Advancing therapeutic frontiers in urothelial carcinoma: targeted strategies and clinical implications

Introduction

Background

Advanced urothelial carcinoma (aUC) presents a formidable challenge in the medical landscape due to its aggressive nature and widespread prevalence. For decades, platinum-based chemotherapy has served as the primary treatment modality for aUC, achieving a median overall survival (mOS) of 14–15 months (1). However, recent advances in the molecular understanding of urothelial carcinoma and the development of new targeted therapies have changed this scenario and allowed the development of new molecules to treat this disease.

Rationale and knowledge gap

Initially, immune checkpoint inhibitors (ICIs) have exhibited efficacy as monotherapy in patients who have progressed on platinum-based chemotherapy (2). Additionally, targeted therapy with antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) have shown efficacy in multiple trials for aUC post platinum-based chemotherapy (3). The success of these novel treatment options in pre-treated patients has spurred the development of clinical trials evaluating these drugs, alone or in combination, in the frontline setting. Initial evaluations of ICIs against first-line platinum-based chemotherapy, as monotherapy or in combination with chemotherapy, yielded disappointing results in phase 3 trials such as Keynote 361 (4), Imvigor 130 (5), and Danube (6). Conversely, ICIs used as a maintenance strategy after 4–6 cycles of platinum-based chemotherapy for patients who did not progress during chemotherapy demonstrated an OS gain in the Javelin 100 phase 3 trial, with a mOS of 21.4 months for maintenance avelumab vs. 14.3 months for the control arm [hazard ratio (HR) =0.69; P=0.001] (7). Recently, the CheckMate 901 trial demonstrated an OS gain for the combination of nivolumab with cisplatin and gencitabine in untreated aUC patients eligible for receiving cisplatin, with a mOS of 21.7 months for the combination compared with 18.9 months for the control arm (HR =0.78; P=0.02) (8).

ADCs and TKIs are also being evaluated in combination with ICIs, with the combination of enfortumab vedotin (EV) with pembrolizumab, assessed in the large phase trial EV 302 (9), demonstrating impressive and unprecedented results in aUC. The mOS was 31.5 months for the EV-combination arm compared to 16.1 months for the control arm composed of platinum-based chemotherapy (HR =0.47; P<0.001) (9). Despite these significant advances, we still have a lot to learn. For example: how to best select patients for these treatments and how to further improve the effectiveness.

Objective

This article aims to delve into this novel targeted therapy, particularly ADCs and novel TKIs, and review the latest data on these treatment strategies in aUC.

Biomarkers for targeted therapies

The predictive value of biomarkers in aUC remains modest, with only a few biomarkers approved for clinical use, such as fibroblast growth factor receptor (FGFR) (10). Several biomarkers are under review in urothelial cancers, including human epidermal growth factor receptor 2 (HER2), DNA damage response (DDR) proteins, and poly(ADP-ribose) polymerase (PARP), with potential to guide therapies like PARP inhibitors (iPARPs), HER2 inhibitors, and ADCs. However, none of these biomarkers have undergone prognostic validation to date.

The development of molecular and genetic markers is a crucial area that can enhance clinical decision-making. Promising biomarkers serving as predictive and/or prognostic tools include FGFR mutations, epidermal growth factor receptor (EGFR) expression or mutations, HER2 expression, programmed death ligand-1 (PD-L1), tumor mutational burden (TMB), excision repair cross-complementing protein 1 and 2 (ERCC1 and ERCC2), PARP expression, DNA repair mutations, and circulating tumor DNA (ctDNA). FGFR 2/3 alterations have shown to be a valuable predictive biomarker, as demonstrated in the phase III THOR trial, indicating superior survival outcomes, median progression-free survival (mPFS) of 5.6 vs. 2.7 months and mOS of 12.1 vs. 7.8 months, and higher response rates for erdafitinib compared to single-agent chemotherapy (11). Increased expression of phosphorylated epidermal growth factor receptor 3 (pERBB3) appears to be a critical adaptive resistance mechanism to FGFR inhibitors. Combination therapy with a pan-ERBB inhibitor and an FGFR inhibitor may potentially overcome this resistance (12).

The human epidermal growth factor receptor (HER) family plays a significant role in carcinogenesis, cell proliferation, invasion, and metastasis (13). Both HER1/EGFR and HER2 (ErbB-2) are potential targets, with HER2 amplification being linked to unfavorable outcomes in aUC (14). The phase II evaluation of the EGFR-targeted agent cetuximab yielded disappointing results (15), while single-agent monoclonal antibodies or oral small-molecule inhibitors targeting HER2 have also shown limited clinical benefit (16,17). However, anti-HER2/3 ADCs present a promising avenue, with overall response rates reaching as high as 51% in aUC (18).

PD-L1 is a predictive biomarker for immunotherapy response in various cancer types; however, its predictive value in aUC appears inconsistent, with conflicting data from different studies. For instance, the phase II Imvigor210 trial demonstrated similar response rates between PD-L1(+) and PD-L1(−) subgroups when treated with atezolizumab (19). The phase III JAVELIN Bladder 100 trial revealed a 1-year survival enhancement with avelumab maintenance therapy (71.3% vs. 58.4%) irrespective of PD-L1 expression. While the overall benefit appears more pronounced in the PD-L1-positive group, it remains significant in both populations (7).

Urothelial carcinoma exhibits a notably high TMB (20), which consistently predicts response to ICIs in several aUC trials. For instance, in the CheckMate 275 study, nivolumab demonstrated improved PFS, OS, and objective response rate (ORR) in high-TMB patients compared to the overall study population (21). Similar associations between higher TMB and increased response rate were observed in the IMvigor 210 and PURE-01 trials evaluating atezolizumab and pembrolizumab, respectively (22,23).

Biomarkers associated with DDR pathways and PARP expression or activity hold potential as prognostic and predictive markers, although their value has not been consistently demonstrated. Reduced DNA repair capacity due to mutations or inactivation in these repair mechanisms has been linked to heightened sensitivity to cisplatin-based chemotherapy and iPARPs (24-26).

ADCs

The ideal systemic anti-cancer treatment should maximize its effect on malignant cells while sparing healthy cells from off-target toxicity, a concept envisioned by Paul Ehrlich in 1907 (27). Traditional chemotherapy and targeted therapies, such as TKIs, have yet to achieve the “magic bullet” ideal. To address this challenge, ADCs were developed to deliver therapeutic agents specifically to tumor cells expressing certain antigens.

ADCs comprise four components: a target antigen, a monoclonal antibody, a linker molecule binding the payload to the antibody, and the cytotoxic payload. Upon antibody binding and internalization via endocytosis, the payload is released in a bioactive form (28). Various antigen targets have been identified in urothelial carcinoma, prompting exploration of ADCs in aUC patients. Table 1 summarizes the results of clinical trials evaluating ADCs for aUC patients.

Targeting Nectin-4

EV is an ADC consisting of monomethyl auristatin E (MMAE), which destabilizes microtubule formation, linked to a protease-cleavable linker and a fully human IgG1 kappa antibody targeting the junction protein Nectin-4 (44). Poliovirus receptor-related protein 4 (PVRL4), also known as Nectin-4, is a type I transmembrane polypeptide and a member of the immunoglobulin-like nectin family. While functioning as an adhesion molecule in normal cells, it exhibits low expression in normal tissues but is highly expressed in certain tumors. In bladder, for instance, we have data showing overall positive expression rates of 83% (45). This elevated expression makes Nectin-4 a promising therapeutic target in urothelial carcinoma.

In the phase I study EV-101, EV demonstrated an ORR of 43% in heavily pretreated patients with aUC (29). To further evaluate its efficacy, the phase II trial EV-201 was conducted, comprising two distinct cohorts. Cohort 1 included 125 patients with aUC who had experienced disease progression or recurrence after platinum-based chemotherapy or immunotherapy. In this cohort, an ORR of 44% was observed, with 15 complete responses (12%) (30). For context, single-agent chemotherapy following platinum and ICI progression typically yields lower response rates, approximately around 14% (46). Based on the results from cohort 1 of the EV-201 trial, EV received accelerated approval from the United States Food and Drug Administration (FDA) in 2019 for progressive aUC refractory to platinum-based chemotherapy and PD-1/PD-L1 inhibitors.

The phase III trial EV-301 compared EV, dose of 1.25 mg/kg on days 1, 8, and 15 of each 28-day, with physician’s choice chemotherapy (either taxmen or vinflunine) in 608 patients with aUC who progressed after platinum-based chemotherapy and ICIs. EV demonstrated a significant improvement in mOS by 3.91 months (12.88 vs. 8.97 months, HR =0.70; P=0.001) and longer PFS with 5.55 vs. 3.71 months (HR =0.62; P<0.001) (44). Long-term outcomes confirmed EV’s efficacy, leading to FDA approval for aUC in patients who progressed after first-line systemic treatment (31).

In the first-line setting, EV alone or with pembrolizumab was evaluated in Cohort K of the phase Ib/II study EV-103 for cisplatin-ineligible patients. The trial randomly assigned 151 patients in a 1:1 ratio to two arms without performing any statistical comparison between them. EV plus pembrolizumab demonstrated an ORR of 64.5% [95% confidence interval (CI): 52.7–75.1%], with mOS of 22.3 months (95% CI: 19.09–not reached), while EV monotherapy showed an ORR of 45.2% (95% CI: 33.5–57.33%) (32). The FDA granted accelerated approval for the combination therapy.

The phase III trial EV-302/KEYNOTE-A39 further assessed the synergistic effect of EV and ICIs. This study compared the combination of EV plus pembrolizumab with platinum-based chemotherapy (gemcitabine associated with cisplatin or carboplatin) in previously untreated patients with aUC. The final outcome analysis was finished in August 2023 with 886 patients recruited. The experimental treatment significantly improved mPFS (12.5 vs. 6.3 months, HR =0.45; 95% CI: 0.38–0.54; P<0.001) and mOS (31.5 vs. 16.1 months, HR =0.47; 95% CI: 0.38–0.58; P<0.001). The combination showed a better response rate with an ORR of 67.7% vs. 44.4% for the chemotherapy arm (P<0.001) (9). This study highlights the association of EV and pembrolizumab as the new potential standard of care in first line.

Treatment-related adverse events (TRAEs) were notable, with over 50% grade 3 side effects in EV studies. Common TRAEs included alopecia, peripheral sensory neuropathy, pruritus, and fatigue. Hyperglycemia was observed, particularly in diabetic and overweight patients, with 19 reported cases in the EV-301 study, including one death (9,44).

Targeting TROP2

Sacituzumab govitecan (SG) is a therapeutic agent consisting of an IgG1 kappa antibody fused with SN-38, the active metabolite of irinotecan, a topoisomerase I inhibitor (36). The antibody targets TROP2, a transmembrane calcium signal transducer expressed in healthy multi-stratified epithelial and trophoblast cells, as well as in various carcinomas. TROP2 is involved in intracellular signaling pathways governing cell proliferation, migration, and adhesion. Higher TROP2 expression is particularly evident in invasive bladder cancer compared to non-invasive bladder cancer and normal urothelium. Moreover, increased TROP2 expression correlates positively with disease severity, suggesting its potential as both a prognostic marker and a therapeutic target (47-49).

The TROPHY-U-01 trial, a phase II study comprising multiple cohorts, investigated the efficacy of SG, dose of 10 mg/kg SG intravenously (IV) on D1 and D8 every 3 week (Q3W), in aUC. In Cohort 1, consisting of 113 patients who had previously received platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 therapy, SG demonstrated an ORR of 27% (95% CI: 19.5–36.6%), with six confirmed complete responses. mPFS was 5.4 months (95% CI: 3.5–7.2), and mOS was 10 months (95% CI: 9–13.8) (36). Based on these findings, SG received accelerated approval from the FDA for aUC patients who had previously received platinum-based chemotherapy with PD-1/PD-L1 inhibitors in 2021. The phase III Tropics-04 study aims to validate these results in patients who progressed after platinum-based chemotherapy and PD-1/PD-L1 inhibitors (NCT04527991).

In Cohort 3, comprising 61 patients with platinum-refractory aUC who had not undergone immunotherapy, SG plus pembrolizumab demonstrated an ORR of 34% and a 6-month PFS of 47% (37). Cohort 2 is evaluating SG after first-line immunotherapy only, and Cohorts 4 and 5 are investigating its combination with cisplatin, with or without avelumab, or induction therapy with the anti-PD-1 antibody zimberelimab, followed by maintenance therapy with avelumab or zimberelimab.

The most common grade ≥3 TRAEs observed in the TROPHY-U-01 trial were myelotoxicity-related, including neutropenia (35%, including 10% febrile neutropenia), leucopenia (18%), anemia (14%), and diarrhea (10%) (37).

The Double Antibody Drug Conjugate (DAD) study investigated the combination of SG and EV in patients with aUC who had prior progression on platinum-based chemotherapy and/or ICIs. This phase I trial enrolled 24 patients to assess the feasibility and toxicity of the combined treatment. Results showed an impressive ORR of 70% (95% CI: 47–87%), with 86% of patients alive after 12 months, and 41% experiencing no disease progression during this period. However, notable toxicities included diarrhea (87%) and neuropathy (57%), while myelotoxicity was observed in 35% of patients with grade 3 anemia and neutropenia. Based on the toxicity profile, the recommended phase II doses were determined as SG 10 mg and EV 1.25 mg/kg, both administered on days 1 and 8 every 21 days. The DAD-IO trial will further evaluate the combination of this antibody conjugate doublet, either alone or in combination with pembrolizumab (43).

Targeting SLITRK6

Sirtratumab vedotin (SV) is a novel ADC that combines an IgG2 antibody targeting the transmembrane protein SLITRK6 with MMAE via a protease-cleavable linker. The SLITRK family, consisting of six members, is primarily expressed in the central nervous system, where they regulate neuronal cell growth and synaptic development (50,51). Pre-clinical study have demonstrated SLITRK6 expression in 88% of tested samples, with 100% expression observed in metastatic bladder tumors (51).

The safety and pharmacokinetic profile of SV were assessed in a phase I dose-escalation, IV at six levels (0.10 to 1.25 mg/kg), trial involving 93 patients with aUC. The trial reported an ORR of 18.3%, with 17 partial responses in the total study population. The median duration of response (DOR) was 15 weeks, and the mPFS was 16 weeks. The most significant TRAEs included fatigue (54.8%), nausea (37.6%), and reduced appetite (35.5%). Notably, there were 27 cases of ocular toxicity, two of which were grade 3 (40). Despite these preliminary findings, comprehensive efficacy data for SV remains to be further explored.

Targeting HER2

HER2 is a type I transmembrane protein belonging to the ERBB family, playing a crucial role in activating signaling pathways associated with tumorigeneris (13), making it a significant therapeutic target in breast and gastric cancers (52,53). In urothelial cancer, HER2 is the third most prevalent malignancy with overexpression rates ranging from 6% to 12.4% (54,55). Despite this prevalence, the efficacy of HER2-targeting agents in urothelial carcinoma remains under investigation.

Trastuzumab emtansine (T-DM1), the first ADC to receive FDA approval, combines an anti-HER2 humanized antibody with the anti-microtubule agent DM-1 via a non-cleavable linker. In a basket trial involving 58 patients, including 4 with urothelial cancer, the ORR was 26%, with a median DOR of 8 months. However, none of the urothelial cancer patients responded to T-DM1 (56). The KAMELEON study, a single-arm, non-randomized phase II trial, aimed to evaluate T-DM1’s (2.4 mg/kg once weekly or 3.6 mg/kg Q3W) efficacy in bladder cancer, cholangiocarcinoma, and pancreatic cancer. Among the 20 enrolled patients, 13 had urothelial carcinoma, with an ORR of 38.5%. However, due to recruitment issues, the study was prematurely terminated without meeting its primary endpoints (38).

The novel ADC disitamab vedotin (DV) combines a new-generation humanized anti-HER2 antibody, hertuzumab, with MMAE via a cathepsin-cleavable linker (57). Its efficacy and safety, at a dose of 2 mg/kg IV every 2 weeks (Q2W), were evaluated in two phase II single-arm studies recruiting patients with HER2-positive aUC that had progressed after at least one line of systemic treatment. The combined analysis of 107 patients showed an ORR of 50.5% (95% CI: 40.6–60.3%), with a higher response rate observed in patients with 3+ in IHC or with 2+ and fluorescence in situ hybridization (FISH) +. The median DOR was 7.3 months (95% CI: 5.7–10.8). mPFS was 5.9 months (95% CI: 4.3–7.2), and mOS was 14.2 months (95% CI: 9.7–18.8) (39). DV was also evaluated in patients with aUC HER2 negative (IHC 0 or 1+) and ≥1 prior systemic treatment. Notably, all patients with HER2 0 in IHC had stable disease. The ORR was 26.3% (95% CI: 9.1–51.2%). mPFS and mOS were 5.5 months (95% CI: 3.9–6.8) and 16.4 months (95% CI: 7.1–21.7 months), respectively (41). The main TRAEs reported in the combined analysis of phase II trials with DV were peripheral neuropathy (68.2%, 18.7% of them grade 3), leucopenia (50.5%), and aspartate aminotransferase (AST) increase (42.1%). Neutropenia was reported in 42.1% of the patients, with 12.1% of them grade 3 (39).

DV was also evaluated in combination with ICIs. Preliminary results from a phase Ib/II trial accessed the safety and activity of the combination of DV (2 mg/kg IV Q2W) and the anti-PD-1 toripalimab (3 mg/kg Q2W) in patients with aUC. The study showed promising efficacy, with an ORR of 73.2% (95% CI: 57.1–85.8%) (42). An ongoing phase II trial is assessing DV with or without pembrolizumab in patients with HER2-expressing aUC, with three cohorts focusing on different treatment lines and HER2 expression levels (NCT04879329).

Trastuzumab deruxtecan (T-Dxd) combines an anti-HER2 antibody with a topoisomerase I inhibitor payload via a cleavable linker. Its higher drug-to-antibody ratio (DAR) (8:1) and cytotoxic effect, explain the efficacy of this ADC in scenarios such as HER2-low metastatic breast cancer (58,59). The phase II basket trial DESTINY-PanTumor02 evaluated T-Dxd (5.4 mg/kg Q3W) in patients with metastatic tumors refractory to at least one line of systemic treatment and a HER2 expression of 3+ or 2+ in IHC. Two hundred sixty-eight patients were enrolled, 41 of them with bladder cancer. After a median follow-up of 12.75 months, the ORR for the entire population was 37.1% (95% CI: 31.3–43.2%), mPFS was 6.9 months (95% CI: 5.6–8), and mOS was 21.1 months (95% CI: 15.3–29.6). The bladder cancer cohort reported an ORR of 39% (95% CI: 24.2–55.5%), with one complete response. mPFS in the bladder cancer cohort was 7 months (95% CI: 4.2–9.7), and mOS was 12.8 months (95% CI: 11.2–15.1) (34).

The combination of T-Dxd at 5.4 mg/kg and nivolumab 360 mg IV Q3W, was investigated in a phase Ib/II trial with 34 patients with HER2-positive aUC. The primary analysis showed an ORR of 36.7% (95% CI: 19.9–56.1%) with 4 complete responses. The median DOR was 13.1 months (95% CI: 4.1–not evaluable). Drug-related pneumonitis occurred in 23.5% of the patients (35).

TKIs

In the context of aUC, immunotherapy, cytotoxic chemotherapy, and, more recently, ADCs represent fundamental components of systemic treatment. However, there remains a critical need to enhance therapeutic outcomes. The exploration of combination therapies and the strategic sequencing of these treatments are pivotal endeavors.

Protein kinases play critical regulatory roles in signaling pathways and cellular mechanisms, including proliferation, differentiation, survival, and apoptosis (60). Tyrosine kinases, found in nuclear and membrane-bound forms, act as transmembrane receptors, often upregulated in tumors, crucial for cancer initiation and progression. TKI strategies show effectiveness in targeted tumor therapies (60).

For aUC, the presence of mutations or overexpression of tyrosine kinases significantly accelerates tumor proliferation and progression (61). Given the considerable heterogeneity in behavior and aggressiveness of aUC, gene expression profiling and molecular pathway analysis emerge as promising modalities for evaluating patient prognosis and guiding treatment selection (61). Table 2 summarizes the results of clinical trials evaluating TKIs for aUC patients.

FGFR

The FGFR family is made of four genes: FGFR1–4 (76). They regulate angiogenesis in adults and in embryonic development, as well as cell migration, survival and proliferation (77). Molecular alterations, such as mutations and fusions, are prevalent in aUC and are related to carcinogenesis (78). These molecular alterations can be found in up to 20% of patients with bladder aUC and 37% in those with upper tract urothelial carcinoma (79,80).

In 2019, erdafitinib, an FGFR1–4 TKI, became the first targeted therapy approved for aUC, based on the BLC2001 study, which demonstrated its efficacy in chemotherapy-refractory patients with FGFR molecular alterations (62). A 24-month follow-up confirmed its efficacy, with an ORR of 40% (95% CI: 31–50%) and a mPFS of 5.5 months (95% CI: 4.2–6.0). Among these patients, 46% experienced TRAEs of grade 3 or higher. Hyperphosphatemia (77%), stomatitis (58%), diarrhea (51%), and dry mouth (46%) were the most common TRAEs of any grade. Common TRAE of grade 3 or higher were stomatitis (10%), hyponatremia (10%) and asthenia (7%) (62).

The Phase 3 THOR study assessed erdafitinib (8 mg orally once daily) vs. standard chemotherapy (Cohort 1) or pembrolizumab (Cohort 2) in aUC patients with susceptible FGFR3/2 alterations. In Cohort 1, patients must have progressed during or after one or two prior systemic therapy regimens including an ICI. Patients were randomized to erdafitinib or chemotherapy (docetaxel or vinflunine). Erdafitinib significantly increased OS with a median of 12.1 vs. 7.8 months for chemotherapy (HR =0.64; P=0.005) and improved mPFS (5.6 vs. 2.7 months, HR =0.58; 95% CI: 0.44–0.78). The erdafitinib group had a higher ORR compared to chemotherapy (45.6% vs. 11.5%; P<0.001). Grade 3 and 4 TRAE occurred in 45.9% of patients receiving erdafitinib. The most common grade 3 TRAEs were palmar-plantar erythrodysesthesia syndrome (9.6%), stomatitis (8.1%), and onycholysis (5.9%) in the erdafitinib group. Hyperphosphatemia of any grade occurred in 80% of patients receiving erdafitinib (11).

Cohort 2 evaluated aUC patients who progressed on one prior line of systemic treatment and had not received ICIs (81). Patients were randomized to erdafitinib or pembrolizumab (200 mg IV Q3W). There were no significant differences in OS (HR =1.18; 95% CI: 0.92–1.51; P=0.18) or PFS (HR =0.88; 95% CI: 0.70–1.10) between erdafitinib and pembrolizumab. mOS for erdafitinib was 10.9 months (95% CI: 9.2–12.6) vs. 11.1 months for pembrolizumab (95% CI: 9.7–13.6), and mPFS 4.4 months (95% CI: 4.1–5.5) and 2.7 months (95% CI: 1.6–3.0), respectively. The ORR was higher with erdafitinib at 40% vs. 21% for pembrolizumab. Hyperphosphatemia (72.8%), stomatitis (45.1%), and diarrhea (44.5%) were the most common TRAEs of any grade in the erdafitinib group (63).

Other FGFR inhibitors are currently under investigation. In a phase I trial, infigratinib, a selective FGFR 1–3 TKI, was administered orally once daily in a 28-day cycle (21 days on, 7 days off) at a starting dose of 125 mg per day. Eligible patients had received prior platinum-based chemotherapy or were ineligible for such treatment. Of the 67 enrolled patients, 13 (19.4%) received infigratinib as first-line therapy due to ineligibility for platinum-based chemotherapy. The ORR was 30.8% (95% CI: 9.1–61.4%) for first-line patients and 24.1% (95% CI: 13.5–37.6%) for second-line or later patients. Among all 67 patients, there were no significant differences in mPFS and OS times between early-line and salvage scenarios. The most common TRAEs, of any degree, were increased creatinine (40.3%), fatigue (38.8%), and hyperphosphatemia (38.8%) (64).

In the phase II/III randomized, open-label FORT-1 trial, rogaratinib (an FGFR1–4 inhibitor) at a dose of 800 mg orally twice daily was compared with second-line chemotherapy (either a taxane or vinflunine) in 175 eligible patients. Results indicated that rogaratinib did not improve OS or PFS despite showing similar antitumor activity. The ORRs were 20.7% (95% CI: 12.7–30.7%) with rogaratinib and 19.3% (95% CI: 11.7–29.1%) with chemotherapy. mOS was 8.3 months (95% CI: 6.5–not estimable) with rogaratinib and 9.8 months (95% CI: 6.8–not estimable; HR =1.11; P=0.67) with chemotherapy. mPFS was 2.7 months (95% CI: 1.6–4.6) with rogaratinib and 3.2 months (95% CI: 2.7–4.4) (HR =1.23; P=0.86). Grade 3 TRAE occurred in 43% of patients receiving rogaratinib and 39% of patients receiving chemotherapy. Six patients (7.0%) receiving rogaratinib had grade ≥2 retinal disorders. Gastrointestinal toxicities were among the most frequently reported adverse effects, with hyperphosphatemia being the second most frequent adverse effect associated with rogaratinib (65).

Evaluations of combination regimens, such as FGFR inhibitors with immunotherapy, present new therapeutic prospects. The phase 2 NORSE study investigated erdafitinib (8 mg orally once daily) alone or in combination with the anti-PD-1 cetrelimab (240 mg IV Q2W) in first-line cisplatin-ineligible metastatic urothelial cancer (mUC) patients with FGFR alterations (mutations/fusions). Out of 87 enrolled patients, results favored erdafitinib plus cetrelimab over erdafitinib alone. The combination demonstrated an ORR of 54.5% (95% CI: 38.8–69.6%) vs. 44% (95% CI: 29.1–60.1%) for erdafitinib alone. mPFS was 10.97 months (95% CI: 5.45–13.63) vs. 5.62 months (95% CI: 4.34–7.36) with erdafitinib alone. Median DOR was 11.1 months (95% CI: 8.77–NE) vs. 9.72 months (95% CI: 4.60–NE) (66).

Similarly, the FORT-2 study reported promising outcomes for rogaratinib plus atezolizumab combination therapy, although caution is advised due to a potential increase in grade 3 and 4 adverse events. In the FORT-2 phase Ib/II trial, the safety and efficacy of first line rogaratinib (600 mg oral twice daily) plus atezolizumab (1,200 mg IV Q3W) were analyzed in cisplatin-ineligible patients with FGFR 1–3 mRNA overexpression. The overall disease control rate was 68% (95% CI: 47–85%), with an ORR of 44% (95% CI: 24–65%), including four complete responses. The most frequent TRAEs were nausea (42%), hyperphosphatemia (58%), and diarrhea (65%). Grade 3/4 TRAE included elevated lipase without pancreatitis (19%), elevated amylase (12%), rash (2.8%), and syncope (2.8%). The maximum tolerable dose of rogaratinib was established at 600 mg twice daily (67).

Vascular endothelial growth factor receptor (VEGFR)

Angiogenesis plays a significant role in carcinogenesis of most cancers including urothelial carcinoma. The role of VEGFR in aUC has been extensively investigated (82). C-MET, a cell surface tyrosine kinase receptor primarily expressed in epithelial cells (83), is linked to a poorer prognosis and shorter OS in patients with muscle-invasive bladder cancer (84). Cabozantinib, a non-selective TKI targeting c-Met, VEGFR2, FLT3, KIT, AXL, and RET, is being explored in aUC, showing promise both alone and in combination with ICIs (68).

A phase II trial at the National Cancer Institute assessed cabozantinib in platinum-refractory aUC and rare genitourinary histologies. Cohort 1 comprised platinum-refractory aUC patients with measurable disease, while Cohorts 2 and 3 were exploratory. Cabozantinib at 60 mg/day yielded a clinical benefit of 64.3%, with an ORR of 19.1% and mPFS and mOS of 3.7 and 8.1 months, respectively. Grade 3–4 TRAEs were fatigue (9%), hypertension (7%), proteinuria (6%) and hypophosphatemia (6%). The study showed that cabozantinib has innate and adaptive immunomodulatory qualities that may combat tumor-induced immunosuppression, according to exploratory translational assessments (68). This justifies integrating cabozantinib with ICIs.

In another phase I study, cabozantinib plus nivolumab and cabozantinib plus nivolumab and ipilimumab were evaluated in aUC and other genitourinary malignancies. Recommended phase 2 doses were established at cabozantinib 40 mg/day plus nivolumab 3 mg/kg and cabozantinib 40 mg/day, nivolumab 3 mg/kg and ipilimumab 1 mg/kg. The ORR in aUC patients was 38.5%, with a mPFS of 12.8 months and mOS of 25.4 months. Grade 3 or 4 TRAEs occurred in 87% of patients receiving cabozantinib and nivolumab plus ipilimumab and 75% in patients treated with cabozantinib and nivolumab and fatigue (10% and 17%, respectively), diarrhea (7% and 4%, respectively) and hypertension (10% and 21%, respectively) were the most common (69). Subsequently, a study assessed cabozantinib plus nivolumab in aUC patients who progressed on previous ICIs, reporting an ORR of 16.0% and mPFS and mOS of 3.6 and 10.4 months, respectively (70).

The COSMIC-021 trial evaluated cabozantinib 40 mg daily and atezolizumab 1,200 mg IV Q3W in solid tumors, showing an ORR of 27% in aUC patients previously treated with platinum-based chemotherapy (Cohort 2). Cohorts 3, 4, and 5 investigated this combination in locally advanced or metastatic urothelial carcinoma, with ORRs ranging from 10% to 30% and mOS ranging from 8.2 to 14.3 months (72) (Table 2). Additionally, cabozantinib is under evaluation with avelumab in the MAIN-CAV trial for maintenance therapy after platinum-based chemotherapy.

In patients with cisplatin-ineligible and PD-L1-positive aUC, defined as having a combined positive score (CPS) of ≥10, the LEAP-011 trial, a randomized phase III study, evaluated the efficacy of first-line treatment with pembrolizumab (200 mg IV Q3W) plus the broad-spectrum tyrosine-kinase inhibitor lenvatinib (20 mg orally) compared to pembrolizumab plus placebo. The study found no significant differences in mPFS and mOS between the two groups. mPFS was 4.5 months in the combination arm vs. 4.0 months in the pembrolizumab arm (HR =0.90; 95% CI: 0.72–1.14), and mOS was 11.8 vs. 12.9 months, respectively (HR =1.14; 95% CI: 0.87–1.48). However, the combination arm showed increased toxicity, with grade 3 or higher TRAEs occurring in 51% of patients compared to 27% in the control arm (85).

The phase II PemCa trial investigated pembrolizumab (200 mg IV Q3W) plus cabozantinib (40 mg orally once daily) as first-line therapy in aUC patients ineligible for cisplatin-based chemotherapy. Patients with PD-L1 CPS ≥10 or ineligible for platinum-based chemotherapy, irrespective of PD-L1 status, were eligible. Out of 36 patients, 22% were PD-L1 positive. The ORR was 46% (95% CI: 30.5–61.8%), with a median follow-up of 14.3 months. mPFS was 7.6 months (95% CI: 5.3–12.6) and mOS 17.1 months (95% CI: 12.6–not estimable). Grade ≥3 TRAEs occurred in 50% of patients, with fatigue (63.9%), diarrhea (58.3%), and palmar-plantar erythrodysesthesia syndrome (41.7%) being the most common (73).

Sitravatinib, a multi-TKI targeting various receptors, including VEGFR and MET, was assessed in a phase 2 multi-cohort study in combination with nivolumab for aUC patients. Eight cohorts were enrolled based on prior treatments and tested the combination of sitravatinib (120 mg once daily or 100 mg once daily) and nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks IV), depending on prior treatment with ICIs, platinum-based chemotherapy, or ADC. mPFS varied from 3.5 to 7.8 months, while the ORR varied amongst the groups from 0% to 33% (Table 2). Cohort 5, comprising patients who had previously received platinum-based chemotherapy but no ICI, exhibited the highest ORR of 32.1% (95% CI: 19.9–46.3%) with a mPFS of 3.9 months (95% CI: 3.5–5.7). Cohort 2, which evaluated 23 patients, who had previously received immunotherapy but were not eligible for platinum, had an ORR of 21.7% and the longest mPFS of 7.79 months (95% CI: 3.94–14.62). The most frequent TRAEs were diarrhea (55.3%), fatigue (50.8%), decreased appetite (38.5%), dysphonia (34.8%) and vomiting (29.9%) (74).

XL092 (zanzalintinib), an oral inhibitor targeting MET, VEGFR2, and TAM kinases, is under investigation for advanced solid tumors, including urothelial carcinoma, after one prior platinum-based regimen and no prior immunotherapy. Preclinical studies showed anti-tumor activity and synergy with immunotherapy agents. A phase 1b study (NCT05176483) will assess XL092’s safety and clinical activity alone and in combination therapies (86).

EPH

The relationship between cell migration and neoplastic transformation is closely associated with Eph receptor tyrosine kinases and their ephrin ligands. Particularly, EphB4, which interacts with EphrinB2, plays a pivotal role in angiogenesis. Inhibiting EphB4 could potentially induce apoptosis and impede tumor growth (87). A phase II study evaluated EphB4 inhibition using soluble EphB4-human serum albumin (sEphB4-I) in combination with pembrolizumab in patients with aUC who had relapsed or progressed after platinum-based therapy. The study reported a mOS of 14.6 months (95% CI: 9.2–21.5), with patients expressing Ephrin-B2 showing an OS of 21.5 months (95% CI: 12.4–not reached) and a complete response rate of 24% (11 of 46; 95% CI: 12–36%). The most common TRAE of any grade were hypertension (74%), fatigue (44%), and anemia (17%), with 46% of patients experiencing grade 3 or 4 hypertension (75). Currently, a phase II study is ongoing to further investigate this combination in aUC, including cohorts for first-line treatment and those previously treated, with a focus on patients exhibiting a positive biomarker for EphrinB2 (NCT04486781).

iPARPs

Up to 25% of aUC patients carry mutations in various genes involved in the DDR, including BRCA1, BRCA2, ERCC2, and ATM, as revealed by extensive genome sequencing studies. One strategy to impede the repair of single-strand DNA breaks is through pharmacological inhibition of PARP. Consequently, iPARPs induce excessive DNA damage, leading to cancer cell death in the context of homologous recombination deficiency (HRD) (88,89).

The ATLAS study assessed the efficacy of the iPARP rucaparib (600 mg orally twice daily) as monotherapy in 97 previously treated aUC patients. HRD-positive tumors were identified in 21% of patients, HRD-negative tumors in 30%, and HRD status undetermined in 48%. mPFS did not significantly differ between HRD-positive and HRD-negative tumors (1.4 vs. 1.8 months). The three most common any-grade TRAEs were anemia (36.1%), nausea (42.3%), and asthenia/fatigue (57.7%) (90).

Initial data from the BAYOU trial, a randomized phase II study, compared an ICI with an iPARP. This trial evaluated durvalumab (1,500 mg IV every 4 weeks) in combination with olaparib (300 mg orally twice daily) or placebo for untreated patients with aUC ineligible for platinum-based chemotherapy. A total of 154 patients were randomized. In the intention-to-treat (ITT) group, there was no significant difference in mPFS between the combination and durvalumab alone arms. mPFS was 4.2 months (95% CI: 3.6–5.6) in the combination group vs. 3.5 months (95% CI: 1.9–5.1) in the durvalumab alone group (HR =0.94; P=0.78). In the subgroup of patients with homologous recombination repair gene mutations (HRRm), mPFS was 5.6 months (95% CI: 1.9–8.1) for the combination group vs. 1.8 months (95% CI: 1.7–2.2) for durvalumab monotherapy (HR =0.18; 95% CI: 0.06–0.47). Grade 3 or 4 TRAEs occurred in 18% and 9% of patients, respectively (25).

Targeting DDR signaling pathways may potentially be a successful strategy in patients with aUC, although the results of studies testing iPARPs that did not meet the primary endpoint, and the current outcomes with these drugs, introduce uncertainty. Nonetheless, alternative approaches utilizing these drugs are under investigation, such as the NICARAGUA study (NCT03397394), which is exploring niraparib plus cabozantinib in unselected patients with treatment-refractory aUC.

Conclusions

In this article, we explore the latest therapeutic advancements in the treatment of aUC, a challenging disease due to its aggressive nature and widespread prevalence. Traditionally, platinum-based chemotherapy has been the mainstay treatment modality for decades. However, in recent years, we have witnessed the emergence of new therapeutic options such as ICIs and targeted therapy with ADCs, and TKIs. Recent clinical trials have demonstrated the efficacy of these approaches, both as monotherapy and in combination, in patients with platinum-refractory aUC. Promising results from trials such as EV-302/KEYNOTE-A39 have highlighted the combination of EV with pembrolizumab as a new standard of care in the first-line setting. Additionally, targeted therapies such as ADCs targeting TROP2 and HER2 and TKIs for receptors like FGFR, VEGFR and c-MET are also emerging as promising strategies. While these advancements have significantly improved treatment outlooks, challenges remain, such as managing TRAE and identifying predictive biomarkers of response. However, it is undeniable that we are witnessing a transformation in the treatment paradigm of aUC, providing patients with new hopes and opportunities for prolonged survival and improved quality of life.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-67/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-67/coif). D.M.G. reports that he has taken part as invites speaker for Pfizer, Merck, BMS Brazil, Jansen oncology, Bayer, Adium Brazil and Ipsen. He has received support from Pfizer, Ipsen and Adium for meeting registration, accommodation and/or travel expense. Additionally, he has received consulting fees from BMS Brazil and Jansen Oncology and has received payment for expert testimony from Jansen Oncology. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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