Results from a real-world retrospective cohort analysis provide early evidence that upfront dose reduction of enfortumab vedotin-ejfv (Padcev) administered alongside pembrolizumab (Keytruda) may improve tolerability without adversely affecting treatment continuity or overall survival (OS) in patients with advanced urothelial carcinoma, challenging the assumption that dose intensity is always associated with clinical benefit, according to study investigators.
These data, which were published in JAMA Oncology, showed that patients who initiated dose-reduced first-line enfortumab vedotin plus pembrolizumab (n = 117) had a 51% lower likelihood of treatment interruption compared with those who received the standard dose (n = 379; adjusted HR, 0.49; 95% CI, 0.30-0.82; P = .007).1 Furthermore, no significant difference in OS outcomes were seen with upfront dose reduction vs standard dosing (adjusted HR, 1.24; 95% CI, 0.88-1.76; P = .21).
Survival, Tolerability, and Treatment Continuity With Upfront Dose Reduction of Enfortumab Vedotin
- A real-world retrospective analysis showed that initiating enfortumab vedotin at a reduced dose alongside pembrolizumab in patients with advanced urothelial carcinoma lowers the risk of treatment interruption by 51% (aHR, 0.49) and did not significantly affect OS outcomes (aHR, 1.24).
- The benefits of upfront dose reduction were consistent among older adults and physiologically vulnerable patients, including those ≥85 years old, with a creatinine clearance <30 mL/min, or ECOG performance status ≥2, suggesting this approach can improve tolerability while maintaining efficacy.
- These findings challenge the traditional paradigm that maximum dose intensity always correlates with clinical benefit.
To learn more about the rationale for this study and its implications for clinical practice, OncLive® interviewed the following investigators:
- Ryan D. Chow, MD, PhD, a hematology/oncology fellow at Penn Medicine, the University of Pennsylvania Health System;
- Ronac Mamtani, MD, MSCE, section chief of Genitourinary Cancers, in the Division of Hematology-Oncology and associate professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania;
- Ramy Sedhom, MD, associate director of Penn Center for Cancer Care Innovation; clinical director of Medical Oncology, co-lead of Psychosocial Oncology Services, division chief of the Palliative Care Division, and a clinical assistant professor of medicine (Hematology-Oncology) at Penn Medicine Princeton Health.
“In the clinic, when I'm meeting with patients, we're often having conversations about what's most important to them. I would say a pretty standard answer is that people want to gain as much benefit from [treatment] and live as long as possible, but often not at the compromise of quality of life [QOL]. What's nice is we were able to show that with upfront dose reductions you can hopefully achieve both,” Sedhom said. He added that “This reframes how we think about dose intensity.”
Read on to see their expert insights in the interview below.
OncLive: What real-world observations regarding enfortumab vedotin–related neuropathy and treatment discontinuation led you to prioritize investigating upfront dose reduction over reactive dose modification in this study?
Chow: In our experience, enfortumab vedotin is an incredible, very active drug in urothelial cancer. The problem is that we're seeing our patients develop this terrible neuropathy. It can really affect their QOL. The way we've been managing this neuropathy is [by incorporating a] treatment break. We hold treatment for a few weeks, and we'll restart enfortumab vedotin at a lower dose. However, what's really worrisome for us is that for a lot of our patients—the FDA estimates 90% of these patients—who do develop neuropathy, it's permanent, or only mildly improves after we hold the drug.
This is not a rare issue for patients on this drug; in the phase 3 EV-302 trial [NCT04223856], over half of the patients [experienced] neuropathy, and a third of the patients had to stop the drug altogether.2 What's really striking is that even with all these treatment interruptions and dose modifications, the outcomes with this drug were still so remarkable compared with what we used to do. That really raised this question: ‘Do we really need to put our patients at risk of this potentially life-altering, potentially permanent toxicity if we start everyone at the full dose? If we started patients at a lower dose, how does that affect their survival outcomes and their ability to stay on treatment long term?’ It would be a different way of treating these patients.
What is most important to know about the study design, and how did you define a “physiologically vulnerable population”?
Mamtani: This was a retrospective, real-world cohort study of patients that had advanced urothelial cancer, all of whom started first-line enfortumab vedotin plus pembrolizumab. We used a large, nationwide electronic health record–derived dataset called Flatiron Health.
There are 3 key features of the cohort. Number one, it reflects routine clinical practice, and that's important. This means that we included patients treated both in the community and in academic settings, and we did not restrict to clinical trial–eligible populations. The second key feature is that we looked at upfront enfortumab vedotin dose reduction, defined as enfortumab vedotin dosed at 1 mg/kg or 0.75 mg/kg for either of their first 2 doses in that cohort. This was compared with standard dosing at 1.25 mg/kg for both of the first 2 doses. We were really thoughtful about this definition because it captures a real-world strategy; this is what many clinicians already use for patients who they think are at higher risk for toxicity.
[Regarding how we defined] physiologic vulnerability, we used what we think is a pragmatic definition: [patients] age 85 years or older with a creatinine clearance of less than 30 mL/min and ECOG performance status of 2 or higher. We think that these factors influence tolerability in the clinic.
[Notably,] because these dose reductions aren't randomized, in practice, we used a propensity score–based technique called inverse probability of treatment waiting. That allowed us to balance the groups and compare our primary end point of interruption–free survival, which is a real-world measure of treatment tolerability.
What did these real-world data show about the effect of upfront dose reduction on the risk of treatment interruption and survival outcomes? Was this effect consistently observed across all groups of "physiologically vulnerable" patients?
Chow: We're finding in real-world practice that 1 in 4 patients are already starting [treatment with enfortumab vedotin with] this upfront dose reduction [strategy.] With that in mind, when we account for other confounding variables, it looks like upfront enfortumab vedotin dose reduction really cuts the risk of treatment interruption in about half. [Moreover,] OS was not significantly different between patients who started at the full dose compared with those who were started at the lower dose.
What we found really striking is this effect was very much consistent when we did a subgroup analysis of these patients who have physiologic vulnerabilities. Again, we're cutting the risk of treatment interruption in half, and the survival outcomes are pretty similar.
Notably, we're using treatment interruption here as a surrogate for toxicity. The idea [behind this is that] if patients are experiencing some sort of toxicity from the drug, we're holding the treatment for a few weeks and trying to help them recover from that before we restart it. We think that upfront dose reduction might be helping patients tolerate treatment better [without] compromising the efficacy of the drug, which is really important.
How do these findings challenge the traditional oncology paradigm that dose intensity is synonymous with clinical benefit?
Sedhom: For decades, oncology has been guided by dose intensity as a paradigm. It's [centered] around the idea that giving the highest tolerated dose [of an agent] as early as possible is synonymous with benefit. This framework, historically, came from the era of cytotoxic chemotherapy. It's important to point out that typically, patients on these trials are younger and fitter. What our findings highlight is that in modern day oncology with enhancements in drug delivery and drug development, this assumption may not universally translate to practice, particularly in our cohort of older adults and for patients with physiologic vulnerability.
What we found is that preserving treatment continuity may be just as important, if not more important than starting at the maximum indicated dose up front. A modest upfront dose reduction reduced early toxicity, lowered the likelihood of treatment interruptions, and allowed patients to remain on effective therapy longer.
Rather than focusing solely on the number of mg given up front, we should be thinking about how we can maximize the delivered therapy over time. [We need to think about] what patients perceive, tolerate, and sustain. More broadly, this aligns with a shift in thinking about how we can personalize treatments for patients beyond tumor biology. Precision medicine has been heavily focused on molecular targets, but precision care can also be about how we make alterations based on patient physiology, patient functional reserve, and ultimately, patient goals. Of course, we cannot ascertain [that information] from this dataset, but practically, it's something that we could translate into clinic when we're meeting with patients.
You noted that the dataset lacked information on metastatic disease sites and tumor burden; how might these specific variables influence a physician's decision to utilize upfront dose reduction, and could their absence have led to residual confounding in the survival analysis?
Mamtani: This came up in peer review, which is important to strengthen the paper. We thought about this and concluded that disease burden is so unique that it's bidirectional. Patients with high disease burden who are super symptomatic, which we [often] see in clinic, may be more likely to receive the full dose. Disease burden can also go in the opposite direction. Patients with extensive disease are oftentimes more fragile because they have organ dysfunction or poor functional status, and this could push us the other way toward dose reduction. The net direction of confounding is not always straightforward in pharmaco-epidemiology, but importantly, we didn't observe a detrimental effect on survival with dose reduction. Regardless, all these results should be interpreted as associations not causalities. They just reinforce the need for prospective studies.
What prospective data or longitudinal outcomes are most critical to validate these findings before upfront dose reduction can be formally integrated into treatment guidelines?
Chow: Traditionally, the burden of proof has been to show noninferiority when evaluating treatment de-escalation in a randomized trial. That's our gold standard. But these types of trials are hard to execute. The industry is not interested in funding these, we need really large sample sizes to demonstrate noninferiority, and patients and clinicians are worried that the treatment won't be as effective if we're reducing it. There is a growing [trend] in the field, though, that maybe the burden of proof should be for oncologists to show that giving more treatment is superior to less treatment, especially for a drug like enfortumab vedotin, which we're seeing can have a real risk of permanent toxicity. There are some precedents now for designing superiority trials for treatment de-escalation; there's a phase 3 trial called SONIA [NCT03425838] looking at whether CDK4/6 inhibitors in breast cancer need to be given in the first line or [if they can be administered] safely in the second line without affecting survival.
[Study results] showed that it was fine to wait until later to give this drug. These creative studies that use a superiority design might be a meaningful path forward to [evaluate if it is] safe to do early dose reduction [of enfortumab vedotin], reducing what we normally do.
The other element about our study that would be interesting to look at prospectively is treatment-related QOL outcomes, how patients experience treatment, and what their journey is like when they're on this treatment. Looking at toxicity profiles in a prospective fashion and comparing QOL between upfront dose reduction vs the full dose would be informative. One could argue there might be a route forward for looking at multiple end points at the same time; not just looking at survival, but also looking at how patients get through treatment in terms of QOL and toxicity. Patients don't want to just live longer, they also want to live better. That should be accounted for, especially for patients with metastatic disease.
What’s your final message for colleagues regarding the importance of real-world research in oncology?
Sedhom: I see a lot of older patients as an oncologist out in the community, and the reality is those patients in clinic often look different than those enrolled on trials. Although we are doing everything we can to improve equitable representation for those on trials, studies like this are important to mend the data gap. There is a reality of both over and under treatment. The real value of real-world evidence is that we try to answer some questions, and it just makes conversations in the clinic more informative. To share that we were able to look at real-world usage and say, ‘I don't think reducing your dose up front will lead to lower survival and it may improve your QOL’ can be meaningful, especially for savvy patients who are able to look into the literature. As a call to action for researchers and rising young stars, these data can be very meaningful for oncologists in the field.
References
- Chow RD, Sedhom R, Mamtani R. Reduced-dose enfortumab vedotin, treatment continuity, and survival in urothelial cancer. JAMA Oncol. 2026;12(1):104-106. doi:10.1001/jamaoncol.2025.4566
- 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
