Sacituzumab tirumotecan feasible in advanced urothelial carcinoma

Treatment with sacituzumab tirumotecan (sac-TMT) shows a promising antitumour activity and an acceptable safety profile in patients with heavily pretreated advanced or metastatic urothelial carcinoma (UC), according to a phase II study.

Sac-TMT is a trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) with a “unique, bifunctional linker that maximizes payload delivery to tumour cells,” the researchers said. “TROP2 is overexpressed in advanced or metastatic UC, representing a promising therapeutic target.”

By data cutoff, 49 patients with locally advanced or metastatic UC and disease progression on one or more prior line of platinum-based chemotherapy and anti-programmed cell death protein 1/ligand 1 therapy received sac-TMT 5 mg/kg monotherapy every 2 weeks until disease progression, unacceptable toxicity, or participant/physician decision.

The primary endpoint was objective response rate (ORR), while secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Of the participants, 37 (76 percent) had received two or more prior lines of therapy. Over a median follow-up 18.8 months, 31 percent (95 percent confidence interval [CI], 18‒45) had confirmed ORR, while disease control rate was 71 percent (95 percent CI, 57‒83). [Ann Oncol 2026;37:378-387]

The median DOR was not reached: range, 2.1‒22.2+ months (+ indicates censored data for the longest DOR, suggesting that patients may have achieved longer remission duration), with a 53-percent probability of sustained response at 12 months.

In terms of survival, PFS was 5.5 months (95 percent CI, 3.6‒7.2), and OS was 12.1 months (95 percent CI, 9.9‒15.3). At 18 months, survival rates were 26 percent and 33 percent, respectively.

Safety profile

Thirty-one (63 percent) patients had grade 3/4 treatment-related adverse events (TEAEs). The most common AE was anaemia (41 percent), followed by decreased neutrophil count (35 percent), decreased white blood cell count (20 percent), stomatitis (12 percent), and decreased platelet count (8 percent). No grade 5 TEAEs or febrile neutropenia events were reported.

“While grade ≥3 TEAEs occurred in 63 percent of participants, only one (2 percent) discontinued sac-TMT treatment due to TEAEs,” the researchers said. “[N]o TEAEs led to death, and although 35 percent of participants experienced grade 3 or 4 neutropenia events, no febrile neutropenia events occurred.”

Furthermore, no grade ≥3 diarrhoea occurred among patients treated with sac-TMT. This finding is relevant given the increased risk of fatal complications associated with diarrhoea combined with neutropenia, according to the researchers.

“In addition, no participants received primary prophylactic granulocyte colony stimulating factor (G-CSF), although secondary prophylactic G-CSF was administered during the study upon observation of neutropenia,” they said.

TROP2

Previous studies of TROP2-directed ADCs demonstrated antitumour activity in patients with UC, including the phase I TROPIONPanTumor01 study of datopotamab deruxtecan (ORR, 25 percent; median PFS, 6.9 months). [J Clin Oncol 2025;43(suppl 5):663]

In addition, the phase III TROPiCS-04 study of sacituzumab govitecan showed a 23-percent ORR, but there was no significant PFS or OS benefit seen. [Ann Oncol 2025;36:561-571]

“Taken together with the findings reported in this analysis, the evidence suggests that TROP2 represents a compelling tumour-associated antigen to target with ADCs in patients with UC, warranting further clinical investigation of TROP2-directed ADCs,” the researchers said.