Identifying Actionable Genetic Alterations in Metastatic Urothelial Carcinoma

Roger Li, MD, is a genitourinary oncologist at Moffitt Cancer Center, in Tampa, Florida. His clinical focus includes surgical treatment of bladder, prostate, kidney, and penile cancer. His research interests include genomic characterization of genitourinary malignancies to tailor therapy to the individual patient and development of novel immunotherapeutic strategies for early-stage bladder cancer.

Why is it critical to identify key differences in the genomic landscape of urothelial carcinoma? How can these differences help alter treatments?

Over the past 7 years since the presentation of The Cancer Genome Atlas data on the genomic makeup of urothelial cancer,¹ we have learned that this is a very heterogeneous group of cancers, and that not all patients respond the same way to the same treatment. So, to come up with personalized solutions for each tumor, it is key for us to understand the molecular differences between tumor types and to learn how those differences dictate responsiveness to different therapies.

How are actionable mutations addressed in patients with mUC?

Three agents have been approved by the FDA in the metastatic setting targeting specific molecular alterations. The first mutation elucidated was an FGFR mutation; erdafitinib targets these mutations and is approved for use after we have exhausted chemotherapy and immunotherapy options.

More recently, we have developed antibody-drug conjugates, which is a newer drug class that targets specific protein expressions on cancer cells. Enfortumab vedotin targets nectin-4² and sacituzumab govitecan targets trop-2; both of these proteins are widely expressed on bladder cancer cells, at least in the metastatic setting.

These drugs are approved for use in a postchemotherapy and postimmunotherapy setting. Enfortumab vedotin was also approved recently for use in chemotherapy-ineligible patients who have undergone immunotherapy. The bottom line is that these drugs have been approved in only those settings so far, because they have been studied only in those settings. Whether they have activity in earlier settings remains to be seen; trials are ongoing.

How has next-generation sequencing improved the ability to target treatment for mUC?

For a while, we had a variety of genomic testing options that were based on tissue analysis; certainly, those methods are able to detect specific mutations so that we can better personalize treatment. But the excitement that is emerging is in the field of liquid biopsy. With this modality, instead of relying on tumor-tissue specimens to identify specific mutations, we can now detect DNA mutations specific to cancer by using peripheral blood. From those mutations, we can generate a rationale for using some of these targeted agents.
 
Imagine the advantage of using such a test — especially when some of these tumor specimens are buried deep within the body, where needle biopsy can cause a lot of damage and complications. With liquid biopsy, we can now obtain a specimen of peripheral blood from these patients relatively noninvasively and use that to determine whether these targets exist in a patient.
 
Specifically for urothelial cancer, because the cancer is exposed to the urinary tract, we also have access to the patient’s urine, especially if the bladder is still intact. If the cancer is in the bladder proper, there is high likelihood that we can detect cancer-specific mutations by testing urine. That way, we progressively reduce invasiveness to get specimens from patients to drive choice of treatment.

Are there indications for using erdafitinib earlier in disease?

We know that FGFR mutations exist in the mUC setting. However, FGFR-mutated tumors are, in fact, much more prevalent in earlier stages of bladder cancer, so medical scientists have started to think about using erdafitinib much earlier in the disease process. However, there are concerns about using erdafitinib in earlier settings. In metastatic settings, the patient is often simply out of options, so drug toxicity is of less concern. In earlier settings, however, these toxicities do come into play. In some cases, to prevent recurrence in the bladder, patients want to take these agents, but if they are too toxic, the risk of taking them outweighs the benefit.
 
Clinicians are thinking about switching from systemic delivery to putting agents directly into the bladder. That way, the drugs have greater exposure to the cancer itself, while reducing the rest of the body’s exposure to toxicity. I believe that if we can design a urine test to detect the presence of FGFR mutations, we will have truly found the Holy Grail: a noninvasive test to diagnose the mutation and a relatively noninvasive way to treat the cancer.
 
Trials to address delivery methods are in the works. Oral FGFR inhibitors have been tested in settings of earlier disease but without much fanfare because of increased toxicity. Researchers are still working through those problems, but I am confident that, in the near future, we will have both a diagnostic test that can effectively identify FGFR mutations and a drug that has a relatively lower toxicity profile.

Could these gene-informed treatments replace standard therapy?

We are definitely moving toward having them be stand-alone therapy. For example, studies of enfortumab vedotin in combination with pembrolizumab as first-line combination therapy for mUC³ are ongoing. Those studies are based mainly on a smaller phase 2 study conducted in the metastatic setting that showed a response rate as high as 70%, which is unheard of in the realm of mUC.⁴ Again, that was a smaller study, so we have to use caution in interpreting those results. But such a high response rate has generated a lot of excitement, to the point at which some experts have advocated replacing chemotherapy with enfortumab vedotin in combination with pembrolizumab as front-line treatment for mUC.

What are the shortcomings of treatment with traditional chemotherapy models?

Chemotherapy has been used in bladder cancer for a long time. We know that it is an effective treatment, but it is also a very toxic treatment. We think that there is room for improvement in reducing the toxicity profile, especially in the cohort of patients with metastatic bladder cancer, who are often very frail because of the high burden of their disease.
 
But even if they have just been through gold-standard treatment — chemotherapy in early stages before undergoing surgery to remove their bladder — these patients face a challenge with toxicity, because soon after they finish chemotherapy, they undergo an intensive surgical procedure that has many associated morbidities.
 
As a result, many patients have to wait for or, in some cases, avoid surgery because they are doing so poorly on chemotherapy. If we are able to come up with a drug combination that reduces the toxicity profile (which may express in neurotoxicity, ocular side effects, skin rashes, fatigue, hepatic and renal dysfunction, as well as anemia⁵) seen with current systemic delivery methods for enfortumab vedotin and sacituzumab govitecan , which people are exploring now, then that can even supplant chemotherapy in early disease without impacting quality of life as it might now.  

Do new gene-informed treatments improve survival significantly?

Absolutely. With the advent of immunotherapy and targeted agents, we are incrementally increasing survival. Patients with mUC have, on average, a prognosis of 12 to 14 months of life expectancy with chemotherapy. With immunotherapy and third-line treatment agents, we incrementally add 2 to 4 months on the back end to those patients’ lives.⁶ That does not sound like a big deal, but when you add them all up — especially given the setting — I think that those 2 to 4 months make a huge difference for patients and their families.