Emerging Targeted Therapies in Bladder Cancer: Frontline Options and Beyond

GU Oncology Now spoke with Arlene O. Siefker-Radtke, MD, of the Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, regarding the current and novel targeted therapies entering the market for bladder cancer—in the frontline setting and throughout the treatment continuum—as well as how these agents are being assessed in combination approaches.

To begin, can you highlight the systemic treatment options for patients with metastatic urothelial carcinoma? What is the standard of care in the frontline setting, and what are some of the new targeted agents entering the market?

Dr. Siefker-Radtke: We have recently seen an advance in the frontline treatment of metastatic surgically unresectable urothelial carcinoma. The most recent standard was systemic chemotherapy with either a cisplatin- or carboplatin-based regimen, followed by maintenance avelumab, which had been shown to extend patient lives. However, this approach did require patients to have stable disease or better following their frontline systemic chemotherapy.

Even more recently, we have seen the combination of enfortumab vedotin plus pembrolizumab join the frontline standards. In fact, it was just this past April that it was granted US Food and Drug Administration (FDA) accelerated approval based upon the very promising early evidence that has been presented. With enfortumab vedotin plus pembrolizumab, we are seeing in a cohort of patients who are cisplatin-ineligible (not the typical candidates for frontline cisplatin-based chemotherapy) objective response rates that are over 70% and a regimen that appears to be more tolerated than most systemic chemotherapy options. We are also seeing durability of response, with survival that is approaching several years. So, it appears to be a very promising combination, and I understand entirely why it was granted an accelerated approval designation while we await frontline clinical trial results confirming a survival benefit over the current standard of care.

How are these new therapies projected to change the treatment landscape, and are they expected to make an impact in the frontline setting or elsewhere in the treatment continuum?

Dr. Siefker-Radtke: We are definitely seeing an impact on patient outcomes by the addition of novel agents and these targeted strategies that are now available. If you compare them with the treatment standards that were in place when I began over 20 years ago, we had platinum-based chemotherapy as the standard with a median survival that was around 1 year for patients with metastatic surgically unresectable tumors. With the addition of immune checkpoint inhibitors, we started to see an expansion of life expectancy, patients living longer when we were able to sequence from chemotherapy to a checkpoint inhibitor and then use maintenance avelumab even in the frontline setting for patients with stable disease.

Nowadays, there are several new targets, including Nectin-4, which is targeted by enfortumab vedotin and is the first antibody-drug conjugate approved for urothelial cancer. We have erdafitinib, which was granted FDA accelerated approval and targets FGFR3-altered urothelial tumors, and this was followed by sacituzumab govitecan, an additional antibody-drug conjugate targeting Trop-2 expression on patient tumors. We are also seeing a targeted treatment strategy move earlier into the treatment paradigm. In fact, enfortumab vedotin with pembrolizumab is now approved in the frontline setting, and there is very promising evidence for it in the neoadjuvant setting. Erdafitinib is being studied earlier as well, especially in patients with non-muscle invasive bladder cancer, where the presence of FGFR alterations drive tumor growth in nearly 60% of patients.

Interestingly, there are even novel ways of administering these targeted therapies. There is a new “pretzel” approach that is being developed where a drug-eluting “pretzel” is inserted into the bladder with the drug inside it, and the drug is slowly released into the urine to target tumors in the bladder lining, resulting in more sustained concentrations in the urine and impacting tumors locally without causing systemic side effects.

In short, there is a lot of excitement and many clinical trials ahead of us to better understand where to place these novel strategies and how to impact patients—all the way from superficial bladder cancer to muscle-invasive curative bladder tumors and metastatic disease.

How are these therapies being assessed in combination with immunotherapy agents?

Dr. Siefker-Radtke: To use an analogy, it often feels like peanut butter and chocolate; we have 2 great tastes, and we have to see if they go well together. We have immune checkpoint inhibitors, which were one of the first novel classes of agents that started to extend patient lives for metastatic disease. Then, we have targeted therapies, and the natural progression is to combine them with a checkpoint inhibitor on the potential of additive versus synergistic effects. Early data with this approach—enfortumab vedotin combined with pembrolizumab—showed 70% objective response rates with durability of responses, thus leading to its accelerated approval.

The success story of enfortumab vedotin plus pembrolizumab has spawned similar clinical trial designs, including the NORSE trial, which evaluates erdafitinib combined with the PD-1 inhibitor cetrelimab. Early results from NORSE showed an objective response rate in over 60% of patients with unresectable metastatic unresectable urothelial carcinoma. We are awaiting results from NORSE in a larger cohort of patients, but all signs point to this option as another combination that will overcome some of the limitations of single-agent therapy.

There is a third combination of sacituzumab govitecan with an immune checkpoint inhibitor, but it does not appear to be quite as promising. Data do not suggest a substantial increase in objective response rate compared with what was achieved with sacituzumab govitecan alone. I wonder if this is due to the myelosuppressive nature of sacituzumab govitecan. We see a lot of neutropenia, neutropenic fevers, and lymphopenia in patients receiving sacituzumab govitecan, so it is possible that the therapy may be inhibiting the lymphocytes that are needed to generate an immune response.

Can you speak to the toxicity profiles of these novel targeted therapies and how they compare with chemotherapy or immunotherapy options?

Dr. Siefker-Radtke: We have yet to achieve novel agents or combinations that have zero toxicity. The ability to manage toxicity and pick the appropriate patient for the appropriate treatment will impact how long they are able to continue beneficial therapy.

In the frontline setting, I am asked how to choose between gemcitabine-carboplatin with maintenance avelumab or enfortumab vedotin with pembrolizumab. Certainly, the latter option appears quite attractive based on lesser toxicity implications. Most patients find it easier and more tolerable than the chemotherapy they have had previously. However, we still have to watch for liver toxicity.

In fact, the targeted agent that is brought directly to the tumor monomethyl—the “vedotin” part of enfortumab vedotin—is associated with an increased area under the curve concentration of over 40% in patients with mild hepatic impairment. In other words, it should be used cautiously in patients with hepatic dysfunction, and I would suggest avoiding it completely in patients with Child-Pugh score B and C cirrhotic livers.

In the frontline strategy, patients with worse kidney function should be considered for enfortumab vedotin with pembrolizumab, because carboplatin leads to toxicity in the kidneys. But in patients with cirrhotic livers, the platinum combination followed by maintenance avelumab is more ideal, despite it lessening the chances of being able to give subsequent therapy.

Neuropathy is known to develop in patients after receiving enfortumab vedotin, especially as they stay on treatment longer. A better understanding of the optimal duration of treatment with enfortumab vedotin will be helpful in managing toxicity, especially if we have subsequent lines of treatment that also cause neurotoxicity.

As far as the other novel agents, erdafitinib has shown to be associated with hand-foot syndrome. Most patients who have been on treatment for about 2 to 3 months require a 2- to 3-week break to allow their hand-foot syndrome to heal. Thus, I tend to think of erdafitinib as more of an induction-maintenance strategy. The higher dose of erdafitinib induces a deeper response, but that response can be maintained with dose reduction over time, while allowing for those breaks as needed to permit skin healing.

Another unique toxicity with erdafitinib is central serous retinopathy. Patients receiving erdafitinib should be monitored by an ophthalmologist and should undergo optical coherence tomography and baseline visual exams. If a patient reports any blurred vision or change in their vision, erdafitinib should be paused, the patient should be seen by an ophthalmologist, and if retinopathy is diagnosed, the patient should be followed much more closely. Once retinopathy improvement is observed and vision has returned to baseline, the patient can resume treatment with erdafitinib at a dose reduction.

Lastly, sacituzumab govitecan is associated with neutropenia and neutropenic fever. Many patients with bladder cancer who are eligible for sacituzumab govitecan are older and have received prior aggressive chemotherapy. I am an advocate for growth factor support to be used routinely in these patients due to the high rates of neutropenia and neutropenic fever.

Despite all of the toxicities associated with these therapies, it is fair to say that we have reached a new era in the treatment of urothelial cancer. There are multiple targeted strategies that can be used, and understanding the best way to sequence or combine them with other novel agents is likely to positively impact patient outcomes. We are seeing patients live longer already, and as we build on this baseline and this new paradigm, my hope is that the survival trend will continue to grow.