Treatment patterns and outcomes with second-line therapies in patients with advanced urothelial carcinoma previously treated with first-line enfortumab vedotin with pembrolizumab

Introduction

The landmark EV-302 trial, demonstrated that the combination of enfortumab vedotin and pembrolizumab (EV + pembro) nearly doubled median overall survival (OS) and progression-free survival (PFS) compared to platinum-based chemotherapy, regardless of cisplatin eligibility. ¹ This regimen is now the preferred first-line therapy for locally advanced or metastatic urothelial carcinoma (LA/mUC), reflecting a paradigm shift in clinical practice. As EV + pembro becomes the standard first-line regimen, the optimal approach to second-line and subsequent therapy remains undefined. Per guidelines, biomarker-directed therapies, gemcitabine with cisplatin, gemcitabine with carboplatin or dose-dense methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) chemotherapy with growth factor support are the preferred options following progression on EV + pembro. ² However, data guiding treatment selection after progression on EV + pembro are limited. This study aims to characterize treatment patterns and outcomes in the second-line setting following first-line EV + pembro, addressing a gap in evidence and informing future therapeutic strategies.

Methods

Patient-level data was obtained using the US-based, electronic health record-derived deidentified Flatiron Health Research Database. It includes structured and unstructured data curated via technology-enabled abstraction from a network of oncology clinics representing approximately 280 cancer practices across the United States, from both academic and community settings.

Patient were eligible if they had a diagnosis of advanced urothelial carcinoma (aUC), received first-line EV + pembro, and had documented second-line systemic therapy data available. The analytical cohort included patients diagnosed with aUC on or before January 22, 2025, who subsequently initiated second-line therapy between October 20, 2021, and June 26, 2025. The data cutoff date was June 30, 2025. Second-line treatment regimens were categorized into four groups based on the predominant systemic agent or combination received: (1) cisplatin-based therapy, (2) carboplatin-based therapy, (3) EV rechallenge, and (4) other therapies (including targeted therapies, non-platinum-based chemotherapy, immunotherapy rechallenge, or other non-approved agents).

The primary outcome was real-world overall survival (rwOS), defined as the time from initiation of second-line therapy to death from any cause. Patients were censored at the time of loss to follow-up, as determined by the last recorded structured activity (e.g., clinic visit, medication administration, or laboratory test). Secondary outcome was real-world time to next therapy (rwTTNT), defined as the time from initiation of second-line therapy to initiation of third-line therapy or death, whichever occurred first. rwTTNT was similarly censored at the time of loss to follow-up. Kaplan-Meier method was used to estimate median rwOS and rwTTNT, and their 95% confidence intervals. All the analysis was performed using R version 4.5.1. ³

Results

A total of 15,236 patients with aUC were included. Of these, 10,960 patients had available first-line treatment information. ⁴ Among them, 757 patients received first-line EV + pembro. Following progression on first line EV + pembro, 120 patients initiated a documented second-line systemic therapy (Figure 1). Of these, 2 patients had non-estimable rwOS or rwTTNT and were excluded from the analysis, resulting in a final cohort of 118 patients for outcomes analyses.

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Figure 1.

Flow diagram.

Among the 120 patients who received second-line systemic therapy: the most common second-line regimen category was other therapies in 46 patients (38.3%), followed by carboplatin-based therapy in 42 patients (35.0%), cisplatin-based therapy in 16 patients (13.3%), and EV rechallenge in 16 patients (13.3%). Within the other therapies subgroup: the most frequently administered agents were erdafitinib (n = 11, 24%), trastuzumab deruxtecan (n = 11, 24%), and sacituzumab govitecan (n = 10, 22%).

Median rwTTNT was 4.7 months (95% CI, 2.8–7.5) with carboplatin-based therapy, 3.0 months (95% CI, 2.4-NR) with cisplatin-based therapy, 8.5 months with EV rechallenge (95% CI, 5.1-NR) and 3.9 months with other therapies (95% CI, 3.3-NR). Corresponding median rwOS values were 7.1 months (95% CI, 6.2-NR) for carboplatin-based therapy, 8.3 months (95% CI, 2.4-NR) for cisplatin-based therapy, 8.5 months (95% CI, 5.3-NR) for EV rechallenge, and 14.0 months (95% CI, 7.1-NR) for other regimens (Figure 2). The corresponding rwTTNT and rwOS for erdaftinib, trastuzumab deruxtecan, sacitizumab govitecan reported in Supplement.

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Figure 2.

Kaplan–Meier Curve of A. Real-World Overall Survival (rwOS) and B. Real-World Time to next therapy (rwTTNT).

Discussion

In this large real-world analysis, treatment patterns following progression on EV + pembro were heterogeneous, with carboplatin-based regimens and targeted therapies being the most used second-line therapies. Survival outcomes remained modest, with median rwOS ranging from 7.1 to 14 months.

Another smaller (n = 56), single-institution retrospective study reported that among patients progressing on EV + pembro, platinum-based chemotherapy, primarily gemcitabine combined with cisplatin or carboplatin, was the most common subsequent therapy (68%). This rate is higher than that seen in our dataset, where 48.3% of patients received platinum-based chemotherapy. The reported median PFS was 4.4 months, and median OS was 12 months which is numerically similar to survival estimates in our study. ⁵ Similarly, in a retrospective study of 37 patients treated with first line EV + pembro, 10 received second-line platinum-based chemotherapy (27%). The regimen showed limited activity (median PFS 3.4 months, OS 8.0 months). ⁶ In a retrospective Korean study, there was no significant survival benefit for post-EV chemotherapy or immune checkpoint inhibitors compared to best supportive care. ⁷ Therefore, following progression on EV + pembro, effectiveness of the current available therapeutic options seems to be modest. A recent expert survey and institutional review indicated that, post-EV + pembro, targeted therapies are favored for patients with actionable biomarkers, although their efficacy after this combination has not been specifically demonstrated. ⁸ In the absence of such alterations, platinum-based chemotherapy is the mainstay. For patients with susceptible FGFR3 alterations, erdafitinib is FDA-approved and NCCN-preferred after progression on EV + pembro and chemotherapy. The phase 3 THOR trial demonstrated that erdafitinib significantly improved OS (12.1 vs. 7.8 months) and PFS (5.6 vs. 2.7 months) compared to chemotherapy, with an ORR of 40% and a similar safety profile. ⁹ For HER2-positive IHC 3 + aUC tumors, trastuzumab deruxtecan is also a subsequent-line option ² and has shown a confirmed ORR of 56.3%, median PFS of 7.4 months and OS of 13.4 months in the DESTINY-PanTumor02 Phase II Trial. ¹⁰

The limitations of this study include its retrospective nature, the small sample size, the small number of patients who received second line therapy following EV + pembro, lack of data on genomics, treatment related adverse events, patients and physicians’ preferences, radiographic response rates, baseline disease characteristics, patients’ comorbidities, and subsequent third line therapies was not taken into account which all may render these results exploratory and hypothesis generating.

Conclusion

This is the largest real-world study to date evaluating treatment patterns and outcomes with various second-line therapies after progression on first-line EV pembro in aUC. Platinum-based therapies and targeted therapies are the most common second-line therapies. Median rwOS and rwTTNT were modest across all treatment groups. These findings highlight the limited efficacy of current second-line treatment options in the post-EV + pembro setting, reveal the substantial heterogeneity of treatment patterns in clinical practice and underscore the urgent need for development of novel therapies and sequencing studies in this setting. Our results also provide survival estimates for future trial design and patient counseling.

COIs

V. Tateo: reports personal fees (advisory) and nonfinancial support (travel and accommodation for conferences) from Astellas, personal fees (advisory) and nonfinancial support (travel & accommodation for conference) from Bayer S.p.A., personal fees (speaker) and nonfinancial support (travel & accommodation for conference) from Johnson & Johnson, nonfinancial support (travel & accommodation for conference) from Ipsen S.p.A., and nonfinancial support (travel & accommodation for conference) from Merck Serono outside the submitted work Ciglioli: AstraZeneca: advisory board. Johnson & Johnson: travel support.

S. Gupta: received funding to the institution as PI for research from Mirati Therapeutics, Novartis, Pfizer, Viralytics, Hoosier Cancer Research Network, Rexahn Pharmaceuticals, Five Prime Therapeutics, Incyte, MedImmune, Merck, Bristol Myers Squibb, Clovis Oncology, LSK BioPharma, QED Therapeutics, Daiichi Sankyo/Lilly, Immunocore, Seattle Genetics, Astellas, EMD Serono, Acrotech,Astra Zeneca, VA Merit Award, NCCN. Received research support from Astellas and Oncocyte for collaborative research projects. No direct payments were made to me.

N. Agarwal: has received honoraria before May 2021 and during his lifetime for consulting to Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and has received research funding during his lifetime (to his institution) from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Meyers Squibb, Calithera, Celldex, Clovis, CRISPR Therapeutics, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.

U. Swami: US reports consultancy to Astellas, AstraZeneca, Adaptimmune, Exelixis, Flatiron Health, Gilead, Imvax, Janssen, Kairos, Pfizer, Seattle Genetics, and Sanofi and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics.

Supplemental Material