomarkers associated with higher response rates to immune checkpoint inhibitors across tumor types, including urothelial cancer. Also, we now have data that shows that if you have mutations in DNA damage repair genes like BRCA or other similar genes in the DNA repair pathway, you might have a higher chance of responding to immunotherapy. The question is whether the mechanism of that is because of genomic instability and mutations, or if there is some separate mechanism there that can predict response to immunotherapy. The other thing that I think we have to delve into more is that there are some molecular profiling data that show some subtypes, luminalor basal, may respond better to immune checkpoint inhibitors and of course, we have the PD-L1 expression in some patients. In my opinion, we have to do a better job at validating biomarkers in the context of each other and not in silos. Ideally, we have to measure with the same platform across clinical trials to help develop biomarker and validation context. We have viability and heterogeneity in biomarkers which is great for discovery, but when it comes to validation, some more, as I would say, alignment and centralization is [necessary] across clinical trials.Grivas: I think chemotherapy is here to stay, and there are many patients who benefit already and will benefit in the future from chemotherapy. I think, right now, we have a one-size-fits-all approach because we don’t have many predictive biomarkers to enrich our patient populations. However, I think in the future we may have some more sophistication in our approach and more precision and personalized medicine where we can use biomarkers fully to identify the right treatment for the right patient. Some patients may benefit from chemotherapy more than other therapies or maybe just 1 part of the treatment paradigm. We have to identify the better sequence. Do we start with chemotherapy and follow with immunotherapy, or vice versa, or [do we] use a combination? I think this is all going to be defined in the next few years, but I think chemotherapy will have some role in this overall treatment paradigm in urothelial cancer. It’s definitely a huge number/plethora of trials with multiple agents, so I will just give you some examples of mechanisms of function because it is hard to delve into all the trials. If you think of antibody drug conjugates (ADC), we hear data of at least 2 of them, enfortumab vedotin and sacituzumab govitecan, which are being evaluated in clinical trials in patients with advanced urothelial cancer, [as either] single agents or in combination with immune checkpoint inhibitors. We also have vaccines that are being evaluating and combined with checkpoint inhibitors. The trials looking at those are very, very exciting and definitely accruing in first- and second-line settings, as far as I can recall. There are also trials in targeted therapies. We hear data about FGFR3 inhibitors in clinical trials. There are also clinical trials with PARP inhibitors looking very promising either as single agent or combined with checkpoint inhibitors and other targeted therapies against EGFR, HER2, and definitely other checkpoint inhibitors in combination, chemotherapy/immunotherapy combinations. Some trials look at radiation therapy with checkpoint inhibition. There is a plethora of different mechanisms, and I just want to make the point that all of those trials are very interesting. I think it is worth accruing into different mechanisms, and [there is] definitely a plethora of potential biomarkers.Grivas: It’s likely we are going to have some approvals in this disease in the future. Of course, it’s hard to predict when and which agents, so we just have to wait for the trials to read out. If you look at the current landscape, we have only chemotherapy and immunotherapy [options] that we are using. I had a slide looking at this current paradigm, but if you look at the publicized information, there are 2 agents that the FDA has designated as breakthrough statuses. One is an FTLA inhibitor, and the other is an ADC. These agents are being evaluated in clinical trials, and we will have to wait and see how the trials read out. My prediction is, in the next couple of years, we are going to hopefully have more therapies approved in this disease, we are going to have more biomarkers, and hopefully, we are going to identify patients for the outright treatment based on both clinical and molecular factors. Right now, it is only [based on] clinical factors. The last point to make is that we have to be conscious of the frequent germline mutations in urothelial cancer. Genetics counselling for patients and their families is very important, even more in upper-tract urothelial cancer, based on age at diagnosis and personal and familial history of cancer. Definitely keep an eye on utilizing the genetic counselling accordingly. Of course, there are more and more data for genomic sequencing that we do both in tumor tissue and circulating DNA as we have to define further the sequencing approaches for this disease. Many more data and much more information is coming out. I think we will experience some interesting emerging data presentations.Grivas: I think right now we have to utilize the evidence and the evidence, as I mentioned in my talk, is in patients with localized bladder cancer, muscle-invasive disease. We want to do clinical trials to improve upon cisplatin-based chemotherapy. If there is no trial available, cisplatin-based chemotherapy neoadjuvant is the standard of care. Immunotherapy is investigational in the localized non-metastatic disease setting. We definitely have to support clinical trial accrual. That’s a message for across the board in academic and community sides. There are trials across the spectrum of disease for nonmuscle-invasive disease, neoadjuvant, adjuvant, chemoradiation trials with immunotherapy in advanced disease, and of course in the advanced disease setting, right now probably a good problem to have is more trial slots than patients, meaning we have much more opportunity to develop therapies in this disease. The [take-home] message is to follow the evidence but accrue in clinical trials.