Real-World Data Help to Inform Treatment Selection in Metastatic Urothelial Carcinoma

Amit Mehta, MD

With findings from real-world studies further displaying the benefit of treatments such as enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) or avelumab (Bavencio) maintenance therapy in patients with urothelial carcinoma, these data, along with patient characteristics such as metastatic sites, safety considerations, and the presence of biomarkers, can be used to better individualize therapy, according to Amit Mehta, MD.

“Real-world studies are great because we want to see the concept of external generalizability. In real-world practice, we need to know if the patient we have in front of us fits the clinical trial population. Maybe they’re much older than the trial population or have certain comorbidities that weren’t represented in the trial population,” Mehta, a physician consultant at Premier Hematology, said in an interview with OncLive®.

For example, data from the real-world AVENANCE study [NCT04822350], presented during the 2025 Genitourinary (GU) Cancers Symposium, showed that first-line maintenance therapy with avelumab was effective among patients who did not experience disease progression after frontline platinum-based chemotherapy, specifically in those with a low tumor burden and various metastatic sites.1 Patients with locally advanced disease (n = 47), nonvisceral metastases (n = 79), and lymph-node only metastases (n = 60) achieved a median overall survival (OS) of not reached (NR; 95% CI, 17.4-not estimable [NE]), 27.2 months (95% CI, 16.5-NE), and NR (95% CI, 19.9-NE), respectively. The respective median progression-free survival values were 19.8 months (95% CI, 10.8-NE), 9.0 months (95% CI, 5.7-14.2), and 13.4 months (95% CI, 6.9-26.5).

In the interview, Mehta discussed additional updates in urothelial carcinoma shared during recent meetings, including the 2025 ASCO Annual Meeting, how these data have affected his clinical practice, and strategies to address treatment toxicities.

OncLive: What were some of the most notable updates in metastatic urothelial carcinoma over the past year?

Mehta: There were many presentations at ASCO GU and the ASCO Annual Meeting that followed the theme of selecting a therapy for a given patient. There’s a wide heterogeneity among patients with metastatic urothelial carcinoma. Some have distant, visceral metastases. There are patients with bone lesions, primarily in their metastatic presentation, and others have lymph node–only disease.

Lymph node–only disease is a recent subset of interest. For example, a subset analysis [was shared during the 2024 ASCO Annual Meeting] of the phase 3 CheckMate 901 study [NCT03036098] which evaluated the combination of cisplatin, gemcitabine, and nivolumab [Opdivo] as frontline therapy for [patients with] metastatic urothelial carcinoma. The results showed the median OS for that group of patients [n = 54] was 46.3 months [95% CI, 24.0-not estimable (NE)]. That [speaks to] the idea that, for a patient with lymph node–only metastases, we may select [treatment for them] in that way.

The chemotherapy followed by avelumab maintenance approach had similar data in that regard. Those patients had a better [median] OS if they only had distant lymph nodes as metastatic sites and not visceral metastases or bone lesions. That second set of patients [with distant metastases or bone lesions] may be more likely to benefit from the enfortumab vedotin and pembrolizumab combination vs chemotherapy and immunotherapy.

With that being said, the most common treatment now used in practice is enfortumab vedotin plus pembrolizumab. [However], there are a lot of nuances around selecting a therapy for [a given] patient. Part of the real-world application of data is that you must consider who the patient receiving the therapy is. It’s one thing to have the data, but when you apply a therapy to a patient, you need [to consider] their age, comorbidities, and other factors. So far, [most] urothelial carcinoma data are from an unenriched population. It is [usually] not subcategorized by HER2 amplification or other biomarkers [such as] Nectin-4 amplification.

Another data set showed that patients with Nectin-4 amplification who received enfortumab vedotin plus pembrolizumab [experienced a significant OS benefit] vs those with nonamplified status. Enfortumab vedotin targets Nectin-4 and [features such as HER2 or Nectin-4 amplification] may help determine [response likelihood]. For example, if a patient has visceral metastases and Nectin-4 amplification, I can be more confident that they’ll respond to enfortumab vedotin plus pembrolizumab. For patients with lymph node–only metastases, we may go back and forth about the therapy. Maybe they will get chemoimmunotherapy then an antibody-drug conjugate in the second-line setting. These are just some of the nuances regarding how these data have informed us.

What trends are you seeing throughout these data and how are you using them to inform your clinical practice?

In terms of enfortumab vedotin plus pembrolizumab, the data are very strong. The median OS was 31.5 months [95% CI, 25.4-NE] with that combination in EV-302. [However], to get your patient to that number, you have to keep them on therapy and maintain some level of dose intensity.

A few abstracts were presented at ASCO GU that showed that patients with more adverse effects [AEs] had a correlation with better response and prognosis. That tells me that if they’re having AEs, they’re staying on the drug with good intensity. One message I would share with colleagues of mine who don’t normally focus on GU cancers is to remember that patients who are maintaining dose intensity and staying on therapy as long as safely possible may likely benefit more.

We also have [consider] how to sequence these therapies, and there’s not one answer for all patients. [For example], we have learned that some patients who receive chemoimmunotherapy, such as cisplatin-gemcitabine followed by avelumab maintenance, could also receive enfortumab vedotin or enfortumab vedotin plus pembrolizumab afterwards. That was supported by data from AVENANCE.

You could do the opposite, but we learned from a study [presented during the ASCO Annual Meeting] in patients who received enfortumab vedotin plus pembrolizumab first then platinum doublet chemotherapy, enfortumab vedotin plus pembrolizumab had very short efficacy. In other words, platinum doublet chemotherapy post enfortumab vedotin plus pembrolizumab may not be the best choice, but giving single-agent chemotherapy or other approaches could be a better option for those patients. You could also test for HER2 and potentially use HER2-directed therapies rather than a platinum doublet. Our understanding of how to sequence treatments is still evolving. We’re still trying to understand who will benefit the most from these treatments.

Have there been any data from real-world studies that have influenced your practice?

A study was done in the United Kingdom of the real-world performance of maintenance avelumab. The big message from this and other data sets is that the investigators demonstrated a similar OS profile compared with the phase 3 JAVELIN Bladder 100 trial [NCT02603432]. Patients receiving avelumab in real-world practice seem to be achieving similar outcomes across multiple countries to what we saw in JAVELIN Bladder 100.

When we use this therapy in our practices, across the US or elsewhere in the world, we can hopefully get similar outcomes with what was seen in the clinical trial. Otherwise, if the clinical trial shows a great result, but in real-world practice there’s a big downgrade, we’re less enthusiastic about a given treatment.

In terms of enfortumab vedotin with pembrolizumab, an intriguing data set looked at the benefit of the combination in patients who are elderly. In this retrospective study of 26 patients with a median age of 86.5 years [range, 80-97] patients responded well to enfortumab vedotin plus pembrolizumab. So, even in older patients, enfortumab vedotin plus pembrolizumab may still be applicable, even though that was not the typical patient that was enrolled in the EV-302 trial.

It's encouraging that as we apply these treatments to real-world practice, we’re able to get results that are similar on a population level to the clinical trials. However, my strong belief is that you still have to individualize therapies very carefully to the patient in front of you. There are so many factors that go into whether a patient may accept a therapy, whether it may be right for that individual. But on a population level, across large numbers of patients, [the real-world data sets] seem to be performing similarly to the phase 3 trials, which is encouraging because we don’t always see that in medicine.

What are some of the most common toxicities you encounter with some of these regimens and how do you mitigate them?

All these treatments that are typically being used, whether it’s enfortumab vedotin plus pembrolizumab or a chemotherapy plus immunotherapy combination, contain immunotherapy as a [component] of the regimen. Therefore, they all have a risk of immune-related AEs [irAEs].

The good news is that we can use our knowledge from the many years of giving immunotherapies in practice and know what to watch for. The key to this in real-world practice is having a plan for how to monitor for a given toxicity. Pneumonitis, colitis, autoimmune colitis, autoimmune hepatitis, hypothyroidism, and hyperthyroidism are all common irAEs that we have to monitor for.

For example, if a patient has autoimmune pneumonitis, what’s the protocol in your practice to diagnose it, manage it, and, if necessary, treat it? It may be necessary to refer them to a specialist who may be able to help. There are different aspects that come into play, but having a plan is very important.

Secondly, you must educate your team. It’s great if you know what to do, but you have to keep you whole team informed on how to best manage the patient and keep them safely on treatment. Most of us are quite savvy with these kinds of therapies nowadays because we use immunotherapies across so many tumor types. That’s great because in real-world practice, the more familiarity we have with a given therapy class or drug will make it that much easier for us to use a therapy in practice and make our patients more likely to benefit. The less common a therapy is, the more there’s going to be a learning curve in order to apply it to a patient in practice.

Immunotherapies are well known in practice, across the US and the world. That helps us leverage our knowledge. We just need to educate our teams, make sure everybody’s up to speed about what to monitor for, how to diagnose if a problem is happening, and then treat when necessary.

Reference

1. Barthelemy P, Loriot Y, Thibault C, et al. AVENANCE real-world study of avelumab first-line (1L) maintenance treatment for advanced urothelial carcinoma (UC): analyses in low tumor burden subgroups. J Clin Oncol. 2025;43(suppl 5):718. doi:10.1200/JCO.2025.43.5_suppl.718