Advances in antibody-drug conjugates for urothelial carcinoma treatment

EV

Nectin-4, which is overexpressed in various cancers including UC, is targeted by EV, an anti-Nectin-4 ADC comprising a human IgG1 antibody linked to monomethyl auristatin E (MMAE) via a protease-cleavable linker⁴. MMAE is a potent microtubule-disrupting agent that, after internalization and payload release within tumor cells, inhibits cell division and induces apoptosis. EV has markedly reshaped the mUC treatment landscape (Table 1).

In December 2019, the FDA granted accelerated approval for EV as the first ADC for locally advanced or metastatic UC (la/mUC), on the basis of the phase II EV-201 trial (NCT03219333). In platinum- and ICI-pretreated patients (cohort 1, n = 125), the objective response rate (ORR) was 44%, and the complete response (CR) rate was 12%, whereas in cisplatin-ineligible patients (cohort 2, n = 89), the ORR was 52%, and the CR was 20%⁴. Before EV-201, single-agent chemotherapy was the standard third-line treatment; however, it resulted in poor outcomes. Despite comorbidities (12% Eastern Cooperative Oncology Group Performance Status 2, 13% hearing loss, and 69% creatinine clearance < 60 mL/min), EV-201 showed the highest ORR among monotherapy trials for locally advanced/metastatic UC (la/mUC).

The phase III EV-301 trial (NCT03474107) led to full FDA approval in 2021. EV, compared with chemotherapy, significantly increased overall survival (OS) (median 12.9 vs. 8.9 months; hazard ratio 0.70, P = 0.00015) and progression-free survival (PFS). The ORRs were 41.3% for EV and 18.6% for chemotherapy. All-grade and grade ≥3 treatment-related adverse events (TRAEs) were similar between groups, although EV was associated with distinct toxicities, including alopecia (45.6%), peripheral sensory neuropathy (34.8%), pruritus (32.4%), and fatigue (31.4%), and the most common grade ≥3 events were maculopapular rash (7.4%) and fatigue (6.8%)⁶. Notably, EV carries risks of severe and occasionally fatal skin-associated TRAEs, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

In 2023, on the basis of EV-103 cohort K (NCT03288545), the FDA granted accelerated approval for EV plus pembrolizumab (EV+P) in cisplatin-ineligible patients⁷. The confirmatory phase III EV-302 trial (NCT04223856) demonstrated that EV+P, compared with chemotherapy, significantly increased OS (33.8 vs. 15.9 months; hazard ratio 0.51, P < 0.00001) and PFS. The benefits were consistent across cisplatin-eligible and cisplatin-ineligible patients, and in subgroups with visceral or lymph node metastases. The ORRs were 67.5% and 44.2%, and the CR rates were 30.4% and 14.5%, respectively. EV+P was well tolerated, with peripheral sensory neuropathy (50%), pruritus (39.8%), and alopecia (33.2%) as the most common TRAEs, whereas chemotherapy was most frequently associated with anemia and neutropenia. Grade ≥3 AEs occurred in 55.9% of the EV+P group and 69.5% of the chemotherapy group⁸. EV+P demonstrated remarkable efficacy: with respect to chemotherapy, this treatment achieved a doubled OS and the highest ORR, with a manageable safety profile. On the basis of these results, the FDA granted full approval in 2023 for EV+P as a first-line therapy for la/mUC, and this treatment was rapidly integrated into clinical practice.

SHR-A2102

SHR-A2102 is a novel Nectin-4-targeted ADC composed of a fully human IgG1 antibody, a cleavable linker, and a topoisomerase I inhibitor. In a phase I trial (NCT05735275) in 81 patients with la/mUC, 57.5% had received ≥2 prior systemic therapies, and 42.5% had prior exposure to disitamab vedotin (DV), a HER2-directed ADC delivering MMAE. On the basis of safety, 6 mg/kg and 8 mg/kg were selected for dose expansion. The ORR was 38.3%, and the response was greater at 8 mg/kg (50.0%) than 6 mg/kg (41.9%). The mPFS was 5.8 months. These findings suggested that SHR-A2102 induced rapid tumor regression with durable responses. Notably, SHR-A2102 demonstrated activity (ORR, 36.1%) in patients previously treated with DV, an ADC with a distinct target and payload, thereby suggesting limited cross-resistance. In the 6 mg/kg cohort, the ORR reached 54.5%, thereby exceeding the 41.3% reported in the critical EV-301 trial, whereas the 8 mg/kg group achieved an ORR of 42.9%. In terms of safety, grade ≥3 TRAEs occurred in 44.4% of patients overall, primarily anemia (23.3%) and neutropenia (19.2%); the incidence was lower in the 6 mg/kg cohort (38.7%). On the basis of its efficacy and safety, the lower dose of 6 mg/kg Q3W was selected as the recommended dose, because of its favorable safety profile¹⁰. Given its encouraging activity and manageable safety profile in heavily pretreated patients, SHR-A2102 was granted a Breakthrough Therapy Designation by the Center for Drug Evaluation of National Medical Products Administration (China) in December 2024.

Nectin-4 remains a well-validated and highly effective target in UCs. EV has been established as a standard of care across both pretreated and cisplatin-ineligible populations, because of its consistent clinical benefits and broad regulatory endorsement. SHR-A2102, a topoisomerase I-based ADC, has promising activity, even after prior ADC exposure, and therefore has potential for sequential use. Early clinical data on other Nectin-4 ADCs, such as 9MW2821, have been promising (Table 1), thus reinforcing the clinical relevance of this target class. Ongoing studies are essential to define the optimal agent selection, sequencing, and combination strategies.

Disitamab vedotin

HER2 is a growth-promoting tyrosine kinase receptor involved in cell proliferation and tumorigenesis²⁵. UC is the third most common HER2-expressing malignancy after breast and gastric cancers, and the presence of HER2 overexpression in approximately 10–30% of bladder cancers highlights its potential as a therapeutic target. DV, a HER2-targeted ADC composed of hertuzumab associated with MMAE, has shown robust preliminary activity in UC (Table 1)²⁵.

The phase II RC48-C005/C009 study (NCT03507166/NCT03809013) enrolled 107 previously treated patients with mUC expressing HER2 immunohistochemistry (IHC) 2+ or 3+, and reported an ORR of 50.5%, mPFS of 5.9 months, and mOS of 14.2 months. Patients with high HER2 expression (IHC 3+ or IHC 2+/FISH-positive) achieved an ORR of 62.2%. The common TRAEs included peripheral sensory neuropathy (68.2%), leukopenia (50.5%), and neutropenia (42.1%). Although approximately 50% of patients had upper tract UC carcinoma, the outcomes were comparable between upper tract UC and urothelial bladder carcinoma, including similar ORR (50.0%), mPFS (5.3 months vs. 6.2 months), and mOS (14.9 months vs. 15.2 months). Further analysis revealed an ORR of 39.6% in HER2 IHC 2+/FISH-negative tumors, thereby indicating activity even in low HER2-expressing disease¹⁶. Subsequently, the RC48-C011 study (NCT04073602) evaluated DV monotherapy in patients with mUC and HER2 IHC 0 or 1+. Among the 19 patients, the ORR was 26.3%, and the mPFS and mOS were 5.5 months and 16.4 months, respectively. All 6 patients with IHC 0 achieved stable disease, whereas the ORR in patients with IHC 1+ was 38.5%. This activity in low HER2-expressing tumors might be attributable to the bystander effect of MMAE, high antibody affinity, and intratumoral HER2 heterogeneity. These findings led to the FDA’s granting of a breakthrough therapy designation to DV for HER2-overexpressing UC in September 2020.

DV was also evaluated in a phase Ib/II trial (RC48-C014, NCT04264936) in combination with toripalimab, in which an ORR of 73.2%, mPFS of 9.3 months, and mOS of 33.1 months were achieved in 41 patients with mUC. Moreover, HER2 overexpression (IHC 2+ or 3+) was observed in 58.5% of patients. Subgroup analyses showed consistent efficacy across treatment history (ORR: 76.0% in untreated patients vs. 68.8% in chemo-refractory patients) and HER2 expression levels (ORR: 80.0%, 84.2%, 64.3%, and 33.3% for IHC 3+, 2+, 1+, and 0, respectively). The most common TRAEs were elevated liver enzymes and peripheral sensory neuropathy, and grade ≥3 TRAEs occurred in 51.2% of patients¹⁸. Overall, DV plus toripalimab demonstrated an ORR and OS comparable to those of EV+P in EV-302 and a manageable safety profile. An ongoing phase III trial (RC48-C016, NCT05302284) is comparing DV plus toripalimab with chemotherapy in patients with untreated HER2-expressing la/mUC. If positive, the results could establish a stronger evidence base to inform clinical decision-making.

Trastuzumab deruxtecan (T-DXd, DS-8201)

T-DXd is an anti-HER2 ADC composed of a trastuzumab-derived antibody, cleavable linker, and topoisomerase I inhibitor DX-8951f. DX-8951f induces DNA damage by interfering with DNA replication and transcription, thus leading to tumor cell apoptosis. T-DXd has been approved for the treatment of metastatic HER2-positive (IHC 3+ or ISH-positive) or HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer, HER2-positive gastric cancer, HER2-mutant non-small cell lung cancer, and HER2-overexpressing solid tumors. However, its role in UC remains unclear. The DESTINY-PanTumor01 trial (NCT04639219), a phase II basket study, evaluated T-DXd in HER2-mutant solid tumors. Among the 7 patients with mUC, 2 achieved partial response. The DESTINY-PanTumor02 study (NCT04482309) evaluated the efficacy and safety of T-DXd in previously treated patients with HER2-expressing (IHC 2+/3+) solid tumors. Among the 41 patients with mUC, T-DXd demonstrated an ORR of 39% overall, with a higher ORR of 56.3% observed in patients with HER2 IHC 3+ tumors. The mPFS and mOS were 7.0 months and 12.8 months, respectively. The patient safety profile was manageable²¹. These results suggest that T-DXd might offer a promising treatment option for patients previously treated for HER2-mutant or HER2-overexpressing la/mUC. Confirmatory data will be critical to define the optimal role of this therapy in this population. On the basis of these findings, T-DXd received accelerated FDA approval for metastatic HER2-overexpressing tumors in April 2024.

Collectively, DV and T-DXd are the leading HER2-directed ADCs under clinical evaluation for UC. DV has shown high response rates both as a monotherapy and in combination with ICIs, and its activity extends to tumors with low HER2 expression. Building on its success in breast and gastric cancers, T-DXd has demonstrated meaningful activity in IHC 3+ UC. Agents such as MRG002 are under investigation but have shown early signals of efficacy and tolerability. Further studies are needed to clarify their roles in HER2-expressing UC and to inform treatment sequencing (Table 1).

Sacituzumab govitecan (SG)

SG is a humanized IgG1 antibody targeting trophoblast cell-surface antigen 2 (TROP-2), conjugated via a cleavable linker to SN-38, a topoisomerase I inhibitor. Its mechanism is similar to that of DX-8951f described above. TROP-2 is overexpressed in several epithelial cancers, including breast cancer, and is involved in cell migration and growth²⁶. SG was initially approved for the treatment of triple-negative breast cancer but has demonstrated activity against UC. The phase II TROPHY-U-01 study (NCT03547973) has reported an ORR of 28%, mPFS of 5.4 months, and mOS of 10.9 months after prior ICI and platinum therapy. Key grade ≥3 TRAEs included neutropenia (35%) and anemia (14%). Subsequent cohorts showed ORRs of 32% and 41% in the cisplatin-ineligible and pembrolizumab combination settings, respectively¹². On the basis of these results, SG received accelerated FDA approval in April 2021 for previously treated mUC. However, the phase III TROPiCS-04 trial (NCT04527991) did not meet its primary endpoint (mOS, 10.3 months with SG vs. 9.0 months with chemotherapy; HR, 0.86; P = 0.087), although SG achieved a higher ORR (23% with SG vs. 14% with chemotherapy). Several factors might have contributed to the negative outcome, including the lack of mandatory granulocyte colony-stimulating factor prophylaxis, which led to a high rate of neutropenia (56%), as well as the inclusion of heavily pretreated patients with substantial comorbidities¹³. These safety issues might have decreased treatment adherence or led to early discontinuation. Although SG did not demonstrate an OS benefit over chemotherapy, the higher ORR with SG (23% vs. 14% with chemotherapy) consistent with the TROPHY-U-01 findings suggested retained antitumor activity. These findings underscore the importance of patient selection, supportive care, and biomarker development in future ADC trials for UC. The FDA subsequently withdrew approval for SG for mUC.

Sacituzumab tirumotecan (Sac-TMT)

Sac-TMT, a TROP-2-targeted ADC carrying KL610023, a topoisomerase I inhibitor payload, has shown efficacy in triple-negative breast cancer and advanced non-small cell lung cancer. In a phase I/II MK-2870-001 study (NCT04152499), Sac-TMT monotherapy was evaluated in patients with la/mUC who had progressed during or after prior anticancer therapy (cohort 9). The ORR was 45.5% in the second-line setting and 26.3% in the later-line setting, the mPFS was 5.78 and 5.03 months, respectively, and the mOS was not reached and 11.5 months, respectively. Grade ≥3 TRAEs occurred in 59.2% of patients, and primarily comprised anemia (38.8%) and neutropenia (28.6%)¹⁵. Sac-TMT maintained a relatively high ORR and favorable safety profile in the later-line treatment setting. The ongoing KEYMAKER-U04 trial (NCT06483334) is evaluating Sac-TMT combined with EV, with or without pembrolizumab, in previously treated or treatment-naïve patients with mUC.

Currently, SG and Sac-TMT are the most clinically advanced TROP-2-targeted ADCs for UC. SG initially gained accelerated approval on the basis of early phase activity; however, its withdrawal after a negative phase III result highlights the challenges in translating response into survival benefits. Sac-TMT, which demonstrated encouraging results in later-line settings, is under active evaluation and includes novel combinations. Dato-DXd, which remains under investigation, has shown early signs of activity and is currently being studied in tumor-agnostic trials. Further studies are required to determine whether TROP-2 ADCs can be refined to achieve broader and more durable benefits in patients with mUC (Table 1).

BL-B01D1

Epidermal growth factor receptor (EGFR, also known as ERBB1 or HER1) and human epidermal growth factor receptor 3 (HER3, also known as ERBB3) are ERBB-family receptor tyrosine kinases implicated in tumorigenesis through ligand-independent signaling. Both are attractive targets because they are highly expressed in multiple solid tumors. BL-B01D1 is a first-in-class bispecific ADC targeting EGFR and HER3 conjugated to a novel topoisomerase I inhibitor (Ed-04) via a cleavable linker. In a phase I study of BL-B01D1 in advanced solid tumors, the ORR reached 52.5%, and the disease control rate was 87.5% among heavily pretreated patients with EGFR-mutant non-small cell lung cancer resistant to third-generation tyrosine kinase inhibitors, thus markedly outperforming historical standards. In another ongoing phase Ib/II study (NCT05785039), BL-B01D1 was evaluated in patients with la/mUC. The patients had received a median of 2 prior frontline therapies. Among the 23 evaluable patients treated with 2.2 mg/kg, the ORR of 34.8% and the mPFS of 5.5 months indicated that BL-B01D1 retained moderate efficacy even in heavily pretreated patients. Among patients who received only prior first-line chemotherapy, the ORR was 80%, and mPFS was not reached. Common TRAEs (≥20% all-grade/≥grade 3) included anemia (74%/17%), leukopenia (65%/26%), thrombocytopenia (65%/26%), and neutropenia (44%/22%). These findings suggest that BL-B01D1 exhibits encouraging antitumor activity and has a manageable safety profile in patients with la/mUC. However, larger studies are required to confirm these results²⁷.