 The greatest unmet needs in bladder cancer could be summarized in 1 word: biomarkers. We are missing good biomarkers that help us select treatment. This is highly needed. That would help us a lot to guide treatment selection. The only targeted treatment that we have in advanced bladder cancer right now is a family of FGFR inhibitors that are indicated in patients who have alterations in their GFR [glomerular filtration rate]. Other than that, we’re guessing too much when we deliver treatment for our patients with metastatic bladder cancer. Predictive biomarkers of response is, to me, the highest unmet need.

In terms of the most promising data coming up, we’re all very excited about new combos. One combo that’s generated more expectation is the combination of the antibody-drug conjugate enfortumab vedotin [Padcev] plus pembrolizumab [Keytruda]. This combo already demonstrated a very high rate of response in a small group of patients with metastatic urothelial carcinoma who were cisplatin unfit. Based on those data, a randomized phase 3 study has been launched and is ongoing, and we’re participating. It’s recruiting very quickly. It compares enfortumab vedotin [Padcev] plus pembrolizumab [Keytruda] vs chemotherapy in first-line metastatic urothelial carcinoma, including cisplatin-eligible and cisplatin-ineligible patients. This combination could probably change the way we treat bladder cancer for the first time in the last 4 years.

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Expert reflection on the current unmet needs in metastatic urothelial carcinoma and hope for future improvements in the treatment armamentarium. 

Metastatic Urothelial Carcinoma: Unmet Needs and Future Directions 

What do you do with a patient who has received what we consider the standard: chemotherapy followed by maintenance immunotherapy? To me, the answer with the highest level of evidence is enfortumab vedotin [Padcev]. Enfortumab vedotin [Padcev] is an antibody-drug conjugate that has been tested in a phase 3 trial comparing this drug vs chemotherapy of choice, and it demonstrated significant survival benefit. If want to be academic, the No. 1 choice should be enfortumab vedotin [Padcev]. There are other choices. You could have tested your patient for 

 mutations which is something we tend to do in my clinic. If the patient has a mutation in 

 perfusion, you could use erdafitinib [Balversa], which has advantages and disadvantages. One advantage is that it’s an oral medication. The disadvantage is that the data that we have for erdafitinib [Balversa] doesn’t come from a phase 3 randomized trial; it comes from a phase 2 trial. The activity was remarkable and comparable to enfortumab vedotin [Padcev] in terms of overall response rate, but it’s not a randomized phase 3 trial.

Erdafitinib [Balversa] is also an option I’d consider in my clinic. There are also other components that we leave for further lines of therapy. In the United States, you can use sacituzumab govitecan, which isn’t approved in Europe. It’s another antibody-drug conjugate approved in the United States in a phase 2 study with a phase 3 study ongoing. Then there are classical cytotoxics with much less activity in terms of overall response or impact in survival, like taxines or vinflunine [Javlor], which are approved in Europe but not in the United States.

How is adjuvant therapy going to influence our treatment decisions in the near future? We don’t have data level 1. In our clinic we’re looking at the timing between the end of the adjuvant treatment and the relapse. We’re setting a limit of 12 months. If we have a patient who’s received adjuvant treatment and then has a relapse 12 months later, I’d consider that patient to be I/O [immuno-oncology]–free. I’d treat this patient the same way I treat any patient with metastatic bladder cancer. However, if the relapse happens within 12 months following the conclusion of adjuvant therapy, then I’d have to deal differently. I’d have to consider that the patient most likely is not going to benefit from any I/O approach in that context.

Following frontline maintenance therapy in metastatic urothelial carcinoma, Ignacio Duran, MD, PhD, considers optimal second-line treatment options. 

Treatment Options After Frontline Maintenance Therapy in mUC

When we discuss what to do to patients in my clinic, and when we gather with other specialists, we tend to do things when they are going to clearly determine our treatment choices. Nowadays, the determination of PD-L1 does not clearly determine what to do with my patients. We do not test for PD-L1 on a regular basis in my clinic. Some other groups do it. In my country [Spain], that could somehow direct you to treat a very small percentage of patients with I/O [immuno-oncology] in first line, but it’s not the case in my practice. I do not do this regularly.

Discussing starting maintenance treatment in patients with metastatic bladder cancer is something clinicians should be very clear about. When you try to wear the shoes of a patient who has received 4 to 6 cycles of chemotherapy, they’re probably tired of coming to the hospital and have accumulated some toxicities. When the patient comes for reassessment and has a CT scan, and the CT scan shows very good results, the patient probably wants to move on and say, “This is it. Now I’m treatment-free for a while.” At that point, you have to convince your patient that maintenance is probably the way to go.

How do you deal with that? How do you convince your patient that that’s probably the best option, rather than waiting for a relapse? There are a number of arguments. One is that bladder cancer, even though it’s a tumor that’s highly responsive to chemotherapy, is also going to relapse quickly in most patients. When the tumor comes back, patients might deteriorate quickly and might not be in a good condition to receive further treatment. They may lose that second-line option. That’s 1 reason for moving forward with treatment and going with maintenance.

Second, we believe in biology. The maintenance principle is based on some rationale. It’s not only a matter of sequencing things. It’s also believing that chemotherapy has some effect on overcoming tumor resistance by different mechanisms. We know that chemotherapy may induce what we call immunogenic cell death. It’s going to kill cancer cells, and it’s going to turn those cancer cells in a much better target for our immune system. Chemotherapy also causes depletion of immunosuppressive cell types, causing some breaks of the immune system. It also increases the presentation of tumor antigens and also triggered what we call T-cell infiltration, attracting T cells to the tumor. There’s biology behind the strategy of sequencing chemotherapy and immunotherapy.

The third argument that I use with my patients is that immunotherapy is not chemotherapy. Any maintenance treatment needs to be a treatment that has a very good balance in terms of safety. Once you get through the first doses, patients feel much more comfortable when they see that adverse effects are, in most of the cases, anecdotal. There’s a small percentage of patients that will have immune-related adverse events. But most patients are going to do very well with this treatment approach. Those are my arguments to justify maintenance.

Shared insight on the use of maintenance therapy in metastatic urothelial carcinoma with regard to PD-L1 testing and patient education.

Metastatic Urothelial Carcinoma: Optimizing Use of Frontline Maintenance Therapy  

Let me review the data for the JAVELIN Bladder 100 trial. I mentioned it before, but I’ll get more to into the precise design of the study and the major outcomes. JAVELIN 100 was designed to test the value of a switch maintenance strategy with a drug targeting PD-L1, called avelumab [Bavencio]. Basically, the study tried to test the benefits of continuing with avelumab [Bavencio] after receiving chemotherapy based in platinum 4 to 6 cycles and obtaining some degree of benefit. JAVELIN 100 included about 700 patients who did not have progression after receiving chemotherapy, for 4 or 6 cycles, with cisplatin-gemcitabine or carboplatin-gemcitabine. Then the patient had a treatment-free interval that was 4 to 10 weeks from the last dose of chemotherapy. These patients were randomized to either avelumab [Bavencio] at a dosage of 10 mg/kg every 2 weeks until progression or best supportive care.

What was the primary end point? It was overall survival in the entire population but also in patients considered PD-L1 positive. What were the main results? Median overall survival was 21.4 months for the experimental arm vs 14.3 months for the control arm. That was statistically significant. The hazard ratio was 0.69. This is an impressive benefit, which is statistically significant and, more important, clinically meaningful. That was the result from the first interim analysis. We continued to analyze the data later, and the benefit was maintained with a similar hazard ratio. The overall survival benefit for patients who were high expressers of PD-L1 was even more remarkable. The hazard ratio was 0.56 in that population. Overall survival was not reached. The median was not reached for the experimental arm vs 17 months in the control arm. This is the key design and the key efficacy data.

Safety is always a critical question. Safety in JAVELIN 100 was not a major concern…. Among patients who were treated with avelumab [Bavencio], about a third presented what we call immune-related adverse events, although only a minority were really severe. About 7% of the patients had a grade 3 immune-related adverse event, and 9% required high doses of steroids for the treatment of this immune-related adverse event. In summary, I would say that safety was not a major concern in general in JAVELIN 100 with the use of avelumab [Bavencio] every 2 weeks.

No other maintenance strategies in bladder cancer have succeeded. From a historical perspective, there were different attempts in the past looking at maintenance. One of the studies was called the MAJA study. That was a maintenance study with vinflunine [Javlor]. Patients who received chemotherapy were treated with vinflunine [Javlor]. This study was reported and not so long ago updated. It demonstrated a benefit in progression-free survival for the maintenance zone that did not succeed at showing a benefit in overall survival. It’s also true that we should refer to another smaller study, the Hoosier [Cancer Research Network] study, which tested the same hypothesis with pembrolizumab [Keytruda]. Patients with metastatic bladder cancer after receiving a maximum of 8 cycles of chemotherapy were randomized to receive pembrolizumab [Keytruda] or placebo in this case. The crossover was permitted. That study was small, about 108 patients. It was an academic study. It was not a large multicenter, multicountry study. It was able to demonstrate a benefit in progression-free survival, but it did not demonstrate a benefit in overall survival. A number of reasons could explain those results. The first 1 is because the study was not powered to demonstrate an improvement in overall survival. The second 1 is because this study allowed crossover: patients who progressed in the control arm were rapidly crossed and received treatment rapidly, so they could benefit. Those 2 reasons could explain the lack of benefits. In summary, other than the avelumab [Bavencio] maintenance study, JAVELIN 100, you can mention the Hoosier study with pembrolizumab [Keytruda] and the MAJA study years ago.

Ignacio Duran, MD, PhD, reflects on the JAVELIN Bladder 100 trial, which analyzed avelumab as frontline maintenance therapy in metastatic urothelial carcinoma.

Interpreting JAVELIN Bladder 100: Avelumab in Metastatic Urothelial Carcinoma

 There’s no doubt that immunotherapy has changed the landscape of bladder cancer in the last 7 to 10 years. It started with the first study with atezolizumab [Tecentriq] in patients who had been heavily pretreated. In that context we observed some responses in which the drug was stimulating their immune system. That family of drugs, called checkpoint inhibitors, started its development in bladder cancer. We came to the conclusion that a number of compounds were very active in advanced bladder cancer. Two of them, atezolizumab [Tecentriq] and pembrolizumab [Keytruda], made it to the top of that list because of 2 randomized phase 3 trials. Pembrolizumab [Keytruda] was the 1 with the highest level of evidence, and it became the standard of care in patients who have progressed after receiving chemotherapy. That was the first hit of immunotherapy in bladder cancer, becoming the preferred second line.

What’s happened there since? What we’ve seen is the switch of chemotherapy from advanced stages to more initial stages of bladder cancer in the metastatic context. What I mean by more initial stages is that we went from second or third line to patients in the first line of treatment. Those attempts had different outcomes. Let me explain. One thing we tried was to introduce immunotherapy in the first line as a single agent. The results were relatively disappointing. We didn’t have a lot of data to support the use of immunotherapy single agent as a first-line approach. That would be strictly recommended in a very small portion of patients: those whom we consider unfit for any kind of platinum-based therapy and who have a high PD-L1 expression. That was a relative success.

The second attempt to move immunotherapy to earlier stages combined chemotherapy and immunotherapy in the first line. That was a failure. There were 2 studies, IMvigor130 and KEYNOTE-361, that failed to demonstrate an improvement in overall survival combined in chemotherapy plus immunotherapy in the first line. We should not use that strategy. Then came the third attempt, which has been quite successful: incorporating an immunotherapy after receiving first-line chemotherapy, not as a rescue treatment but as a maintenance treatment. There are different ways of doing maintenance strategy. After receiving some kind of therapy you can drop 1 of the compounds and maintain the other 1. That’s called a continuation maintenance therapy. Or you can do what we call a switch strategy. Let’s say you start with 1 treatment and, at 1 point, if there’s benefit, then you switch to a different 1. This is the strategy we’ve used with immunotherapy in the first line of bladder cancer. Patients are treated with 4 to 6 cycles of chemotherapy. If there’s any benefit—partial response, complete response, or stable disease—then we continue with avelumab [Bavencio]. This is what we call a switch maintenance. This is exactly where immunotherapy has a major place right now.

What about the second line? Where is immunotherapy in that context? If a patient doesn’t respond to chemotherapy, there’s no benefit to that treatment. Then we could use immunotherapy, most commonly pembrolizumab [Keytruda], as an alternative rescue treatment. Last, where is immunotherapy trying to go right now? Immunotherapy is developing in combination with different immunotherapies. We’ve got combinations of 2 checkpoint inhibitors. There are ongoing studies that haven’t been concluded. We’re also combining immunotherapy with a new class of drugs called antibody-drug conjugates. Avelumab [Bavencio] plus pembrolizumab [Keytruda] is 1 of these combinations with very appealing results.

Considerations for the role of immunotherapy in metastatic urothelial carcinoma as maintenance or switch therapy. 

Immunotherapy’s Roles in Treating Metastatic Urothelial Carcinoma

What’s the typical patient that we might see in a bladder cancer clinic? We’re talking typically about a man. Bladder cancer is about 3 times more frequent in men than in women. We’re talking about a person who’s probably in his early 70s. The median age at diagnosis in the United States is 72 or 73 years old. Normally, it’s going to be somebody with comorbidities. Bladder cancer has smoking as the main risk factor. Smoking is responsible for about 50% of bladder cancer cases in men and 25% of bladder cancer cases in women. This is the typical patient profile we see in the clinic.

These patients may present with a variety of symptoms. Hematuria is a classic symptom of bladder cancer, but this also applies to localized bladder cancer. When we talk about a metastatic patient, the symptoms may be very diverse and will depend on the location of the metastasis. We see patients who present with weight loss, loss of appetite, and pain in different regions. That could be 1 presentation, but other times they present with actual hematuria and some other symptoms. From a clinical perspective, it’s wide in terms of the clinical vignette for a patient with metastatic bladder cancer.

In terms of the treatment landscape of metastatic urothelial carcinoma, the first question we need to ask when we have a patient in the clinic is whether the patient can receive the best treatment, which is cisplatin. We have to divide our patients into what we call cisplatin eligible or ineligible. We do that by using the [Matthew] Galsky criteria. It’s very easy to do. The Galsky criteria have to do with how your system works in relation to organs that have more relevance when processing cisplatin, and how your body works in relation to those organs or systems that will receive the toxicity of cisplatin.

There are 5 Galsky criteria. The first 1 is creatinine clearance. If you have a patient with a creatinine clearance below 60 mL/min, then your patient would not be eligible for cisplatin. The second thing you need to have in a good shape when you receive cisplatin is your heart. If you have heart failure and you’re New York Heart Association class III or higher, that would be another Galsky criterion. Your heart isn’t good enough to deal with the hydration required to receive cisplatin. Then we have 2 other systems that need to be perfect: 1 is your neurological system. If you have any neuropathy that is grade 2 or higher, you cannot receive cisplatin. Or if your hearing system has an impairment of grade 2 or higher, you also cannot receive cisplatin. The last of the 5 Galsky criteria is ECOG performance status of 2 or higher. If your patient has any of these 5 items, they won’t be eligible to receive cisplatin.

The first question in your clinic is to divide your patients into cisplatin eligible or cisplatin ineligible. Once you’ve done that, you’re going to treat patients with either gemcitabine-cisplatin or gemcitabine-carboplatin depending on if they’re cisplatin eligible or ineligible. Once your patient has completed 4 to 6 cycles, if there’s benefit—benefit can be complete response, partial response, or stable disease—then the right way to go is to put your patients in a maintenance strategy with avelumab, a checkpoint inhibitor immunotherapy, until progression. If your patient doesn’t benefit on first-line chemotherapy, then you have to start thinking about second lines that we can extend later on and other questions.

There’s also an important question as to whether bladder cancer might differ in different regions. One thing that there’s no doubt about is that bladder cancer incidence changes across the world. We have areas that are zones of high incidence and other regions where the numbers are much lower. That’s probably influenced by the main risk factor, smoking. For instance, some countries in Europe—Greece, Belgium, Germany, Italy, and Spain—are probably the top countries in terms of bladder cancer incidence. A lot of that has to do with smoking history.

Other than the pure numbers in terms of incidence of bladder cancer, some varieties of this cancer may differ in their presentation depending on the geographical region. This is the case for a rare form of bladder cancer called squamous cell bladder cancer, which is more typical in Egypt. This is related to an infectious disease due to schistosoma. Schistosoma is very common in Egypt. That chronic infection in the bladder may increase the incidence of this type of bladder cancer. Those are the major differences across the world.

Expert perspective on the current treatment paradigm of metastatic urothelial carcinoma across different regions of the world. 

Ignacio Duran, MD, PhD

Articles

Metastatic Urothelial Carcinoma: Unmet Needs and Future Directions

Treatment Options After Frontline Maintenance Therapy in mUC

Metastatic Urothelial Carcinoma: Optimizing Use of Frontline Maintenance Therapy

Interpreting JAVELIN Bladder 100: Avelumab in Metastatic Urothelial Carcinoma

Immunotherapy’s Roles in Treating Metastatic Urothelial Carcinoma

A Global View on Metastatic Urothelial Carcinoma