Real-World Data Help Fill the Gaps Left by Clinical Trial Results in Urothelial Carcinoma

David J. Benjamin, MD

Data from real-world studies can be useful for choosing a treatment regimen for patients with urothelial carcinoma by providing insights into how agents perform outside of clinical trials, but findings from these studies must be carefully interpreted to confirm that they are applicable to the needs of an individual patient, according to David J. Benjamin, MD.

For example, data from the retrospective UNITE study presented during the 2024 ESMO Congress demonstrated that patients with advanced urothelial carcinoma who received enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in the real-world setting (n = 171) achieved an overall response rate (ORR) of 51% (95% CI, 42%-60%).1 However, data from the phase 3 EV-302 trial (NCT04223856) showed that patients who received the combination (n = 437) achieved a more robust ORR of 67.7% (95% CI, 63.1%-72.1%).2

“[Data from] real-world studies are very helpful now that we have multiple treatment options [for patients with bladder cancer],” Benjamin said in an interview with OncLive®. “We have enfortumab vedotin plus pembrolizumab, platinum-based chemotherapy followed by maintenance with avelumab [Bavencio], and nivolumab [Opdivo] plus cisplatin and gemcitabine. It’s an exciting time.”

In the interview, Benjamin, a medical oncologist at Hoag Family Cancer Institute in Newport Beach, California, discussed how to interpret data from real-world studies, data from UNITE and other notable real-world research that has emerged recently, and the gaps that exist between real-world and clinical studies.

OncLive: What information from real-world studies help inform treatment decisions in your clinical practice?

Benjamin: We have to work backwards when considering real-world evidence [and determine] what is important to us vs what is important to patients. In a recent survey, it was found that [investigators] favor overall survival [OS] as the most important end point, but patients preferred a balance between the OS benefit and the adverse effects [AEs] of the treatment. When [examining data from] real-world studies, those are the two factors I’m [mainly] looking at. We want to help our patients live longer, but [we need to consider] patient quality of life and treatment-related AEs [TRAEs].

[Additionally], when we look at a real-world study, it [begs] the question of what exactly is real-world evidence? Some of these studies come from academic centers, are [conducted] only in certain regions of the US, or are [conducted] across several countries. Others are [conducted] only in a country outside of the US or include different patient populations, including those with [comorbidities], frailty, or different types of insurance for whom there could be differences in access to standard-of-care medicines. There are a lot of factors to consider in order to determine whether these studies are applicable to the setting that you are practicing in.

What recent real-world study data have influenced your practice?

[Data from] the UNITE study, which included data from 171 patients outside of the clinical trial setting [who received enfortumab vedotin plus pembrolizumab, are timely because [this combination] has been increasingly used in the clinical setting since it was approved. It was interesting because we saw there was a difference in efficacy in the real world compared with the clinical trial. A unique feature of UNITE was that it looked at biomarkers. In the EV-302 publication in the New England Journal of Medicine, there were no data about which patients responded based off [the presence of] certain biomarkers. In UNITE, [study authors] found that patients who have TP53 or KMT2D mutations tended to have worse outcomes [with the combination].

Another first-line option is platinum-based chemotherapy followed by maintenance with avelumab, which has been the standard of care for [approximately] 5 years. There have been several real-world studies of maintenance avelumab over the past [few] years. Some of them have been in Europe, including the AVENANCE study [NCT04822350] in France and the READY study in Italy. There’s also a Flatiron database study and the PATRIOT-II study in the US.

There are several [real-world] studies of maintenance avelumab which have replicated the data observed in the [phase 3] JAVELIN Bladder 100 trial [NCT02603432]. It’s an exciting time in the world of bladder cancer where we’ve seen the clinical trial data and now we’re seeing [data from] these real-world studies [showing] whether we see the same efficacy and tolerability of these different regimens.

How can the field use real-world evidence to bridge the gaps left by clinical trial data?

We have a lot of real-world data that replicate what we saw in JAVELIN Bladder 100,but the EV-302 regimen is relatively new and does not have as many real-world studies. UNITE is the most notable, but we are lacking more robust data. More data for this regimen will not only help us but also patients. [We need to] see whether the clinical trial data are being replicated not just in terms of efficacy but also regarding the AEs that are seen with this new combination.

We have data from clinical trials to look at but there are issues with some of these trials. For example, in the platinum-based chemotherapy arm of EV-302, over 60% of patients who were eligible for maintenance avelumab did not receive it. This is a gap in our knowledge when we discuss the survival benefit with our patients [because] the data could be a bit skewed when [some] patients did not receive the standard of care during the clinical trial.

This is where the real-world evidence come in. We can help to fill that gap in terms of looking at the survival benefit with platinum-based chemotherapy followed by maintenance avelumab. In EV-302, in both arms of the trial, patients with an ECOG performance status of 2 represented [approximately] 3% of the study population. But in the real world, we see patients with an ECOG performance status of 2 or higher much more frequently. With real-world data, we can supplement and complement the clinical trial data where there are gaps.

What advice would you offer your colleagues in terms of accessing and interpreting real-world data?

[Data from] real-world studies are intended to complement phase 3 trial data. Prospective clinical trials are very well organized. There’s uniform decision-making and methods of measuring whether a patient is responding and how we record TRAEs.

When we examine observational or retrospective data, it’s open to several confounding factors because we’re looking back in time. Some of these real-world studies are done in university settings, but we know that many patients are being treated in the community. There are differences in access to subspecialists to manage these AEs. There are [also] differences in who is treating the patient. In an academic center, it could be someone who focuses only on bladder cancer, whereas in the community [clinicians] see [patients with] multiple tumor types and may only treat [patients with] bladder cancer a few times a year. There could be differences in the site of the urothelial carcinoma. Is it in the bladder or in the upper tract? There are also other characteristics to consider, such as histology and patient comorbidities.

There are many different factors we have to consider. It goes beyond whether the patient received treatment regimen A vs B. We have to look at the characteristics of where the study was done and what types of patients were included, and that’s why real-world studies are meant to complement and not supersede what we see in clinical trials.

References

1. Jindal T, Jiang CY, Alhalabi O, et al. Enfortumab vedotin (ev) + pembrolizumab (p) outcomes outside clinical trials and biomarkers of benefit in patients (pts) with advanced urothelial carcinoma: analysis of the UNITE study. Ann Oncol. 2024;35(suppl 2):S1149-S1150. doi:10.1016/j.annonc.2024.08.2073
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117