What’s new in advanced urothelial carcinoma?

Enfortumab vedotin and pembrolizumab’s (EV+P) EV-302 trial results represent a major advancement in metastatic urothelial carcinoma (mUC), including in Asian patients, according to Professor Ravindran Kanesvaran of the National Cancer Centre in Singapore, who also discussed managing skin toxicity associated with this regimen and provided an overview of other agents for UC under investigation at Uro-Oncology Asia 2025.

Advanced UC has been an area of unmet need that saw considerable evolution in systemic treatment over the past 5 years, including US FDA approvals for EV, erdafatinib, maintenance avelumab, sacituzumab govitecan (SG), adjuvant nivolumab and, most recently, EV+P. “Most patients will die of metastatic UC, and importantly, not many of them [34–39 percent] will get second-line therapy,” said Kanesvaran. “This highlights the fact that we shouldn’t be thinking about sequencing upfront, but instead about giving our best drug upfront.” [Future Oncol 2019;15:1323-1334; J Med Econ 2019;22:662-670]

EV and EV+P

EV-301 was a global phase III trial (n=608) that established the role of EV, an anti–Nectin-4 antibody-drug conjugate (ADC), vs investigator-choice single-agent chemotherapy in patients with locally advanced (LA)/mUC who previously received platinum-containing chemotherapy and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. EV significantly improved outcomes vs chemotherapy.

“EV was associated with a 30 percent lower mortality [median overall survival (mOS), 12.88 vs 8.97 months; hazard ratio (HR), 0.70; 95 percent confidence interval [CI], 0.56–0.89; p=0.001] and a 37 percent lower risk of disease progression or death [median progression-free survival (mPFS), 5.55 vs 3.71 months; HR, 0.62; 95 percent CI, 0.51–0.75; p<0.001]. It also showed a 2.2 times higher rate of complete or partial response [objective response rate (ORR), 40.6 vs 17.9 percent; p<0.001] and was associated with a significant reduction in mean pain symptom score from baseline [-5.62 vs +0.11; p<0.05],” noted Kanesvaran. [N Engl J Med 2021;384:1125-1135; J Clin Oncol 2021;doi.org/10.1200/JCO.2021.39.15suppl.4539]

Subsequently, the phase III EV-302 trial (n=886) evaluated EV in combination with pembrolizumab vs chemotherapy in first-line treatment of advanced UC. “EV-302’s data presented at ESMO 2023 received a standing ovation. There was a 55 percent improvement in mPFS [12.5 vs 6.3 months; HR, 0.45; 95 percent CI, 0.38–0.54; p<0.00001], with clear benefit observed across all subgroups. Mortality was reduced by 53 percent [mOS, 31.5 vs 16.1 months; HR, 0.47; 95 percent CI, 0.38–0.58; p<0.00001], with all subgroups favouring EV+P. Importantly – as some of you may worry about toxicities – the benefit was consistent in patients ≥65 years of age,” highlighted Kanesvaran. “EV+P achieved an ORR that we’ve pretty much not seen in this space: 67.7 percent [vs 44.4 percent with chemotherapy], with 29.1 percent of patients having complete response [vs 0 percent].” [N Engl J Med 2024;390:875-888]

EV-302’s Asian subset (n=176) analysis results presented at ESMO Asia 2024 were consistent with those of the main study. “Bearing in mind this is a subgroup analysis, it could be said that the outcomes are even better than in the main study. mOS was not reached in either arm, with an HR of 0.34 [95 percent CI, 0.18–0.65],” reported Kanesvaran. [Kikuchi E, et al, ESMO Asia 2024, abstract 2690]

Toxicity

“In terms of treatment-related adverse events [TRAEs], skin manifestations, such as pruritus and maculopapular rash, are a challenge, as well as peripheral neuropathy – both in the overall population and in Asian patients,” shared Kanesvaran. In EV-302, the most common TRAEs of any grade in the EV+P group were peripheral sensory neuropathy (50.0 percent), pruritus (39.8 percent), and alopecia (33.2 percent), while the most common grade ≥3 TRAEs were maculopapular rash (7.7 percent), hyperglycaemia (5.0 percent), and neutropenia (in 4.8 percent). [N Engl J Med 2024;390:875-888]

“EV-related rash can present as early as day 10 of cycle 1. As a result, I recommend seeing patients every week when initiating treatment, as early intervention is critical for enabling optimal use of EV. For instance, blisters are a bad prognostic factor that would necessitate early management, possibly requiring systemic steroids,” shared Kanesvaran. [Clin J Oncol Nurs 2021;25:E1-E9] He added that early manifestation differentiates EV from pembrolizumab as the cause of skin toxicity when using the EV+P regimen.

“If grade 3 skin reaction occurs, EV needs to be withheld until the toxicity subsides to grade 1 or below, which may take up to 1 month. It is possible to rechallenge the patient with the same dose or the dose can be reduced by one level. However, I would caution against starting treatment at a reduced EV dose, as there is a clear dose-response relationship: highest ORRs are observed with the full 1.25 mg/kg dose,” stressed Kanesvaran. [Clin J Oncol Nurs 2021;25:E1-E9; J Clin Oncol 2024;doi.org/10.1200/JCO.2024.42.16suppl.45] He also suggested that patients may be more willing to tolerate side effects if good response to treatment can be demonstrated on a repeat CT scan.

Agents under recent and ongoing investigation

At present, the National Comprehensive Cancer Network (NCCN) guidelines recommend EV+P as the preferred first-line regimen for LA/mUC, but several other agents are under investigation. [NCCN Clinical Practice Guideline in Oncology, Bladder Cancer, version 1.2025]

The combination of disitamab vedotin (DV; an anti-HER2 ADC) plus toripalimab was shown to be active in mUC in a phase Ib/II study (n=41; treatment-naïve patients, 61 percent), with a reported ORR of 73.2 percent and a complete response rate of 9.8 percent. The mPFS was 9.2 months and 2-year OS rate was 63.2 percent. [Sheng X, et al, ASCO 2023, abstract 4566] A phase III trial in previously untreated LA/mUC patients with HER2 immunohistochemistry (IHC) score ≥1 is underway (NCT04264936).

Another anti-HER2 ADC that showed activity in previously treated bladder cancer (HER2 IHC 2+, n=25; HER2 IHC 3+, n=16) is trastuzumab deruxtecan (T-DXd), which achieved an ORR of 39.0 percent in the overall cohort and 56.3 percent among HER2 IHC 3+ patients in the DESTINY-PanTumor02 tumour-agnostic biomarker-driven phase II trial. [J Clin Oncol 2023;42:47-58] “T-DXd could be an option for eligible patients in later lines of treatment, but it does not yet have first-line data,” commented Kanesvaran.

SG, an ADC targeting Trop-2, was another agent investigated for refractory mUC. It initially secured accelerated US FDA approval on the basis of the phase II TROPHY-U-01 study, but its approval was withdrawn following disappointing phase III TROPiCS-04 trial results. [Ann Oncol 2024;35:392-401; Grivas, et al, ESMO 2024, abstract LBA9]

Erdafitinib is a pan–fibroblast growth factor receptor (FGFR) inhibitor approved for treatment of LA/mUC in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. Erdafitinib demonstrated significantly longer mOS than chemotherapy (12.1 vs 7.8 months; HR, 0.64; 95 percent CI, 0.47–0.88; p=0.005) after previous anti–PD-1 or anti–PD-L1 treatment in cohort 1 of the phase III THOR study. [N Engl J Med 2023;389:1961-1971] However, erdafitinib failed to improve outcomes vs pembrolizumab in platinum-experienced anti–PD-(L)1–naïve, FGFR-altered mUC population. [Ann Oncol 2024;35:107-117]