Editor's Note: With advances in clinical research and updates to treatment guidelines, antibody–drug conjugate (ADC) combinations with immunotherapy have become a new standard of first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). The 2026 Congress of the European Society for Medical Oncology (ESMO) will be held in Madrid, Spain, from October 23 to 27, local time, featuring numerous cutting-edge studies in genitourinary oncology. Among them, data from a study of sacituzumab tirumotecan (Sac-TMT), a TROP2-targeted ADC developed in China, in first-line advanced urothelial carcinoma have been selected for a rapid oral presentation [1]. Updated results showed a confirmed objective response rate (ORR) of 68%, a median duration of response (DOR) of 19.4 months, and a median progression-free survival (PFS) of 11.2 months. Effective and durable tumor responses were observed regardless of patients' TROP2 and PD-L1 expression levels, suggesting a potential new treatment option for this population. The full text of the regular abstract has now been released. This article summarizes the latest developments and key findings for our readers.Sacituzumab Tirumotecan Plus Immunotherapy for la/mUC
Latest Abstract Highlights
Abstract Number: 4739RO
English Title: Sacituzumab Tirumotecan (Sac-TMT) + Pembrolizumab (Pembro) for Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC): Results From a Phase 2 Study (2870-002/SKB264-II-06)
Chinese Title: Sacituzumab Tirumotecan (Sac-TMT) + Pembrolizumab (Pembro) for Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC): Results From a Phase II Study (2870-002/SKB264-II-06)
Presenter: Professor Xiaojie Bian, Fudan University Shanghai Cancer Center
Study Background
Pembrolizumab plus enfortumab vedotin has been approved for the treatment of la/mUC, with an ORR of 67.7% and a median PFS of 12.5 months. Sacituzumab tirumotecan is a TROP2-targeted ADC featuring a unique bifunctional linker designed to maximize delivery of a belotecan-derived topoisomerase I inhibitor payload to tumor cells.
In the Phase I/II study 2870-001/KL264-01 (NCT04152499), sacituzumab tirumotecan monotherapy (5 mg/kg every two weeks) demonstrated antitumor activity in previously treated patients with la/mUC, regardless of TROP2 expression level. The Phase II, multi-cohort study 2870-002/SKB264-II-06 (NCT05642780), presented at the 2026 ESMO Congress, evaluated updated results for sacituzumab tirumotecan in combination with pembrolizumab in patients with la/mUC.
Study Methods
Eligible patients had la/mUC, were ineligible for cisplatin-based treatment, and had not previously received systemic therapy. Patients were permitted to enroll if their disease recurred more than 12 months after completing prior (neo)adjuvant platinum-based chemotherapy or nivolumab treatment.
During each 42-day treatment cycle, patients received intravenous sacituzumab tirumotecan at either 4 mg/kg or 5 mg/kg on Days 1, 15, and 29, together with intravenous pembrolizumab at 400 mg on Day 1. Treatment continued until disease progression (PD) or unacceptable toxicity.
The primary endpoints were ORR, assessed according to RECIST version 1.1, and safety.
Study Results
As of November 17, 2025, a total of 40 patients had received sacituzumab tirumotecan (4 mg/kg, n=26; 5 mg/kg, n=14) in combination with pembrolizumab. The median follow-up was 20.5 months (range, 17.5–27.7 months). The median patient age was 66.5 years, 88% had an ECOG performance status (PS) of ≤1, and 60% had upper tract urothelial carcinoma (UTUC).
The confirmed ORR was 68%, with responses observed regardless of TROP2 and PD-L1 expression levels. Median DOR was 19.4 months (range, 2.0–23.0+ months). Median PFS was 11.2 months (95% CI, 5.8 months–not reached). Median overall survival (OS) had not been reached [1].
Regarding safety, 24 patients (60%) experienced at least one Grade 3 or 4 treatment-related adverse event. The most common adverse events were anemia (15%), decreased neutrophil count (15%), and stomatitis (10%) [1]. No fatal treatment-related adverse events occurred.
Study Conclusions
In previously untreated patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin, sacituzumab tirumotecan plus pembrolizumab demonstrated promising antitumor activity, regardless of TROP2 and PD-L1 expression levels. The safety profile was manageable and consistent with the known safety profiles of the individual agents. These findings provide a foundation for ongoing global Phase III studies in urothelial carcinoma.
New Strategies and Emerging Directions for ADC Therapy in Urothelial Carcinoma
TROP2 is widely and highly expressed in urothelial carcinoma and plays an important role in malignant biological processes, including tumor cell proliferation, invasion, and immune evasion. It has consequently become one of the most closely watched targets in ADC development [2].
Against this background, sacituzumab tirumotecan, a TROP2-targeted ADC developed in China, features a differentiated design. Unlike conventional MMAE-based ADCs, it uses a unique bifunctional linker designed to maximize delivery of a topoisomerase I inhibitor payload to tumor cells. This approach combines precise targeting and potent cytotoxic activity with a differentiated toxicity profile.
For patients with previously treated advanced urothelial carcinoma, longer follow-up data presented at the 2026 Chinese Society of Clinical Oncology (CSCO) Annual Meeting showed that sacituzumab tirumotecan monotherapy at 4 mg/kg achieved an ORR of 29.9% and a disease control rate (DCR) of 70.1%. Median DOR was 11.3 months, median PFS was 5.4 months, and median OS was 12.3 months [3].
In the 5 mg/kg cohort, the ORR was 32.7% and the DCR was 69.4%. Median DOR increased to 17 months, median PFS was 5.5 months, and median OS was 12.1 months. These findings indicate meaningful survival benefits for patients with difficult-to-treat advanced urothelial carcinoma, including those with resistance to second-line or later-line treatment and a high tumor burden.
In the first-line la/mUC setting, updated results with longer follow-up for sacituzumab tirumotecan plus pembrolizumab will be formally presented at this year’s ESMO Congress. The abstract reports an ORR of 68% and a median PFS of 11.2 months, with clinical benefit observed regardless of TROP2 or PD-L1 expression. These findings highlight the potentially transformative role of this combination in first-line la/mUC treatment.
In addition, the global Phase III Trofuse-031 study is evaluating sacituzumab tirumotecan monotherapy versus investigator’s choice of chemotherapy in patients with la/mUC. The study plans to enroll 590 patients, with OS as the primary endpoint and PFS, ORR, DOR, and safety among the secondary endpoints.
Meanwhile, the Phase III Trofuse-055 study has been initiated to investigate the potential of sacituzumab tirumotecan in combination with pembrolizumab and chemoradiotherapy in muscle-invasive bladder cancer (MIBC).
These studies are expected to further strengthen the evidence base for sacituzumab tirumotecan and expand its potential role across different stages of urothelial carcinoma, offering patients a broader range of treatment options.
