Platinum-based chemotherapy, such as gemcitabine/cisplatin (GC) or dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (DD-MVAC), has been in an impregnable position as first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC) for more than 30 years. However, the situation will change soon.

Recently, results of 2 pivotal studies on first-line treatment for la/mUC have been published.^1,2 The CheckMate 901 trial (ClinicalTrials.gov identifier: NCT03036098) demonstrated superiority of GC plus nivolumab over GC alone in “cisplatin-eligible” patients with la/mUC.¹ Notably, GC plus nivolumab achieved highly durable complete response of 21.7% and a median CR duration of 37.1 months, suggesting that this regimen might be curative for selected patients if biomarkers could be discovered. Although the results were inconsistent with previous phase 3 trials that assessed the addition of either pembrolizumab (ClinicalTrials.gov identifier: NCT02853305)³ or atezolizumab (ClinicalTrials.gov identifier: NCT02807636)⁴ in “platinum (cisplatin/carboplatin)-eligible” patients, the discrepancies could be explained by the differences in trial settings and thereby in immunomodulatory effects between cisplatin and carboplatin.¹ Nevertheless, based on the CheckMate 901 results, the FDA (US Food and Drug Administration) approved GC plus nivolumab for first-line treatment of adult patients with la/mUC on March 6, 2024. This regimen is the first chemotherapy plus immunotherapy combination approved for la/mUC.

On the other hand, another novel first-line regimen, enfortumab vedotin (EV) plus pembrolizumab, has attracted much attention. This regimen has shown efficacy in “cisplatin-ineligible” patients in cohorts A and K of the phase 1/2 EV-103/KEYNOTE-869 trial (ClinicalTrials.gov Identifier: NCT03288545).^5,6 More recently, the regimen has demonstrated superiority over conventional platinum-based chemotherapy (GC or gemcitabine/carboplatine [GCa]) in “platinum-eligible” patients in the EV-302/KEYNOTE-A39 trial (ClinicalTrials.gov Identifier: NCT04223856).² Based on these epochal results, on December 15, 2023, the FDA approved EV plus pembrolizumab for all patients with la/mUC. This regimen is the first to offer an alternative to first-line platinum-based chemotherapy, or the current standard of care for la/mUC. Aside from the promising oncological outcomes, the new regimen has completely different toxicological profiles (eg, severe rash, hyperglycemia, etc) from current platinum-based ones. Therefore, the careful selection of patients and close monitoring should be considered.

Given that the first-line platinum-based chemotherapy (DD-MVAC, GC, or GCa) will soon be replaced with EV plus pembrolizumab in all patients and/or GC plus nivolumab in cisplatin-eligible patients, the subsequent therapeutic algorithm needs to be substantially revised in the new paradigm. The Figure illustrates current and putative new algorithms for la/mUC. In the current algorithm, platinum-eligible patients undergo first-line platinum-based chemotherapy (DD-MVAC or GC for cisplatin-eligible patients; and GCa for carboplatin-eligible patients). After that, patients who achieved stable disease or better undergo avelumab maintenance, while those who developed progressive disease undergo pembrolizumab. After failure of avelumab or pembrolizumab, EV is the first evidence-based later-line treatment for la/mUC (the EV-301 trial; ClinicalTrials.gov identifier: NCT03474107).⁷ Other options include sacituzumab govitecan (SG) (the TROPHY-U-01 trial; ClinicalTrials.gov identifier: NCT03547973)⁸ and erdafitinib for patients with fibroblast growth factor receptor (FGFR) alterations (the THOR trial; ClinicalTrials.gov identifier: NCT03390504).⁹ On the other hand, platinum-ineligible patients undergo either atezolizumab or pembrolizumab in case of positive programmed cell death ligand 1(PD-L1) status. After failure of atezolizumab or pembrolizumab, EV can be used as later-line treatment. While omitted, conventional chemotherapy (docetaxel, paclitaxel, or vinflunine) can also be used as the last line of each sequence.

In the putative new algorithm, EV plus pembrolizumab, which has just been approved, can be used for all patients, regardless of platinum eligibility. After failure of this first-line regimen, the second-line treatment needs to be stratified according to patients’ platinum eligibility. Platinum-eligible patients undergo platinum-based chemotherapy (DD-MVAC or GC for cisplatin-eligible patients; and GCa for carboplatin-eligible patients), while platinum-ineligible patients can receive erdafitinib in cases of FGFR alterations. After second-line platinum-based chemotherapy in the former patients, those who achieved stable disease or better may undergo avelumab maintenance, while those who developed progressive disease undergo later-line treatment or may undergo rechallenging pembrolizumab (although further discussion is needed of these treatments). As later-line treatment, patients can receive erdafitinib in case of having FGFR alterations, SG, or rechallenging EV. On the other hand, cisplatin-eligible patients may undergo first-line GC plus nivolumab, if the regimen is approved. After its failure, patients can receive EV, SG, or erdafitinib in cases of FGFR alterations. After failure of these second-line therapies, pembrolizumab may be used as later-line treatment. Again, conventional chemotherapy (docetaxel, paclitaxel, or vinflunine) may also be used as the last line of each sequence. As seen above, the new algorithm would be completely different from the current one.

As for limitations of our new algorithm, it does not cover several exceptional cases and/or situations. For example, very frail cisplatin-ineligible patients who are unfit for both EV plus pembrolizumab and GC plus nivolumab may undergo GCa alone as first-line chemotherapy followed by avelumab maintenance (or pembrolizumab if developing progressive disease). On the other hand, prior adjuvant nivolumab may cause a quandary for salvage treatment strategy when metastatic disease occurs. Further studies are warranted for these exceptional cases and/or situations.

In summary, first-line treatment for la/mUC will drastically change soon, and the subsequent therapeutic algorithm needs to be revised accordingly. The treatment strategy for la/mUC should urgently be optimized in the new paradigm to improve the survival of this hard-to-treat disease condition.

Author contributions: S.T. contributed to the conception, study design, analysis, interpretation of data, and drafted the first manuscript. T.K., T.N., and H.K. supervised the study and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Funding: We received no funding/grant support for this study.

Disclosures of Conflicts of Interest: The authors declare that they have no competing interests.