Quality of life with EV-302 in advanced urothelial carcinoma: lessons and implications

The treatment of advanced urothelial carcinoma changed considerably with the advent of immune checkpoint inhibitors in the maintenance and combination therapy settings. Immune checkpoint inhibitors were first used in advanced urothelial carcinoma in the maintenance setting. Specifically, in 2020, JAVELIN Bladder 100 demonstrated that maintenance avelumab in comparison to best supportive care improved overall survival following platinum-based chemotherapy (PBC) (1). Subsequently, immune checkpoint inhibitors were studied in combination therapies for advanced disease. In 2023, EV-302 [enfortumab vedotin plus pembrolizumab (EVP)] and CheckMate 901 (nivolumab plus cisplatin and gemcitabine) both demonstrated improvements in overall survival in the first-line setting in treating locally advanced/metastatic urothelial carcinoma (2,3). Following regulatory approval in the United States, there was subsequently significant uptake in the use of EVP compared to PBC in the first-line setting (4). The National Comprehensive Cancer Network (NCCN) Guidelines currently recommends all three regimens as suitable treatment options in the first-line setting, with EVP being the preferred approach (5).

The field of medical oncology has historically focused on developing therapies that help patients not only live longer but also live better. However, a recent survey of medical oncologists and individuals with urothelial carcinoma revealed a divergence in the ultimate treatment goals. When presented with several potential treatment options with varying survival outcomes and adverse event profiles, patients overwhelmingly picked a regimen which balanced survival with the adverse event profile whereas oncologists chose the regimen with the longest survival benefit (6). Adverse events and quality of life are, indeed, valued by patients as demonstrated by a second survey of one hundred individuals with advanced urothelial carcinoma. The study found that patients were willing to make trade-offs in efficacy if there was an accompanying lower risk of enduring a treatment toxicity (7). For example, individuals were willing to accept a 7.8% lower chance of clinical response if there was a 10% decreased risk of developing peripheral neuropathy. Given the significant clinical use of EVP in the United States and other nations with regulatory approval and the unique side effect profile of EVP, a subsequent publication on quality-of-life outcomes from EV-302 is therefore timely and pertinent to both individuals with advanced urothelial carcinoma and to physicians in determining which of the three first-line regimens may be most appropriate for each unique individual in clinic (8). Hereafter, we discuss the findings of the quality-of-life data evaluating EVP in advanced urothelial carcinoma, as well as several of its pitfalls and shortcomings.

In the quality-of-life publication, the EV-302 authors report patient reported outcomes (PROs) that utilized two questionnaires [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Brief Pain Inventory-Short Form (BPI-SF)] (8). Data on quality of life was collected from initiation of treatment and up to week 26; no known data is available beyond week 26. Investigators found no significant differences in the time to pain progression between EVP and PBC; therefore, further least squares mean change analysis of BPI-SF was not conducted. With regards to results of EORTC QLQ-C30, there were no clinically meaningful differences in quality of life or functioning scale scores between either treatment group in EV-302. Of note, there were clinically meaningful improvements in quality of life in patients in the EVP treatment arm who reported moderate to severe pain at baseline. from the start of treatment up to week 26. Although the EV-302 authors assert that this quality-of-life data support EVP as the preferred first-line regimen in advanced urothelial carcinoma, there are several pertinent concerns and limitations.

First, it is uncertain whether the results from EV-302 and its quality-of-life data are applicable to a moderate proportion of real-world individuals with advanced urothelial carcinoma in a non-clinical trial setting. In EV-302, only 3.4% of patients who received EVP had an Eastern Cooperative Oncology Group (ECOG) performance status of 2, while none had an ECOG performance status of 3 or 4 (2). In contrast, real-world studies for advanced urothelial carcinoma have demonstrated that between 13–25% of patients may have an ECOG performance status of 2 or 3 (9). Given that a poor performance status can be a predictor of chemotherapy toxicities, it is plausible that individuals with a poor performance status who receive EVP may experience more treatment related toxicities and consequently endure a worse quality of life compared to what was found in EV-302 (10). As such, the generation of real-world data sets with EVP is imperative to better understand what effects on quality of life that this rigorous regimen may have on individuals with a poor functional status.

Second, while the quality-of-life data from EV-302 does not necessarily suggest a “detriment” to global health status/quality of life as concluded by its authors, it remains unclear whether there is a net benefit for patients who receive treatment. Notably, post-hoc Q-TWiST analysis was conducted on PROs for maintenance avelumab in JAVELIN Bladder 100 to compare the quality-adjusted time without symptoms or toxicity while on avelumab compared to best supportive care (11). The analysis incorporated three health states including: time with grade 3 or 4 toxicity before disease progression, time without grade 3 or 4 toxicity or symptoms of disease progression, and the time after disease progression. Ultimately, the analysis found a longer mean time without symptoms or toxicity (18.46 versus 15.13 months) with avelumab in comparison to best supportive care, thus suggestive of an improvement in quality of life with receipt of avelumab versus the absence of therapy. To our knowledge, no similar analysis has been conducted for EV-302 or CheckMate 901. As such, it is unclear whether either of these two latter regimens can lead to a net benefit in quality of life in individuals with advanced urothelial carcinoma as shown with JAVELIN Bladder 100.

Third, the quality-of-life data from EV-302 does not adequately capture the short- and long-term implications due to EV-related peripheral neuropathy on individuals who receive therapy or on their caretakers, family and friends. EV-302 investigators reported that 6.3% of individuals who received EV in EV-302 experienced grade 3 or worse peripheral neuropathy (12). The two questionnaires (EORTC QLQ-C30 and BPI-SF) used in EV-302 to assess quality of life in individuals undergoing treatment do not specifically address the sequalae of peripheral neuropathy. The Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0) defines grade 3 peripheral neuropathy as being associated with severe symptoms that limit self-care activities of daily living (13). In other words, individuals who experience grade 3 or worse peripheral neuropathy with EVP may have prolonged longevity at the cost of being limited in self-care tasks such as bathing, feeding and dressing. Consequently, it is the responsibility of caregivers, family members and friends of patients to support the patient in these activities of daily living. This burden on caregivers as well as family and friends can, in turn, translate to financial toxicity, psychological strain, and other consequences to them that are not captured in quality-of-life data questionnaires.

Fourth, the potential effects of financial toxicity on an individual’s quality of life are not evaluated in the EV-302 quality-of-life data. In fact, a cross-sectional analysis of quality-of-life studies in oncology found that most studies do not capture the financial toxicity experienced by patients in real-life settings due to several reasons including sponsor-supplied cancer drugs, and a lack of evaluation in patient questionnaires (14). We previously estimated that EVP costs $37,879.78 per cycle of treatment as opposed to $296.26 with each cycle of cisplatin plus gemcitabine chemotherapy (15). In other words, one cycle of EVP is 137 times more expensive than one cycle of PBC. Moreover, it has been shown that EVP is not cost effective compared to PBC in multiple settings such as the United States, United Kingdom and China (16-18). It is unclear what amount of financial toxicity is absorbed by patients as well as family and friends of patients receiving treatment with EVP. Given that financial toxicity has been associated with poorer health related quality of life among those with cancer, the absence of potential effects of financial toxicity from EVP is a significant limitation with the study’s quality-of-life data (19).

Fifth, there are inherent factors with the trial design that may make interpretation of the quality-of-life data challenging. For instance, the study design was open label, and therefore, patients were aware of the therapies they were receiving—which may potentially affect anticipation or expectations regarding potential side effects and quality of life. In addition, the EV-302 authors report a compliance rate to questionnaires of greater than 70% in both treatment groups up to week 17, but with less than 70% subsequently in the PBC group and up to 70% or more up to week 29 of the EVP group. The differences in completing questionnaires, coupled with treatment discontinuation especially at a quicker time date in the PBC group, also provide challenges in interpreting the quality-of-life data between the two groups.

The field of genitourinary medical oncology has seen tremendous strides in the development of treating advanced urothelial carcinoma with the introduction of immunotherapy, antibody drug conjugates, and combination therapies. Three treatment options all prolong survival in individuals with advanced urothelial carcinoma, while each approach offers varying advantages and challenges to patients, caregivers, and treating physicians. It is therefore imperative for physicians to understand the treatment goals as well as personal preferences of each unique individual in clinic while incorporating data from phase III trials including quality-of-life data before deciding the appropriate treatment approach. The quality-of-life data from EV-302 cites a data cut-off of August 8, 2023 (8). Given the longevity of individuals who received EVP in EV-302, we advocate for the publication of long-term outcomes and quality-of-life data with longer follow-up from participants in EV-302. As there are several shortcomings from the quality-of-life data in EV-302, physicians and individuals with advanced urothelial carcinoma may benefit with this longer follow-up data as well as real-world studies in the future to understand whether a rigorous regimen such as EVP helps patients not only live longer but also live better.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0069/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0069/coif). D.J.B. has the following disclosures: Advisory or Consulting Role: AIMED BIO, Astellas, AVEO Oncology, Bayer, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Janssen, Janux, Merck KGaA, Seagen; Speakers’ Bureau: Merck Sharpe Dohme; Travel and Accommodations: DAVA Oncology, Merck KGaA, Merck Sharpe Dohme, Seagen. A.R.K. has the following disclosures: Stock and Other Ownership Interests: ECOM Medical; Consulting or Advisory Role: Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, Bristol Myers Squibb, EMD Serono, Immunomedics, Gilead Sciences; Speakers’ Bureau: Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, Bristol Myers Squibb, Amgen, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas, Myovant Sciences, Gilead Sciences, AVEO. Research Funding: Genentech, Exelixis, Janssen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Macrogenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, Epizyme. Travel, Accommodations, Expenses: Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis, AstraZeneca. The authors have no other conflicts of interest to declare.

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