 The future is looking bright for patients with advanced urothelial cancer. We have several drugs that have been approved, several drugs that we are looking at in the phase 3 setting for antibody-drug conjugate combinations, and cabozantinib and immunotherapy combination were recently shown to be effective in the salvage setting. More recently, single-agent cabozantinib was also shown to be very effective in patients with heavily pretreated advanced urothelial cancer.

We have this added agent, which is a VEGF TKI [tyrosine kinase inhibitor], cabozantinib, which seems to be showing promising activity. We will see how the ongoing trials with immunotherapy combinations pan out. We are also looking at augmenting the immunotherapy maintenance-use backbone with other novel drugs. That will be very interesting. There's a lot of excitement out there to use these agents. As more and more agents are moving earlier on [in treatment], I think the first-line combination trials will be very important and may change the treatment paradigm moving forward.

 I think we are at a very exciting phase of bladder cancer right now. There are a lot of ongoing trials with the use of combinations. The next step in the field is trying to combine immunotherapy with another agent, like enfortumab. In patients who have good targets, who have mutations, this is also an area where we can capitalize on the use of other targeted therapies, like HER2-targeted therapies, antibody-drug conjugates, because we already know that enfortumab has had great success. Other drugs that are in the pipeline are very exciting.

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Bright Future in Advanced Urothelial Cancer

 I think retreatment with a different checkpoint inhibitor, a PD-1 or PD-L1, after failure of 1 checkpoint inhibitor, is challenging. Retreatment with a different PD-1 blockade inhibitor may be especially effective in those who stop their prior treatment for reasons other than disease progression. We have data to show that even a similar PD-1 agent, ie, pembrolizumab and nivolumab, may target a different epitope of PD-1.

That potentially forms the rationale for using another checkpoint inhibitor. One thing to remember, too, is that PD-1 inhibitors also potentially target 3 different inhibitory interactions. For instance, there are interactions between PD-1 and PD-L1, PD-1 and PD-L2, as well as PD-L1 and B7-1. Each of these checkpoint inhibitors can only inhibit 2 of these pathways.

Another way of thinking about this is we also should probably refrain from using multiple PD-1/PD-L1 inhibitors in sequence on a routine basis outside of clinical trials until we have sufficient data to support this practice because the concern there is if one has already failed 1 checkpoint inhibitor, there's very little response to be gained from switching from 1 checkpoint inhibitor to another in real-life practice. Until we get results from prospective trials that allow prior treatment with a PD-1 or PD-L1 drug, I think we need those data to validate this approach to determine whether efficacy and safety are really warranted in this set-up of sequencing.

There is a very strong rationale for using enfortumab because enfortumab is an ADC product, an antibody-drug conjugate, that targets nectin-4, and nectin-4 is actually overexpressed in most urothelial cancer tumors. The early phase trials of EV-103 looked at the combination of enfortumab and pembrolizumab in the cisplatin-ineligible cohort. Even in that cohort, it was a very striking response, over 70%.

The basis of the FDA approval was EV-201. This was a single-arm multicenter trial that got FDA approval for enfortumab; this is in the third-line setting because their patients failed prior chemotherapy and immunotherapy. Even with the heavily pretreated population of these patients, they still had 44% confirmed objective responses. I think this is a good tool for our patients who failed prior immunotherapy. Again, that's the label right now. There are ongoing studies looking at it as first line in combination with pembrolizumab, with or without chemotherapy.

In any of these algorithms, clinical trials are going to be up there. After all, this is how we get approval of these drugs. If these patients did not enroll in these clinical trials, we would not be able to get to where we are right now. Certainly, in clinical practice, too, we all know that not all patients are going to be great candidates for clinical trials, nor will they all be able to avail themselves of it because of lack of access.

In the lack or absence of a clinical trial, we have to resort to standard of care drugs, for which there are not a lot out there. If a patient truly fails 1 checkpoint inhibitor and the chance of response to another checkpoint inhibitor is very low, then we're left with either erdafitinib—but that's only if the patient tests positive for 

 alterations—or enfortumab. This is still an area of increased unmet need in bladder cancer.

Sequencing Considerations in mUC after Frontline IO

 For patients who get first-line platinum-based therapy and then get on avelumab maintenance and progress, we have several options available. Enfortumab vedotin was approved as standard of care for patients with metastatic or advanced urothelial cancer who have had a prior platinum and immunotherapy, so that would be an excellent option. Based on next-generation sequencing, if patients have 

 mutations, then they can also get erdafitinib, which is an oral FGFR3 inhibitor. These options are still available for patients who progress after avelumab maintenance.

 The choice of therapy after progression of metastatic urothelial cancer in the setting of avelumab maintenance is a great question to which I don’t think we have great answers. We may recall in the setting of first-line chemotherapy, let’s say, and in the previous paradigm that we had, we wait until progression and then use checkpoint inhibitors and second-line therapy. We have certain drugs that we could go to.

If a patient does have a targetable mutation or alteration, like 

, then we can use erdafitinib, which is already for that setting. Another drug we can go to is enfortumab. Enfortumab is FDA approved specifically in that setting for patients who have failed prior chemotherapy, as well as immunotherapy.

In terms of the sequencing, a lot of people will go to either enfortumab or erdafitinib in patients who have had great response to chemotherapy. The patients who went on to JAVELIN Bladder 100 achieved a CR [complete response], PR [partial response], or stable disease. I will also potentially recycle. If the patients are having good performance status, and it’s been about a year since they got the first chemotherapy, that may still be an option, especially if there are no good clinical trial options available after failing all these targeted therapies and enfortumab.

Erdafitinib is a small molecule inhibitor for patients with 

 alterations, a very promising drug, and it’s approved by the FDA specifically for these patients. I would say it applies only to a minority of patients who test positive for the 

 alterations. That number is easily about 20% of patients with advanced urothelial carcinoma—a little higher, perhaps, in those who have upper-tract urothelial carcinomas, up to about maybe 40%. The basis of the FDA approval was a small study, an open-label phase 2 trial run by the BLC2001 study group.

They enrolled about 99 patients. Now the primary end point was objective responses, which they met, and the rate of confirmed response to erdafitinib was a striking 40%. They were almost complete responses, about 3%. Thirty-seven percent had PRs, so it is a promising and useful drug to use, especially for those, and only for those, who have 

 alterations. This is not everyone and is the basis and rationale for testing early on for genomic sequencing in patients with metastatic bladder cancer.

Metastatic Bladder Cancer: Progression After Maintenance

 I believe that—and this is true for avelumab and all other checkpoint inhibitors that we have been used to using in practice—the education of patients, particularly in the evaluation and understanding of adverse effects, is very important. Unlike chemotherapy, where we often tell patients, “Look, once you’re done with the chemotherapy or once we hold the chemotherapy, a lot of the adverse effects actually do improve and resolve.”

It’s not quite as much with immunotherapy, so it’s not enough for us to stop. We have to institute steroids. Educating these patients is very important, as well as recognizing the potential immunotherapy adverse effects. There are practical applications in avoiding, or maybe mitigating, infusion reactions. Giving them premedications is unique to avelumab.

With a lot of other checkpoint inhibitors, we don’t usually premedicate, but we do with avelumab with the use of Tylenol or Benadryl to avoid the infusion-related reactions. Education is a very important part of supportive care. If they do ever develop any immune-related toxicities, then steroids or other immunosuppressive drugs are key.

 We talk to the patients about the benefits seen in the study and the commitment of every-2-week dosing. A lot of patients who come to tertiary referral centers come from far away, and it may not be feasible for everyone. Even on study, a lot of patients missed a lot of doses for a variety of reasons. The study does not have an end point to avelumab. Patients can continue until they progress. It is a long-term commitment, and we do present the risks and benefits to the patients and go from there.

The key for my practice that I use is, I tell them the benefits of immunotherapy as opposed to chemotherapy whenever I’m prescribing it. Then I always make it clear that even though immunotherapy is very well tolerated for the most part, there can be some severe adverse effects. We have seen a lot of them, but they are still developing, so patients need to be really on top of their symptoms and inform us, even if they notice a subtle change from baseline, because we could be missing something important. There’s a lot of counseling that goes into this, and we give a lot of materials to the patients so they understand when to call us.

Educating Patients on Maintenance Therapy in mUC

 According to the JAVELIN Bladder 100 data that were presented, all the patients benefited regardless of the subgroup, the site of metastasis, or the kind of chemotherapy used. The benefit seems to be more in those with positive PD-L1 than with negative PD-L1; regardless, the benefit exists. I would say that at this point, based on the available evidence, all patients can be offered avelumab maintenance therapy as long as they meet the criteria.

 There are a lot of factors that we take into consideration when we see a patient who is newly diagnosed with metastatic urothelial cancer: a patient’s age, performance status, kidney function, smoking history, comorbidities—all of them matter. For patient age, I would say it is not necessarily factored into the cisplatin-eligible guidance.

Age is very important, though, as the majority of patients who are diagnosed with bladder cancer are older. This is significant in terms of setting their goals of care. Are they interested in quantity of life versus quality of life or balancing out toxicity? If we’re saying that cisplatin is generally superior to carboplatin, what does that do to their kidney function? Therefore, renal function is a very important factor that we consider in patients who are being treated.

When we talk about chemotherapy, we know that cisplatin causes a predictable decline in their creatinine clearance in renal function. I would say that in the JAVELIN Bladder 100 trial, all patients across the board benefited—whether they got cisplatin or carboplatin—as long as they achieved either CR [complete response], PR [partial response], or stable disease. It’s their response to the treatment, rather than the choice of drug, that dictated whether or not they responded.

Performance status is also an important factor to consider because if it is poor at the very beginning, that is one of the definitions of cisplatin ineligibility or sometimes even platinum ineligibility. They may not be able to receive platinum at all, either cisplatin or carboplatin. Smoking history is a little controversial. Some studies indicate immunotherapy would be better for patients who have a smoking history, whereas others do not support that data.

Comorbidities, of course, do play a role. Whenever we use chemotherapy, any platinum, that ties to renal dysfunction and is closely related to other comorbidities—for instance, in diabetes—we find that a lot of patients may have concomitant problems with their kidney function. All these factors matter in our decision-making for managing patients with metastatic bladder cancer.

I really do think the results of JAVELIN Bladder 100 are revolutionary. Never in the history of bladder cancer have we seen practice-changing responses. This paves the way for more use of maintenance therapy, and for the first time in a long while, we did not have anything other than chemotherapy. Now we have immunotherapy as second-line.

Can we improve on those odds of survival, as well as prolongation of endurability of response by starting them on immunotherapy earlier instead of waiting until progression? I think this is clinically meaningful and changes the standard of care as we know it in metastatic bladder cancer.

Changing the Standard of Care in Metastatic Bladder Cancer

 Immune-related adverse events are actually not very common, especially for grade 3 or 4 adverse events. If and when they do happen, if some of them are life-threatening, it is a very important concept to know for both physicians and patients alike. We often emphasize to patients that anything can happen, including autoimmune-related adverse events, such as autoimmune hepatitis, autoimmune colitis, and autoimmune nephritis. Any organ, in fact, would be at risk, with nephritis as an example.

As a rule of thumb, I often tell patients and other physicians that whenever we encounter any toxicity that could be autoimmune related, one of the things we always want to do is rule out other infectious causes or any other cause that would explain the toxicity. For instance, in a patient who developed renal dysfunction, was there a recent contrast use? Is there acute kidney toxicity because of the use of antibiotics? Is there dehydration? For colitis, we want to make sure they don’t have any infectious causes. It’s the same thing with hepatitis—do they have viral hepatitis? Once we’ve ruled other causes out and there’s no good explanation other than autoimmune, we determine how bad it is.

What is the severity of the grading? We would often go back to our primary source and look at our toxicity grading book. At the same time, there’s also general rules of thumb. If a patient develops a grade 1 toxicity, they’re usually asymptomatic. For instance, with autoimmune hepatitis, there’s a lab abnormality. As long as your AST [aspartate aminotransferase test] and ALT [alanine transaminase test] are less than 3 times the upper limit of normal, you can choose to keep the patient on immunotherapy and closely monitor them.

The moment you hit a grade 2 toxicity, that warrants stopping the drug—at least temporarily—initiating all work-up, and instituting steroids because that’s an essential part of the management of any immune-related toxicity. We usually use prednisone or its equivalent. You can start with 0.5 mg/kg to 1 mg/kg dose per day. Then you escalate, especially if a patient does not respond within 3 to 5 days.

That may be a trigger to escalate your dose steroids. In some cases, let’s say autoimmune colitis, you may take it up a notch by giving them additional immunosuppressant drugs like infliximab. In autoimmune hepatitis, you may choose to use other immunosuppressant drugs like mycophenolate. A lot of this is the idea and option of engaging all your specialists, engaging GI [gastrointestinal] doctors for autoimmune hepatitis or colitis, or engaging nephrologists when you have renal dysfunction.

That is key management. Whenever you see grade 3 or 4 toxicity, that’s an indication of stopping it completely and perhaps never going back, depending again on the toxicity because one cannot risk having a rechallenge once you give the patient the same drug or even a different drug of the same class.

Practical Management of AEs in Metastatic Bladder Cancer

We saw toxicities in the JAVELIN Bladder 100 trial. Although toxicities are seen with avelumab, I would say that most were in line with what you would expect for the use of checkpoint inhibitors in clinical practice. There are 2 general categories of adverse events. One would be the treatment-emergent adverse events [TEAEs], which are any AEs [adverse events], any toxicity that happens, regardless of whether it’s immune related or not.

For this, fatigue is one of the most common we’ve seen in JAVELIN Bladder 100, as well as pruritus and UTI [urinary tract infection], although I would say that some of these may be more related to the disease process itself rather than the drug. There were no grade 4 or 5 AEs, so that is comforting. The treatment-related AEs led to discontinuation rate of 12%.

That’s a reasonably good number. The use of high-dose steroids, which is defined as 40 mg or more of prednisone, was seen in about 9%. That is a reasonable treatment-related AE profile for any drug. One peculiar thing I would say about the use of avelumab is that there is a higher incidence than most of the checkpoint inhibitors of infusion-related reactions. It occurred in 10% of patients in the JAVELIN Bladder 100.

 For grade 2 pneumonitis, which is a serious condition, we obviously hold the immunotherapy and start the patients on steroids. If the patients need to be admitted, then we do that. Most patients improve with steroids. Depending on the severity, we make a decision once everything has resolved; most often, we don’t we challenge with the immunotherapy.

 The adverse effects we saw from avelumab in the JAVELIN Bladder 100 are in line with what we were seeing in the second-line treatment for metastatic urothelial cancers. In the earlier-phase trials for the second-line treatment and beyond, this seems to be a bit more with infusion-related reactions, close to about 30%, which we did not really see in JAVELIN Bladder 100. Other than that, it’s comparable.

Grade 3 or more AEs that were associated with avelumab, including UTI, anemia, hematuria, and fatigue—a lot of them may be related to the disease process itself. It is well known that patients with bladder cancer, especially if they did not get primary treatment because they were metastatic at the time of initial medical assessment, would not have undergone cystectomy. Some of them may present with hematuria. Now it is important to note that none of these treatment-related adverse events, albeit grade 3 or more, had more than 5% in terms of incidence and prevalence. Remember, too, that these were TEAEs, so they’re not necessarily related to immune-related toxicity. It was any AE that happened within the trial.

Safety Data from JAVELIN Bladder 100

 Remember, the primary end point of JAVELIN Bladder 100 was overall survival; it was positive, and they met the primary end point. It was superior in the avelumab arm, which yielded 21.4 months of overall survival compared with the best supportive care arm, which was 14.3 months. If you look further in PD-L1 population and subpopulation of patients, it was even better.

The overall survival was not yet estimated and not reached versus 17.1 months in the best supportive care arm. In terms of progression-free survival, that was also positive across the board between the overall population, which was about 3.7 months, compared with 2 months for the best supportive care arm. In the PD-L1 subpopulation, it was also a little better—5.7 months compared with the best supportive care arm at 2.1 months.

The end point that is meaningful in this study is overall survival. This is the 1 that resonates with everybody—to physicians, to patients on board—because overall survival is the key end point that we need to achieve to translate into clinically meaningful survival benefit.

 A survival outcome tested across various subgroups showed that avelumab was better than best supportive care, regardless of age, ECOG performance status, and first-line chemotherapy, whether it was carboplatin based or cisplatin based in the sites of metastases and PD-L1 status, as well as renal function status. The hazard ratio favored use of avelumab across the board.

 The results of the JAVELIN trial resonate and are clinically meaningful. In terms of upfront chemotherapy used for bladder cancer, there are some patients who fall at the end of the curve where we might say that they may have achieved good response, good remission, and maybe cures. That’s not everybody, but there is still a subpopulation of patients who are considered great responders to chemotherapy.

Those are also the patients for whom we want to be able to maintain those good responses. That’s why a switch maintenance strategy would be clinically meaningful, because we know in the field of bladder cancer that progression can sometimes be rapid in these patients. It’s a very aggressive disease.A subgroup of patients may derive a lot benefit from this maintenance approach with avelumab, and that would translate into clinically meaningful survival and benefit in terms of quality of life as well.

Increased Survival Outcomes with Switch Maintenance in mUC

 Immunotherapy is approved for platinum-refractory disease—that is, patients who progress after receiving cisplatin or carboplatin. The JAVELIN Bladder 100 trial, which looked at maintenance immunotherapy with avelumab, is novel. The concept of switch maintenance was tested—that is, patients who have a response or stable disease at the first-line platinum therapy.

We also did a trial with pembrolizumab as a part of the Hoosier Cancer Research Network study, led by Dr Matt Galsky, in which we used pembrolizumab as a switch maintenance strategy. The whole concept is instead of putting patients on surveillance, those who respond to platinum have stable disease after 6 cycles or so; we don’t treat them until they progress. As a part of the studies, patients received immunotherapy early on because we wanted to see if these patients’ outcomes would be improved.

The data from the JAVELIN Bladder 100 show that patients who received immunotherapy maintenance as opposed to best supportive care had a remarkably improved overall survival and progression-free survival. Looking at the data from platinum-refractory setting with immunotherapy, it appears that the earlier use of immunotherapy is better because we are not missing out on patients who may lose out on getting immunotherapy as well.

 JAVELIN Bladder 100 was a multicenter, international, phase 3, randomized trial of metastatic urothelial cancer patients who received chemotherapy. They received 4 to 6 cycles of platinum-based chemotherapy, so that could have been gemcitabine or cisplatin, or carboplatin with gemcitabine combination. They should have achieved complete response, partial response, or stable disease.

If they progress on the chemotherapy regimens, they would not have been allowed to get randomized. The randomization arm was either maintenance avelumab or best supportive care. Avelumab was given 10 mg/kg every 2 weeks, and there was no limit to how long they were going to get it—until toxicity, perhaps, or progressive disease they continued on with the treatment. The primary end point was overall survival in both the primary analysis, as well as the PD-L1 population of patients.

The population of JAVELIN Bladder 100 is contemporary and relevant in clinical practice. Most patients who have completed or are able to complete chemotherapy are often wiped out. Remember, our bladder cancer patient population tends to be older. By the time they get 4 to 6 cycles of chemotherapy, even though they have good response, a lot of them are having adverse effects from chemotherapy.

In addition, a lot of them may progress after finishing chemotherapy, so a treatment that may be able to consolidate that response would be well received. This is the setting of JAVELIN Bladder 100, and that’s how we are able to translate it into real-world practice. Being able to maintain them on a certain treatment regimen that, hopefully, has no overlapping effects with chemotherapy is really ideal. This is where the switch maintenance approach would really be useful in this population of patients.

Switch Maintenance Strategy for Metastatic Bladder Cancer

 At what point do we test for PD-L1? I usually test early. You can do this as part of a genomics panel. There are certain platforms, like Foundation Medicine, that automatically test for PD-L1. I mentioned earlier that you do not necessarily need to test PD-L1 when using second-line therapy and beyond for checkpoint inhibitors, but the utility of PD-L1 testing is for first-line therapy for metastatic urothelial cancer, especially those who are cisplatin-ineligible.

For those who are cisplatin-eligible, chemotherapy remains the standard of care. In fact, even for those who are ineligible who are otherwise carboplatin-eligible, chemotherapy is still and remains the standard of care. There are, of course, areas of contention. Some people would test only at the time when there are no other options. For the most part, I believe testing early would be the way to go, so that we have that information early enough on hand.

Which tests do we use to determine PD-L1 status? This is highly dependent on each institution—your practice, as well as the comfort level for the pathologist. It’s really dealer’s choice. There are also certain FDA-approved tests that accompany the use of certain drugs. For atezolizumab, it is recommended to use the VENTANA SP142 assay. Their definition of positive also differs. For the VENTANA SP142 assay, the PD-L1 expression of greater than or equal to 5% for the immune cell is considered positive.

For pembrolizumab, they use a different assay. They use the 22C3 antibody, and they’re looking for a combined positive score of more than 10. For avelumab in the JAVELIN Bladder 100 trial, they use SP263 assay; it really varies across platforms. There has been no real great standardization of all these assays, so I would say it’s up to whatever patients, or really physicians and institutions, are comfortable with and whatever drug they mean to use.

 For our advanced urothelial cancer patients, we are getting next-generation sequencing because about 10% of patients may exhibit 

 mutations, for which we have an available drug called erdafitinib. In PD-L1 testing, it is routinely done as a part of these tests to guide therapy for patients who cannot get platinum as first-line therapy. As far as molecular subtyping goals, that’s still an active area of research.

Value of PD-L1 Testing in Metastatic Urothelial Cancer

Immunotherapy is approved for platinum-refractory patients and their 5 immunotherapy drugs, which are approved, but pembrolizumab was the only drug that has level 1 evidence back by the phase 3 KEYNOTE-045 trial. That is our drug of choice for patients who progressed after platinum-based therapy, although any of the other immunotherapy agents can be used.

As far as first-line immunotherapy use goes, patients who are not eligible for cisplatin and have a high PD-L1 expression in their tumors or do not have high PD-L1 expression are recommended to get single-agent immunotherapy, either pembrolizumab or atezolizumab. These are the only 2 agents recommended. In patients who are not eligible to receive carboplatin either, they can get single-agent immunotherapy too.

We don’t have strict definition for patients who cannot get carboplatin, but our group had done a consensus survey last year and presented at GU ASCO (American Society of Clinical Oncology Genitourinary Cancers Symposium) some guiding factors to which patients cannot be recommended carboplatin. There’s still a lot of work to do in identifying those patients.

 Currently, there are 5 checkpoint inhibitors that are approved for metastatic urothelial cancers. In this space, most, if not all, of them are approved in the second-line therapy and beyond. This includes pembrolizumab, nivolumab, and durvalumab, which are all PD-1 inhibitors, as well as avelumab and atezolizumab for PD-L1 inhibitors.

In terms of how the PD-L1 expression levels would factor into these FDA approvals, it is important to recognize and remember that these 5 checkpoint inhibitors that are approved for second-line therapy and beyond do not rely on the PD-L1 expression. That means if a patient has failed prior chemotherapy and they are eligible because they have progressed, they can go on to 1 of these 5 checkpoint inhibitors.

On the other hand, there is 1 disease state that is limited by PD-L1 testing, and that is in the first-line metastatic urothelial cancer setting, in terms of the cisplatin-ineligible patients. You may all recall that in 2018, the FDA set a limit for the use of pembrolizumab and atezolizumab, especially for patients who are considered cisplatin-ineligible. The value of PD-L1 testing is limited largely to this population of patients with a cisplatin-ineligible first-line metastatic setting. That is because the key finding from the data safety-monitoring board showed a key finding of the phase 3 trials of IMvigor130 and KEYNOTE-316, which was that the monotherapy arm of the atezolizumab and pembrolizumab showed decreased survival compared with the platinum-based chemotherapy arm. If we are thinking of a patient who is cisplatin-ineligible, PD-L1 testing would be beneficial because if they have high expression of PD-L1, that’s when we can use this over chemotherapy. Obviously, if they are considered platinum-eligible, meaning they cannot receive carboplatin, then that would be the time that you can use these drugs without really testing.

For the longest time in the history of the metastatic urothelial cancer treatment landscape, we’ve had a dearth of drugs. We’ve only had chemotherapy for the longest time. We know the use of checkpoint inhibitors truly revolutionized treatment. The challenge we face in the bladder cancer community is that the actual responses for the use of this drug still have to be improved. It’s in the order of 20%, sometimes as much as 40%, with those who are PD–L1-positive, so there is still a big area of increased, unmet need. One other thing to consider is while most patients do tolerate it without any issues, it is not truly without toxicity either. These have to be factored in when considering patients for these types of treatments with checkpoint inhibitors.

 The drugs are well tolerated compared with chemotherapy. Most patients do very well. Quality of life is maintained on immunotherapy compared with chemotherapy use. However, the risk of immune-related adverse events needs to be explained to the patients because while rare, some of these adverse events can be fatal, so we have to be good teachers and monitor patients very closely. Now that pembrolizumab dosing has been approved for at least 6 weeks, we still do checks every 3 weeks on patients to make sure we’re not missing anything because immunotherapy-related adverse effects can be quite subtle compared with what patients observe with chemotherapy.

PD-L1 Expression in Metastatic Urothelial Cancer

We’ve seen tremendous progress in treating metastatic urothelial cancer patients over the last few years. Currently, the standard is that the first-line treatment for metastatic or advanced urothelial cancer patients remains platinum-based chemotherapy, either with gemcitabine and cisplatin or gemcitabine and carboplatin. For patients who are cisplatin-ineligible, we have the option to use immunotherapy if they have high PD-L1 levels in their tumor or carboplatin if they do not have high PD-L1 expression.

For patients who are not eligible for carboplatin, immunotherapy can be used as first-line. Chemotherapy remains a backbone in the first-line setting. As far as subsequent line settings go, we see remarkable progress. Immunotherapy is approved for patients who progress after platinum use. We have new drug approvals like enfortumab vedotin, which was approved last year, as well as the FGFR3 inhibitor erdafitinib for patients with qualifying mutations in FGFR. We are making a lot of progress in how we treat advance urothelial cancer patients.

Unfortunately, no screening tests are recommended for people with average risk of bladder cancer. Of course, we’re all aware of patients coming for medical attention because of hematuria. That’s 1 of the most common manifestations for patients. That leads to further work-up and diagnosis in terms of cystoscopy. They undergo TURBT (trans urethral resection of bladder tumor); certain urinary tumor markers have also been used beyond cytology.

In terms of risk factors, for bladder cancer in general, it includes things like smoking and workplace exposure in industries that carry high risk of bladder cancer, including folks who work in the industries of rubber, leather, textiles, paint products, and certain herbals or drugs. Medicines used for diabetes have been linked to bladder cancer and other chemicals, like arsenic in water.

Currently, we are not using genetic and molecular characteristics to guide treatment decisions, but it’s a very important area of research. In the neoadjuvant setting, the molecular subtyping has shown that patients may respond differently to neoadjuvant chemotherapy, depending on the molecular subtype. However, it is not a standard-of-care approach. This is what we are actively studying as a part of our Department of Defense grant. In the future, we hope to have comprehensive genetic and molecular biomarkers to guide therapy, besides using PD-L1 expression.

PD-L1 expression in metastatic urothelial cancer can be answered and determined by varying ways. Currently in the field, PD-L1 testing is unfortunately not uniformly defined in urothelial cancers, so there are a lot of assays and platforms that are being used. It really varies on what tests you use, what study you’re looking at, and whether you’re looking at the tumor cell or the immune cell.

There are differences in the quantification thresholds for PD-L1 expression. In general, tumor cell, or tumor-infiltrating immune cell, positivity in the primary tumor ranges from 32% to 66%. It varies between studies and assays that have been used.

Jeanny Aragon-Ching, MD, Inova Schar Cancer Institute

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