 I’m going to talk about a 73-year-old man with locally advanced urothelial carcinoma of the bladder. This is a 73-year-old man who presents with lower urinary tract symptoms with intermittent hematuria. His past medical history is actually unremarkable—hypertension that is well controlled on angiotensin receptor blockers, mild hepatic and renal impairment. There is really nothing remarkable. Otherwise, the patient complains of past symptoms of intermittent hematuria and occasional difficulty in passing urine.

Upon examination, his initial clinical work-up was pretty unremarkable. Laboratory data showed mild anemia, with a hemoglobin of 11.4 g/dL; white blood cells, 3.5 x 109 cells/L; AST [aspartate aminotransferase] and ALT [alanine aminotransferase] liver enzymes are 3 to 4 times elevated; normal bilirubin; creatinine clearance of 35 mL/min; and the patient has a history of renal impairment. So there’s nothing really surprising here.

A cystoscopy showed a 2.6-cm mass around the neck of the bladder. A transurethral resection of the bladder tumor was performed and showed that the tumor was invading the perivesical tissue. This was a urothelial carcinoma.

The CT scan of the abdomen, pelvis, and chest shows a large bladder mass and evidence of multiple regional lymph nodes involving perivesical and sacral lymph nodes. Locally advanced bladder cancer was negative for distant metastases—nothing was shown on the scans in the liver, lung, bones, etc. It was determined that the patient was unresectable. He was not a candidate for definitive surgery or radiation therapy. The final staging for this patient is stage IIIB, and he has an ECOG performance status 1.

The question is, how do we treat the patient? Just to summarize, this is a 73-year-old, otherwise healthy person. He has mild renal impairment with a slight elevation of liver enzymes; his etiology is unclear. He comes in with hematuria, mild obstructive urinary symptoms, and a cystoscopy shows a bladder mass. This is muscle invasive urothelial carcinoma invading into the perivesical tissue. This patient is not considered a candidate for definitive radiation therapy or surgery. What are the next steps for this patient?

Upon diagnosis of stage IIIB locally advanced unresectable urothelial carcinoma of the bladder, this 73-year-old is otherwise pretty healthy. He has an ECOG performance status of 1. He was started on chemotherapy, with gemcitabine and carboplatin. Carboplatin was selected because his creatinine clearance was 35 mL/min. This patient was not deemed to be a candidate for cisplatin chemotherapy.

After 6 cycles of carboplatin-gemcitabine therapy, the patient had stable disease on scans. There was no evidence of disease progression. A CT scan shows a slight decrease in the bladder mass and improvement in the size of the lymph nodes, really qualifying for stable disease as the best response. During this time, the data from the JAVELIN Bladder 100 trial were presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2020, showing that frontline maintenance avelumab in this setting was associated with improved survival. Based on these data, the patient was started on frontline avelumab maintenance therapy at 3 to 4 weeks after completion of chemotherapy with gemcitabine-carboplatin.

73-Year-Old Man With Locally Advanced Urothelial Carcinoma

 If we look at the prognosis of patients who have renal insufficiency, are not candidates for therapy with cisplatin, and have locally advanced or metastatic urothelial carcinoma, the median survival reported from past studies on patients treated with carboplatin-based chemotherapy has been around 10 to 12 months. In fact, it is inferior for those patients who are able to receive cisplatin-based chemotherapy.

Until now, we really were waiting for these patients to have disease progression after they had completed carboplatin-gemcitabine. They were essentially taking a treatment break, and then we were hoping for the best. Invariably, we see disease coming back in the form of localized recurrence or metastatic disease in most of these patients.

A multidisciplinary approach comes into play when these patients are presenting to us for the first time. For example, in this case where local regional lymphadenopathy is present, and this patient was deemed ineligible for radiation therapy or surgery, this is really a call by a multidisciplinary team. Surgeons, radiation oncologists, medical oncologists all have to chime in.

Of course, the patient’s wishes are paramount. Many patients do not want to have a cystectomy or may not want to have radiation therapy. Of course, those things are taken into account. But in collaboration with the patient, once we have determined that patient is not a candidate for definitive surgery or radiation, the option is systemic chemotherapy. Until now, systemic chemotherapy alone was the definitive answer for these patients. For example, start with cisplatin-based chemotherapy or carboplatin-based chemotherapy and then hope for the best.

Prognosis at Diagnosis of Urothelial Carcinoma

 Obviously, the standard of care for first-line therapy has changed, and it changed during ASCO [American Society of Clinical Oncology Annual Meeting] in 2020. What really changed? The data from the JAVELIN Bladder 100 trial showed that avelumab, a PD-L1 inhibitor, was associated with a dramatic improvement in overall survival. This was the case when avelumab was started after completion of 4 to 6 cycles of chemotherapy, whether it was cisplatin- or carboplatin-based chemotherapy, and if the patient did not have disease progression. They were either responding or had stable disease and were able to finish 4 to 6 cycles of carboplatin and gemcitabine or cisplatin and gemcitabine.

The frontline maintenance therapy with avelumab approach was approved by the FDA within weeks of the data being presented at ASCO. Almost at the same time, all the guidelines, whether they were national guidelines in the United States, such as the NCCN [National Comprehensive Cancer Network] Guidelines, or were European guidelines, ESMO [Clinical Practice] Guidelines, incorporated avelumab as the category 1 treatment, or the preferred treatment option for these patients.

Let’s talk about the data from the JAVELIN Bladder 100 trial, which was presented at ASCO 2020. In this study, 700 patients with locally advanced unresectable or metastatic urothelial carcinoma who had stable disease or a partial response after 4 to 6 cycles of platinum-based chemotherapy were randomized to receive frontline maintenance therapy with avelumab plus best supportive care, vs best supportive care alone. For patients who received best supportive care alone, there were periodic scans and follow-up but with no active intervention.

These patients were randomized to receive frontline maintenance therapy with avelumab vs best supportive care. The primary end point was overall survival. Secondary end points looked at progression-free survival and responses.

Results were really dramatic. I don’t think we have ever seen this magnitude of survival benefit in the context of patients with metastatic urothelial carcinoma receiving treatment with immune checkpoint inhibitors. In patients who were randomized to the avelumab arm, the median survival was approximately 21 months. In patients randomized to best supportive care, the overall survival was 14 months, approximately. So there was a 7-month absolute improvement in overall survival. If we look at the hazard ratio for increase in survival, it is 0.69. We see almost a 30% reduction in risk of death by employing frontline maintenance therapy with avelumab.

If you look at the PD-L1–positive population in a predefined subset analysis, the hazard ratio for improved overall survival was 0.56. So it was very pronounced. Having said that, it doesn’t take away any positivity from the overall survival benefit seen across the population in the JAVELIN Bladder 100 trial. Overall, the hazard ratio for improvement in survival was 0.69, and that was for all patients, regardless of PD-L1 expression in the tumors.

Regarding overall survival, the gold standard was remarkably positive in patients receiving treatment with avelumab. But if you look at the secondary end points, progression-free survival was also improved on treatment with avelumab.

Response rates are really not a very nice way to look at the benefit with avelumab in this patient population. If you recall, these patients had to be responding or have stable disease on treatment with platinum-based chemotherapy. This patient population consists of people who either are responding to platinum-based chemotherapy or had stable disease. They did not have progressive disease at the time of entry. So the objective responses, although better with avelumab, don’t have much clinical relevance. It’s overall survival that really drives my clinical decision as I look at these data.

Results of the JAVELIN Bladder 100 Trial

 Regarding safety and tolerability of avelumab, we have been using PD-1 and PD-L1 inhibitors, PD-1 axis inhibitors, for almost 5 to 6 years now in genitourinary oncology, whether as standard of care or through clinical trials. Most of us have had pretty good experience managing any adverse effects from these drugs.

As we know, 3% to 4% of patients have grade 3/4 autoimmune adverse effects or immune-related adverse events that we all know how to manage by now. Early recognition and patient education are key. Look for colitis, rashes, and hepatitis early on. Frequently monitor patients. Then, early intervention with steroids is recommended whenever we see these adverse effects evolve to grade 3, even if they are persistent grade 2 events. That is really the standard way to treat these patients across all cancer types when they’re being treated with PD-1 axis inhibitors.

One adverse effect that is a little unusual, not very common, is infusion-related reactions with avelumab. This can happen in 15% of patients. Most of the events are grade 1/2. Grade 3 or 4 infusion-related reactions can happen in a small minority of patients. But again, if we monitor them properly up front, these happen mostly during the earlier cycles, during earlier dosing, and the key is to monitor these patients in the infusion room. If they develop grade 1/2 infusion-related reactions, these are easy to manage. If they happen to have grade 3 or 4 infusion-related reactions, that warrants permanent discontinuation of avelumab.

Let’s look at the grade 1 or 2 infusion-related reactions. We have all learned to use acetaminophen, or Tylenol, with Pepcid, famotidine, to manage these patients. Most of these grade 1 or 2 infusion-related reactions can be prevented, in my experience, and patients tolerate the drug very well. Although we rarely see grade 3 or 4 infusion-related reactions, if they do occur that warrants permanent discontinuation of avelumab, which can happen in 1% to 3% of patients. This can happen with other PD-1 axis inhibitors as well. Nothing was dramatically different with avelumab in this trial.

For patients with locally advanced unresectable or metastatic urothelial carcinoma, after the presentation at the ASCO [American Society of Clinical Oncology] 2020 Annual Meeting, frontline maintenance therapy with avelumab is the preferred treatment option in my practice in all patients who are able to finish 4 to 6 cycles of platinum-based chemotherapy and do not have progressive disease. If patients with locally advanced or metastatic urothelial carcinoma are responding or have stable disease after carboplatin- or cisplatin-based chemotherapy, frontline avelumab maintenance therapy is the standard of care. There is no doubt about this.

Managing Patients on Avelumab for Urothelial Carcinoma

 Let’s switch gears and look at what is exciting in the context of treatment of patients with high-risk superficial urothelial carcinoma, or superficial bladder cancer. Before I move into that discussion, let’s look at what high risk is. For medical oncologists who are increasingly treating these patients with PD-1 axis inhibitors, looking at the definition of high-risk urothelial carcinoma, it basically includes patients who have carcinoma in situ, or T1 disease, or high-grade disease. When looking at the low-grade T1, Ta disease, if they have recurrence or the tumor is large in size—more than 3 cm in size—or there are multiple sites, we can categorize them in the high-risk disease category.

Ultimately, there are multiple ways we can define these patients to have high-risk superficial bladder cancer even though there is no muscle invasion. Until recently, these patients received BCG [bacillus Calmette-Guerin] vaccination, BCG therapy, and then BCG maintenance therapy; or they were rechallenged with BCG. After that, if they had recurrence, the only option these patients had was surgical treatment with cystectomy or other definitive treatment. Obviously, this was the work of a multidisciplinary team led by surgeons, in my view. But overall, the treatment landscape for these patients has changed with the studies just reported on. One of these studies was with pembrolizumab, known as the KEYNOTE-057 study. Hopefully more PD-1 axis inhibitors will show benefit in this setting, but other trials will be reported on very soon.

With pembrolizumab, we saw close to 40% responses that were durable, which was exciting news for our patients. Based on the results of these responses, pembrolizumab was approved as therapy for patients who have high-risk recurrent non-muscle-invasive superficial bladder cancer. I expect more PD-1 axis inhibitors to be approved in this setting in the near future. We saw approximately 40% complete responses that were durable, of high degree.

There’s also a subset of patients who don’t want to go for a cystectomy. No matter how much evidence we show them, they just cannot accept the idea of removing the bladder, and we respect their decisions. For those patients, this is a great option—using pembrolizumab therapy after recurrence is established.

As I said, the field is rapidly evolving. There are ongoing trials, and hopefully we’ll have better options for these patients. One trial is avelumab with BCG in patients who have had BCG in the past and have recurrence of bladder cancer, or superficial bladder cancer. Avelumab is combined with BCG. The other trial is looking at atezolizumab with intravesical BCG therapy in high-risk invasive bladder cancer. It’s being led by Dr Daniel Castellano in Spain. The trial was presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2020.

With these trials, in my view, PD-1 axis inhibitors are going to be moving upstream. Right now, we have PD-1 axis inhibitors approved for second-line metastatic urothelial carcinoma. We have avelumab with a category 1 indication for frontline maintenance therapy. We have pembrolizumab approved for patients who have recurrence after BCG therapy in high-risk superficial bladder cancer. We’ll be seeing the movement of PD-1 axis inhibitors like avelumab or atezolizumab continue to evolve further upstream in combination with BCG therapy in patients who have recurrence, or maybe up-front BCG therapy in combination with atezolizumab in those patients who have high-risk superficial bladder cancer.

It will be fascinating to see how these trials pan out. It will be fascinating to see how things evolve and how these immune checkpoint inhibitors move upstream. We are really looking forward to data from these trials that are going on and are really hoping that none of our patients develops metastatic or locally advanced urothelial carcinoma with early intervention.

PD-L1 Therapy for High-Risk Superficial Urothelial Carcinoma

 We have seen exciting advances in the treatment of metastatic or locally advanced urothelial carcinoma. We saw the approval of 5 PD-1 axis inhibitors over the last 3 years in the second-line urothelial carcinoma setting, after disease progression following platinum-based chemotherapy. Then we saw avelumab get approved as frontline maintenance therapy, which dramatically improved the overall survival benefit. We also saw antibody-drug conjugates, or the conjugate enfortumab, garner FDA approval for patients who have had disease progression on earlier lines of therapies in metastatic urothelial carcinoma. In addition, we saw erdafitinib, a FGFR pathway inhibitor, become available for patients who have had disease progression on earlier lines of therapies and are harboring FGFR alterations and fusions. All this is just a start, in my opinion. We are going to be seeing more antibody-drug conjugates get approved. In my view, the data presented on sacituzumab, another antibody-drug conjugate, are very promising. Hopefully we’ll see this agent become available for patients with advanced urothelial carcinoma.

We are seeing combinations of immune checkpoint inhibitors with antibody-drug conjugates moving to frontline therapy in clinical trials. Overall, this is very exciting news for us, for our patients, and hopefully we will not have to tell our patients that the median survival is only 18 months when they see us with a diagnosis of metastatic urothelial carcinoma in the future. Hopefully we’ll keep them alive with good quality of life for years. We are only a few years away from that happening.

A 73-Year-Old Male With Urothelial Carcinoma

73-Year-Old Man With Locally Advanced Urothelial Carcinoma

Prognosis at Diagnosis of Urothelial Carcinoma

Results of the JAVELIN Bladder 100 Trial

Managing Patients on Avelumab for Urothelial Carcinoma

PD-L1 Therapy for High-Risk Superficial Urothelial Carcinoma

Future Directions for Treating Urothelial Carcinoma