Abstract
Background/Aim: The efficacy, safety, and liver toxicity of enfortumab vedotin (EV) for elderly advanced urothelial carcinoma (UC) patients and patients with a poor performance status (PS) are unclear. Patients and Methods: We retrospectively analyzed the efficacy, safety, and liver toxicity of EV in elderly patients and patients with a poor PS between December 2021 and August 2023. Results: Sixty-two patients (≥75 years old, n=22; PS≥2, n=10) were enrolled. Patients with PS≥2 had significantly lower albumin levels than those with PS<2 (p=0.023). The objective response and disease control rates did not differ significantly between patients <75 and ≥75 years old (p=0.598 and p=0.769, respectively) or between those with PS<2 and PS≥2 (p>0.99 and p=0.178, respectively). Progression-free survival (PFS) and overall survival (OS) were not significantly different in patients <75 years and ≥75 years (p=0984, 0.368). A significant difference in PFS (p=0.047) but not OS (p=0.086) was observed between the PS<2 and PS≥2 groups. The rates of any-grade and severe (grade ≥3) adverse events did not differ significantly between patients <75 and ≥75 years (p=0.471, p=0.136) or between PS<2 and PS≥2 groups (p>0.99, 0.99). Aspartate aminotransferase (AST) levels significantly increased, but alanine aminotransferase levels did not, following EV treatment (p<0.001). Multivariate analyses revealed that the albumin level was an independent prognostic factor (hazard ratio=0.159; p<0.001). Conclusion: EV demonstrated similar efficacy and safety in elderly and younger patients with advanced UC. In patients with a poor PS, although the safety was similar, survival was significantly worse in terms of PFS, while the AST levels were significantly elevated.
Advanced urothelial carcinoma (UC), including locally advanced and metastatic disease, is extremely unlikely to be cured, even with platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) (1-4). Recently, antibody-drug conjugates (ADCs) with new mechanisms of action have become available for advanced UC. These may prolong survival.
Enfortumab vedotin (EV), an ADC directed against Nectin-4, is composed of a fully human anti–Nectin-4 monoclonal antibody conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), which undergoes hepatic metabolism via a protease-cleavable linker, and targeted MMAE release in Nectin-4-expressing cells leads to cell cycle arrest and cell death (5, 6). In the EV-301 clinical trial, EV significantly prolonged survival in comparison to standard chemotherapy in patients with advanced UC who had previously received platinum-based treatment and ICIs (7).
The essential principles of treating advanced cancer in elderly adults are the same as in younger patients. However, aging is commonly associated with a decline in the function of critical organ systems, and this decline in organ function likely underlies age-related loss of physiological reserve. As a result, whenever new effective treatments are introduced, clinicians may struggle to assess the risk-benefit ratio regarding whether the results obtained in clinical trials can be achieved in real-world practice, especially in a relatively small populations of elderly individuals or patients with a poor performance status (PS), because these populations are typically underrepresented in clinical trials, and it remains unclear whether these patients can benefit from the new treatment (8, 9). Aging is also associated with a decline in the hepatic volume and blood flow (10, 11). Consequently, drug metabolism and elimination may be slowed, potentially causing hepatic impairment. However, the effects of EV on liver enzymes have not yet been reported in clinical practice.
The present study retrospectively evaluated the efficacy, safety, and changes in liver enzymes tests in patients with advanced UC treated with EV and compared the results of elderly patients and patients with poor PS with those of younger patients and patients with good PS.
Patients and Methods
Patients’ characteristics. This multi-institutional retrospective study was conducted in accordance with the 1964 Declaration of Helsinki and its subsequent amendments. It was approved by the Institutional Review Board of the National Hospital Organization Kyushu Cancer Center (2022-33) and the Ethics Committee of each institution.
We retrospectively reviewed 63 consecutive patients with advanced UC who received EV after platinum-based chemotherapy and ICIs at six institutions between December 2021 and August 2023 (UROKYU study population). One patient was excluded because the therapeutic effect of EV was not evaluated. Informed consent was obtained through an opt-out process due to the retrospective nature of the study.
The following clinicopathological characteristics were assessed: age, sex, Eastern Cooperative Oncology Group (ECOG) PS, primary tumor site, presence of pathologic variants, albumin, presence of visceral metastases, type of ICIs prior to EV, best objective response to EV based on the Response Evaluation Criteria in Solid Tumors version 1.1 (12), and grades of EV-related adverse events (AEs) based on the Common Terminology Criteria for Adverse Events version 5.0 (13). Liver enzymes [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] were measured before and after dosing at the time of progressive disease (PD) in cases where patients treated with EV developed PD, and at the time of the last dose of EV in cases where patients treated with EV did not develop PD and could continue treatment.
Statistical analyses. JMP® Pro, version 15.1.0 (SAS Institute, Inc., Cary, NC, USA), was used for all the statistical analyses. The cutoff value for hemoglobin concentration was <10 g/dl in a previous study (3). The Mann–Whitney U-test was used to compare continuous variables, and Fisher’s exact probability test was used to compare categorical variables.
The objective response rate (ORR) was defined as the proportion of patients who had a partial or complete response to EV. A composite of ORR and stable disease was defined as the disease control rate (DCR). Differences between pre- and post-treatment AST and ALT levels were assessed using the Wilcoxon signed-rank test. The Kaplan–Meier method with log-rank test was used to assess progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox proportional hazards regression models were used to predict the significance of the association between clinical variables and OS. p-Values of <0.05 were considered to indicate statistical significance.
Results
Patient characteristics. The baseline characteristics of the 62 enrolled patients and the characteristics of the patients stratified by age (<75 and ≥75 years) and PS (PS<2 and PS≥2) are shown in Table I. The median age of the patients was 73 years (IQR=68-78), 40 patients (64.5%) were <75 years of age and 22 patients (35.5%) were ≥75 years of age. A total of 52 patients (83.9%) had a PS of <2 and 10 patients (16.1%) had a PS of ≥2. The majority of patients were male (74.2%), and the histological type was pure UC in most of the patients (71.0%). The proportion of patients with upper urinary tract primary tumors was similar to that of the lower urinary tract group (48.4% vs. 51.6%, respectively). The age <75 years group had a significantly higher percentage of male patients (p=0.015). The patients in the PS≥2 group had significantly lower albumin levels in comparison to the PS<2 group (p=0.023).
Patient characteristics according to age and performance status.
Efficacy. Overall, the median follow-up period was 7.1 months (IQR=3.9-11.8 months), an ORR was confirmed in 33 patients (53.2%), and a DCR was confirmed in 46 patients (74.2%). There were no significant differences in the ORR or DCR between the <75 and ≥75 years groups (ORR: 50.0%, 59.1%, p=0.598; DCR: 72.5%, 77.3%, p=0.769). Similarly, there were no significant differences in the ORR or DCR between the PS<2 and PS≥2 groups (ORR: 53.9%, 50.0%. p>0.99; DCR: 78.9%, 50.0%, p=0.178) (Figure 1).
Objective response rates (ORRs) and disease control rates (DCRs) according to age (<75, ≥75 years) and performance status (PS) (<2, ≥2) in patients treated with enfortumab vedotin (EV).
Overall, the median PFS and OS were 5.3 months [95% confidence interval (CI)=4.1-6.4] and 11.3 months (95%CI=7.3-16.4), respectively. The median PFS and OS were 5.3 months (95%CI=3.9-7.4) and 10.2 months [95%CI=5.9-not estimable (NE)], respectively, in the <75 year group, and 5.6 months (95%CI=3.1-8.9) and 16.4 months (95%CI=5.7-NE) in the ≥75 years group. According to the log-rank test, these differences were not statistically significant (p=0984, 0.368). The median PFS and OS were 5.7 months (95%CI=4.4-7.4) and 11.8 months (95%CI=8.9-16.4), in the PS<2 group, and 3.0 months (95%CI=0.6-5.4) and 3.9 months (95%CI=0.6-NE), respectively, in the PS≥2 group. According to the log-rank test, the difference in PFS was statistically significant (p=0.047), while the difference in OS was not (p=0.086) (Figure 2 and Figure 3).
Progression-free survival according to age (<75, ≥75 years) and performance status (PS) (<2, ≥2) in patients treated with enfortumab vedotin (EV).
Overall survival according to age (<75, ≥75 years) and performance status (PS) (<2, ≥2) in patients treated with enfortumab vedotin (EV).
Safety. Overall, EV-related AEs of any grade were observed in 53 patients (85.5%), including 16 patients (25.8%) with grade ≥3 AEs. No significant differences were observed between the 75 and ≥75 years groups or between the PS<2 and PS≥2 groups in the rates of any-grade AEs or severe AEs (grade ≥3). In the <75 and ≥75 years groups, the rates of any-grade AEs were 82.5% and 90.9% (p=0.471), respectively, while the rates of severe AEs were 32.5% and 13.6 (p=0.136), respectively. In the PS<2 and PS≥2 group, the rates of any-grade AEs were 84.6% and 90.0% (p>0.99), respectively, while the rates of severe AEs were 26.9% and 20.0% (p>0.99), respectively (Figure 4).
Incidence of enfortumab vedotin (EV)-related adverse events (any-grade and grade ≥3) according to age (<75, ≥75 years) and performance status (PS) (<2, ≥2) in patients treated with EV.
AST and ALT changes in patients treated with EV. Overall, there were significant differences in the pre- and post-EV treatment levels of AST (p<0.001), but not ALT (p=0.103). When patients were divided into two groups according to the presence of liver metastasis, age, and PS, significant changes in AST level were observed from before to after EV treatment in the group without liver metastasis (p<0.001), in the <75 years group (p<0.001), and in the PS<2 group (p<0.001). No statistically significant change in ALT level was observed in any of the groups classified according to liver metastasis, age, or PS (Table II).
Changes in the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) pre- and post-enfortumab vedotin (EV) according to liver metastasis (present, absent), age (<75, ≥75 years) and performance status (PS) (PS<2, PS≥2).
Univariate and multivariate analyses for OS. A univariate Cox regression analysis revealed that Hb <10 g/dl and the albumin level were significantly associated with the prognosis. The multivariate analyses revealed that albumin was independently associated with the prognosis (HR=0.159, 95%CI=0.060-0.395, p<0.001) (Table III).
Univariate and multivariate analyses of factors associated with overall survival in patients receiving enfortumab vedotin (EV).
Discussion
This study investigated the efficacy, safety, and hepatic toxicity of EV after platinum-based chemotherapy and ICIs for advanced UC in elderly patients (age ≥75 years) and those with a poor PS (PS≥2) in comparison to younger patients (age <75 years) and patients with a good PS (PS<2). According to the efficacy profile, the elderly group showed comparable ORR, DCR, PFS, and OS values to the younger group. The poor PS group showed worse PFS than the good PS group, while the poor PS group showed a comparable ORR and DCR to the good PS group. The albumin levels of the PS<2 and PS≥2 were significantly different and the albumin level was identified as an independent predictor of OS in the multivariate analysis. According to the safety profile, the age and PS groups had comparable rates of any-grade EV-related AEs (≥G3). According to hepatic toxicity, a significant increase in AST was observed, but the range of increase was not clinically problematic.
Clinicians must treat elderly patients and/or patients with a poor PS if they desire treatment. Therefore, similarly to younger patients and patients with a good PS, real-world data on elderly patients and patients with a poor PS are important when clinicians are deciding whether to treat these patient groups, which have not been adequately studied in clinical trials (14, 15). Patients of ≥75 years of age accounted for 17.3% of the patients in the EV-301 trial (7). In EV-301, the ORR of patients of ≥75 years was 29.4%, while that of patients of <75 years of age was 43.0%. Similarly, efficacy in patients of ≥75 years of age tended to be inferior to that of patients of <75 years of age. The HRs for PFS and OS in the ≥75 years group were 0.889 (95%CI=0.58-1.37) and 0.91 (0.55-1.51), respectively, while the HR of PFS and OS in the <75 years group were 0.607 (95%CI=0.49-0.75) and 0.69 (0.53-0.89). Interestingly, these differences narrowed when the two groups were divided at 65 years of age (≥65 years: ORR: 40.7%, HR in PFS and OS, 0.62 and 0.75; <65 years: ORR: 40.3%, HR for PFS and OS: 0.70 and 0.68).
EV is an ADC targeting nectin-4 (16-18). Therefore, the difference in nectin-4 expression between the age groups could be expected to cause differences in effectiveness between the age groups. However, nectin-4 mRNA expression didn’t differ according to age (p=0.11) (19). On the other hand, in the present study, which was based on clinical practice, in which 35.5% of the patients were ≥75 years of age, there were no significant differences in clinical outcomes, including ORR, DCR, PFS, and OS, between the ≥75 and <75 years groups. One of the reasons for the difference in results between the clinical trial and the present study was that there was no difference in albumin between the ≥75 and <75 years groups (p=0.210). Multivariate analyses also confirmed that albumin was the only parameter independently associated with prognosis (p<0.001). Age was not significantly associated with prognosis (p=0.632). Similarly, no significant differences were found in AEs. Although the present study was conducted in a real-world setting, not a clinical trial, and the bias of clinicians choosing to administer EVs to patients with a greater reserve capacity cannot be ruled out, the results suggest that EVs can be expected to be sufficiently efficacious in patients of >75 years of age. In another clinical practice study (UNITE study) from the United States that included 260 patients treated with EV monotherapy [most received EV after two or more prior lines of therapy (67%) and most received EV outside of a clinical trial (78%)], no difference was found in ORR between the ≥75 and <75 years groups (51%, 53%), p=0.85) (20). This finding supports the results of the present study.
The EV-301 trial was limited to patients with a PS of 0 or 1, and restrictive eligibility criteria were applied (7). However, EV is currently only approved in Japan as a standard of care in the 3rd line setting after platinum-based chemotherapy and ICIs. Advanced UC is essentially an incurable disease, thus it is natural to expect the overall condition to worsen, not only because of the advancing cancer but also because of treatment-related AEs with each successive treatment regimen. Chronological age may not correlate with physiological impairment and decline in the functional reserve, both of which vary widely among individuals. Therefore, it is more important to focus on the efficacy and safety in patients with a poor PS than in the elderly, since patients with a poor PS are usually not included in clinical trials. The present study revealed that there were no significant differences in the ORR, DCR, and EV-related AEs between the PS<2 and PS≥2 groups. It was also reported that there was no significant difference in ORR between patients with an ECOG PS of 0/1 and those with an ECOG PS of 2/3 in the UNITE study (56%, 34%, p=0.18) (20). This finding supports the results of the present study. However, the present study showed a significant difference in PFS. Patients with a poor PS tended to have worse OS, although the difference in OS was not significant. One possible reason for the lack of significance was the relatively small number of patients with a poor PS. These results imply that EV may have a temporary therapeutic effect in patients with a poor PS; however, the efficacy of EV may not be sustained. Among patients with a poor PS, particularly those with a poor nutritional status, the benefit from EV may be limited. This is evident from the significant difference observed in the albumin levels between the PS<2 and PS≥2 groups, with albumin identified as a prognostic factor in the present study.
EV is an ADC with an anti–nectin-4 monoclonal antibody linked to MMAE, which undergoes hepatic metabolism, predominantly through cytochrome P450 3A4 (CYP3A4) and is a substrate of P-glycoprotein (21). On the other hand, in the EV-301 clinical trial, dose modifications and interruptions were allowed for the management of AEs based on pre-specified criteria but did not include hepatic toxicity. In the EV-301 trial (n=296), it was reported that the AEs, which occurred in ≥20% of the patients, did not include any hepatic AEs; however, AST elevation that led to dose interruption occurred as a treatment-related AE in six patients (2.0%) (7). Regarding hepatic impairment, it has been reported that pharmacokinetics of EV and free MMAE were studied in patients with advanced UC (n=699), and patients with mild impairment (n=65) had a 37% increase in AUC0-28d and a 31% increase in the Cmax of MMAE in comparison to patients with a normal hepatic function. With regard to the pharmacokinetics of EV and MMAE, no clinically significant age-related (range=24-90 years; > 65 years, 60%), sex-related (male, 73%), or race/ethnicity-related (white, 69%; Asian, 21%; black, 1%; others/unknown, 8%) differences were seen (22). The only liver enzyme to show significant elevation in the present study was AST; however, the changes in AST were small and were not found to be at clinically problematic levels even in patients with liver metastases.
This study was associated with some limitations, including its retrospective, non-randomized design, small sample size (especially the number of patients in the elderly and poor PS groups), and short observation period. In addition, due to the multicenter nature of the study, there was heterogeneity in the prior history of platinum-based chemotherapy and ICI, dosing schedule, timing of regimen changes, and timing of the assessment of responses and treatment-related AEs. Several other conditions that could have affected liver enzymes, such as a history of alcohol consumption, medication with CYP3A4 inhibitors, and hepatitis viruses, were not considered.
Conclusion
EV demonstrated similar efficacy and safety in both elderly and younger patients with advanced UC. In patients with a poor PS, although safety was similar, PFS was significantly worse in comparison to patients with PS<2. AST levels were significantly elevated but not to levels that would be problematic in clinical practice.
Acknowledgements
The Authors thank Japan Medical Communication (https://www.japan-mc.co.jp/) for editing the English language of this manuscript.
Footnotes
Authors’ Contributions
Study concept and design: N.F. (Nobuki Furubayashi), A.M. T.N., K.H. and M.N.; acquisition of data: A.M., T.T., H.M., Y.H., K.K. (Keijiro Kiyoshima), T.N., Y.H., T.K. Y.S. and K.H.; statistical analysis: N.F. (Nobuki Furubayashi), and H.M.; analysis and interpretation of data: all Authors; drafting of the original manuscript: N.F. (Nobuki Furubayashi), A.M. and M.N.; critical revision of the manuscript for important intellectual content: all Authors; supervision: K.K. (Kentaro Kuroiwa), N.S., N.F. (Naohiro Fujimoto) and M.N. All Authors have read and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
Funding
No funding was received.
- Received May 27, 2024.
- Revision received June 12, 2024.
- Accepted June 13, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
